Gonorrhea Workup

Updated: Dec 19, 2017
  • Author: Brian Wong, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD  more...
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Workup

Approach Considerations

Culture is the criterion standard test in the workup of gonorrheal infections. Bacterial culture has high sensitivity and high specificity, is relatively low cost, is suitable for different types of specimen sources, and can be used for epidemiologic and resistance testing purposes. However, culturing for Neisseria is problematic because it is difficult to maintain the bacteria’s viability during transport and storage in various settings. Another drawback is that 24-72 hours is needed before a preliminary culture result may return.

Based on CDC guidelines and the USPS Task Force recommendations, nucleic acid amplification test (NAAT) assay is the test of choice to evaluate for urogenital infections in both males and females, whether symptomatic or asymptomatic. [36, 37]

One benefit of NAAT assay is that it does not require live organisms yet can yield a positive result with minimal genetic material available, using specimens such as first catch urine and vaginal swabs. Sensitivity for detection exceeds 90%, and specificity is 99% or higher. NAAT assays approved for use with vaginal swabs may also be approved for use with patient-collected vaginal specimens. Among patients engaging in oral or anal receptive sexual intercourse, NAAT assays may be useful to detect gonorrheal infection. However, NAAT assays using specimens collected from extragenital sites have not been approved by the US Food and Drug Administration (FDA). [38]

For specific CDC screening recommendations based on sex and health state, see the 2015 Sexually Transmitted Diseases Treatment Guidelines.

For the clinical guideline summary from the US Preventive Services Task Force, see the Screening for Gonorrhea: Recommendation Statement.

Culture and nonculture testing for N gonorrhoeae

Perform a culture or nonculture detection test for N gonorrhoeae on endocervical, urethral, pharyngeal, or rectal discharge. Because organisms are intracellular, attempt to obtain specimens in a manner that will contain mucosal cells and not merely discharge (similar to a Papanicolaou smear).

Nonculture tests are less accurate in the presence of blood or during menses. Use culture instead at these times.

Culture is performed on Thayer-Martin plates that must be stored refrigerated but warmed to room temperature before obtaining a sample. The plate is then incubated in a carbon dioxide atmosphere. Poor technique drastically reduces test sensitivity.

Medicolegal cases (eg, child abuse, rape) require culture due to the possibility of false-positive results with nonculture methods. However, performing the more sensitive PCR assay-based tests to raise the likelihood of detecting an infection and then following up with culture to produce admissible evidence is appropriate.

Complete blood count

Patients with gonococcemia may have an elevated white blood cell (WBC) count, in the range of 10,000-15,000/µL.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) is usually mildly elevated, with values from 20-50 in most patients. Less than 50% of patients have an ESR of higher than 50.

Serologic tests

These tests include latex agglutination, ELISA, immunoprecipitation, and complement fixation tests. Because of their lower sensitivity and specificity, especially in populations with a low prevalence of disease, these tests are not routinely used for diagnosis, but they can be used as adjuncts to the other laboratory tests and may help in making the diagnosis.

Echocardiography

Because of the potential severity of pericarditis and endocarditis, a cardiologic examination, including echocardiography, is recommended, even though these conditions are rare.

Suspected disseminated gonococcal infection

Gram stains, cultures, and nucleic acid amplification tests (NAATs) of genital, rectal, conjunctival, pharyngeal secretions and/or other extragenital sites, as applicable, should also be obtained when DGI is suspected. Specimens from disseminated sites of infection, such as skin, synovial fluid, blood, and CSF, are recommended. Perihepatitis is also an occasional complication.

The highest yield of N gonorrhoeae organisms in gonococcemia is from mucosal sites, including the pharynx, urethra, cervix, or rectum. Urethral and cervical cultures are typically the most revealing. Blood cultures yield positive culture results in 10-30% of patients and joint fluid in 20-30% of patients. Skin lesions yield organisms in only about 10% of patients. Immunofluorescence studies may improve the effectiveness in skin and joint fluid. Gram stain of material from unroofed skin lesions may show typical organisms.

Other STDs

Other tests that may be indicated are those for concurrent STDs. For example, the Preventive Services Task Force recommends that women at increased risk of gonorrhea also be screened for chlamydia, HIV, and syphilis. [39]

Patients in whom gonococcal disease is suspected should be evaluated for syphilis infection, as well as for infection with C trachomatis (high rate of asymptomatic carriage), HIV (with counseling), hepatitis B virus, herpes simplex virus, and any STDs that are suggested by the history and physical examination findings. Administer hepatitis B vaccination to these individuals unless they have received the full vaccine series.

Rapid HIV test technology makes testing in the emergency department (ED) and referral more practical than enzyme-linked immunosorbent assay (ELISA). The need for additional testing depends on the situation; they are often performed as a battery of tests in suspected rape and child abuse cases.

HIV testing in cases of rape or new-onset abuse does not acutely diagnose a new infection but does establish a baseline status of the patient such that subsequent seroconversion might be linked back to the event in question.

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Smears With Gram Stain

Urethritis in males

The presence of typical gram-negative intracellular diplococci and polymorphonuclear leukocytes on Gram stain from a specimen collected from a symptomatic male establishes a diagnosis of gonorrhea (sensitivity, >95%; specificity, >99%). [36] A negative Gram stain result is not sufficient for excluding neisserial infections in asymptomatic men. Results are considered equivocal if typical morphotypes not associated with neutrophils are present or if cell-associated, but morphologically atypical, organisms are observed.

Urine

In men, urethritis can be diagnosed using either of 2 methods of Gram staining. The first is via a urine sample. Preferably, examine the patient at least 2 hours after micturition or before his first morning void. The patient should provide a first-morning void, with the first 10-15mL of the urine being saved. The urine is centrifuged so that the sediment may be analyzed microscopically under high power or oil immersion. The presence of 10 or more polymorphonuclear leukocytes (PMNs) seen under high power suggests urethritis.

Urethral exudate

The second method is a Gram stain of urethral exudate. The presence of 4 or more PMNs per oil-immersion field is diagnostic for urethritis. In symptomatic males, Gram staining of urethral exudate yields a sensitivity of 90-98% and a specificity of 95-98%. However, in asymptomatic males, the sensitivity of the Gram stain is only 60%. Therefore, culture studies are recommended if an asymptomatic gonococcal infection is suggested.

Cervicitis in females

In women with positive cervical culture results, the Gram stain results from the endocervix are 50-60% sensitive and 82-97% specific. In addition, the presence of more than 10 PMNs per high-power field on an endocervical smear is consistent with cervicitis. In women who lack a cervix because of hysterectomy, use urethral culture to make the diagnosis.

Emergency department use

Gram stain is a rapid and inexpensive test available in many emergency departments (EDs). The positive predictive value is high for urethral infection, but a negative Gram stain does not rule out infection in asymptomatic men. Collect specimens from the urethra, endocervix, pharynx, rectum, conjunctiva, urine, or blood.

A Gram stain of urethral or cervical discharge may show gram-negative intracellular diplococci (diagnostic in the male) and PMNs. This is very useful if the physician has easy access to a microscope, because the diagnosis may be made without waiting for culture results.

The sensitivity and specificity of the Gram stain are lower for endocervical and rectal specimens. Gram stains from these sites are not recommended for routine use in the ED. In addition, Gram staining is not useful for the diagnosis of pharyngeal infection, because the oropharynx may be colonized by other Neisseria species that can lead to false-positive results.

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Isolation Via Culture

Specific culture of a swab from the site of infection is a criterion standard for diagnosis at all potential sites of infection. Bacterial culture has high sensitivity and specificity, is relatively low cost, and is suitable for different types of specimen sources. Cultures are particularly useful when the clinical diagnosis is unclear, when a failure of treatment has occurred, when contact tracing is problematic, and when legal questions arise. However, culturing for Neisseria is problematic because the bacteria’s viability is difficult to maintain during transport and storage in various settings. Another drawback is the time; 24-72 hours may be needed before a preliminary culture result is available. Therefore, empiric treatment is often necessary in patients awaiting diagnosis via culture. [40]

A small percentage (approximately 5%) of isolated gram-negative diplococci from genital, rectal, and pharyngeal cultures are actually Neisseria meningitidis, which can cause clinical disease that is identical to gonococcal infections of the urethra, cervix, or rectum. Hence, speciation from samples from pharyngeal and rectal sites should be standard, while samples from genital sites are recommended.

Antimicrobial susceptibility testing is generally unnecessary except in cases of resistance surveillance testing or cases of disseminated infection.

N gonorrhoeae is a fastidious organism that requires an enriched medium, such as Thayer-Martin or Martin-Lewis medium, and must be incubated at 35-36.5°C with supplemental 5% CO2. Poor technique, failure to store collected specimens appropriately, and slow transport to the microbiology laboratory drastically reduce test sensitivity.

If multiple specimens are to be collected from one anatomic site, it is recommended that the N gonorrhoeae culture specimen be obtained first, as this will increase likelihood of successful culture. [36] Gonorrheal cultures should be obtained with a plastic or wire shaft with rayon, Dacron, or calcium alginate tip, as wooden shafts and cotton-tip swabs might be inhibitory and may prevent optimal recovery of the organism. Culture swabs should be inserted 2-3 cm into the male urethra or 1-2 cm into a female endocervical canal followed by 2-3 rotations of the swab. If there is urethral discharge, exudate collection is adequate for gonorrheal culture.

Sensitivity

A single culture on most selective media yields a sensitivity of 95% or more for urethral specimens from men with symptomatic urethritis. A sensitivity rate of about 80-90% is found for endocervical infections in women. For maximized yield in cervical specimens, simultaneous inoculation on selective and nonselective media is recommended. Culture may take several days to weeks.

Specimen collection

Although the urethra is commonly infected in women with gonorrhea, culturing urethral specimens does not materially increase the diagnostic yield except in women who lack a cervix because of hysterectomy.

Patients with possible disseminated gonococcal infection (DGI) should have culture samples taken from all possible mucosal sites (ie, pharynx, urethra, cervix, rectum) and from blood and synovial fluid. Rectal and pharyngeal specimens are inoculated onto selective medium only.

When collecting specimens in males, any discharge present at the meatus can be easily recovered for examination. If no discharge is present at the meatus, urethral material must be recovered by inserting and rotating a small swab 2-3 cm into the urethra. A calcium alginate or Rayon swab on a metal shaft is recommended.

When collecting specimens in women, the exocervix is first wiped of exudate. A swab is then placed into the external os and rotated for several seconds. However, take care to avoid contact with vaginal mucosa or secretions, as vaginal fluids are inadequate.

Cultures of the conjunctiva

Chocolate agar in a carbon dioxide–enriched environment is the best medium. Blood agar, MacConkey medium, and phenylethyl alcohol with 5% sheep blood also are good media.

Isolation through other bodily fluid cultures

In patients who may have DGI, all possible mucosal sites should be cultured (eg, pharynx, cervix, urethra, rectum), as should blood and synovial fluid (in cases of septic arthritis). Three sets of blood cultures should also be obtained. Specimens from any mucosal site should be inoculated immediately in selective media for gonorrheal organisms, such as modified Thayer-Martin, or on chocolate agar at room temperature, which should be incubated in an enriched carbon dioxide environment. The growth of typical oxidase-positive colonies that consist of gram-negative diplococci strongly suggests gonorrhea.

Samples from normally sterile sites (eg, blood, cerebrospinal fluid [CSF], synovial fluid) should be plated on nonselective and broth mediums. On the other hand, rectal and pharyngeal specimens, locations where commensal Neisseria may be present, should be inoculated onto selective medium only.

Synovial fluid aspirations in patients with septic arthritis usually yield greater than 50,000 leukocytes/µL, while synovial fluid culture is variably positive. Blood cultures, at this point, are often negative.

Gram stain and culture of vesicular or pustular skin lesions were found to have a diagnostic yield of less than 5%. Immunofluorescent techniques may be used to achieve better results.

Blood cultures

When disseminated gonococcal infection is suspected, a minimum of three sets of blood cultures should be obtained, given that bacteremia is intermittent.

If a patient is suspected of having gonococcal arthritis-dermatitis, gonococci may be recovered in blood culture.

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Imaging Studies

Plain radiography

Chest radiography may show hemidiaphragm elevation in Fitz-Hugh-Curtis syndrome. Joint plain films to evaluate septic joints are often unrevealing but may help to rule out fracture or other disease processes.

Ultrasonography or CT scanning

Ultrasonography may be indicated in women to investigate suspected pelvic inflammatory disease (PID) and to visualize the appendix and ovaries as other possible causes of the symptoms. Pelvic ultrasonography or computed tomography (CT) scanning may demonstrate thick, dilated fallopian tubes or abscess formation.

PID is uncommon in pregnancy when the cervical mucus plug may provide some protection to the upper tract. Ultrasonography should be used to rule out ectopic pregnancy whenever a pregnant patient has signs and symptoms of possible PID.

Abdominal imaging may give indications of peri-hepatic adhesions or abdominal loculated fluid collections or help to exclude other diagnoses.

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Nucleic Acid Amplification Tests

NAATs amplify genetic sequences (DNA or ribonucleic acid [RNA]) from a few copies to millions in a short period of time. One of the key benefits of NAATs is that a wide variety of specimen types may be sampled, including swabs from the endocervix, vagina, urethra (men), and urine (men and women). Variations of this process include ligase chain reaction tests and strand displacement amplification.

These tests are very sensitive; they are also more rapid than culture, more specific than immunoassays, and do not require viable organisms. [41] However, they are expensive, and results must be interpreted carefully because of false-positive results in certain settings. [42, 43]

NAATs may be of particular use when examination and mucosal swab are difficult (in children or extremely apprehensive patients) and urine specimens are more easily obtained. However, although these tests can be used on eye secretions, their performance is less well validated. In addition, NAATs are not all recommended for rectal and pharyngeal specimens at this time.

Clinicians should be familiar with specimen collection guidelines and performance parameters of the test available at their own hospitals.

NAATs of genital, rectal, conjunctival, and pharyngeal secretions should also be obtained, regardless of presenting symptoms or exposure history, when disseminated gonococcal infection (DGI) is suspected, even if the patient has no localized symptoms at any of those sites.

Pharyngeal gonococcal infections can occur in heterosexual men diagnosed with urethritis. Screening for pharyngeal colonization by N gonorrhoeae and C trachomatis using validated NAATs has been recommended for heterosexual men diagnosed with urethritis. [44]

PCR and LCR

PCR and ligand chain reaction (LCR) are gene amplification techniques that markedly increase the sensitivity of specimen testing. Both techniques amplify the genetic fingerprint of specimens with very few organisms present in order to more easily detect and identify the organisms.

These methods have a high sensitivity and a high specificity (78.6% and 96.4%, respectively). They are easily performed on urethral specimens and can even be performed on first-void urine specimens. PCR and LCR are noninvasive, rapid, sensitive, and specific, and they have facilitated the diagnosis of gonococcal infection. [45] However, they cannot report antibiotic sensitivities; therefore, these techniques do not eliminate the need for culture in these patients.

In addition, specific molecular tests may produce erroneous results. [43] In certain circumstances, it may be advisable, in consultation with a medical microbiologist, to take a sample for culture or to perform a second molecular test aimed at a different part of the bacterial genome.

N gonorrhoeae was identified as the causative agent in a case of culture-negative dermatitis-arthritis syndrome using real-time PCR. [46] This technology can improve the speed and sensitivity of diagnosis and consequent management of patients with this syndrome.

Some studies have been shown promise in the use of DNA polymerase chain reaction (PCR) assay for porA pseudogene detection, possibly even in nongenital sites. [47]

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Nucleic Acid Probe Signal Amplification

Nucleic acid probe signal amplification (NAPSA) detects DNA sequences using RNA probes. Located sequences are then coated with detection antibodies, which allow detection. One commercial product uses a single test to detect gonorrhea and chlamydia. More study is needed to evaluate the sensitivity of this technique compared with that of NAAT.

Consider verifying positive urogenital nucleic acid detection test results (PCR, LCR, strand displacement amplification, ribosomal RNA or DNA sequence amplification tests) when false-positive results are likely. In 2002, the CDC recommended testing a second specimen with a different test to confirm the positive results. [48] Australia and the United Kingdom have proposed guidelines to test the initial specimen with supplementary tests using different target sequences. The recommendations were that a result be reported as positive only if both test results were positive. [49]

Be aware that nonculture tests do not provide antimicrobial susceptibility results. Thus, in scenarios in which resistance or treatment failure is considered, culture and antimicrobial susceptibility testing may be warranted.

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Antibody-Antigen Testing

The immunochromatographic strip test (IST) combines antibodies from a patient’s specimen (secretions or urine) and N gonorrhoeae antigens on a nitrocellulose strip. One study showed that this technique yielded a sensitivity of 70% and specificity of 97%. [50]

Optical immunoassay (OIA) also uses antigen-antibody reactions (monoclonal), but on a silicon wafer; a positive reaction is evidenced by a color change. A sensitivity of 60% and specificity of 90% was reported.

Both rapid tests yield results within 30 minutes and require minimal training to use. Initial test results show some promise, but additional verification of their utility in appropriate settings is still needed. [51]

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Procedures

Laparoscopy

In women with symptoms and signs suggestive of pelvic inflammatory disease (PID) who are difficult to diagnose clinically, laparoscopy may be indicated to rule out (and, if need be, to treat) appendicitis, ovarian torsion, ectopic pregnancy, or other surgical emergencies. When evaluating perihepatitis, laparoscopy may demonstrate the classic "violin string" adhesions seen between the liver capsule and the parietal peritoneum.

Imaging studies such as ultrasonography are obviously a less invasive means of obtaining diagnostic information, but potentially emergent cases may require a more definitive examination, which permits rapid intervention if required.

Culdocentesis

In PID, culdocentesis, although rarely indicated, may demonstrate free purulent exudate and provide material for Gram stain and culture.

Arthrocentesis

In septic arthritis cases, arthrocentesis may show purulence and/or causative organisms.

Lumbar puncture

Perform lumbar puncture and joint aspiration, if indicated by clinical findings. Rarely would CSF fluid yield positive results in cases of meningitis secondary to gonorrhea.

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Histologic Findings

Exudate of PMNs is typical. Gram-negative intracellular diplococci are seen microscopically (see the image below). In pelvic inflammatory disease (PID), loss of ciliated columnar epithelium from the fallopian tubes may occur. Tubes, pelvic mesentery, and ovaries may be bound together with dense fibrosis and abscess formation.

Cytologic smear of cutaneous acral pustule showing Cytologic smear of cutaneous acral pustule showing gram-negative, intracellular diplococci.
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Testing for Gonorrhea in Males

According to the latest US Preventive Task Force (USPTF) statement, there are insufficient data to assess the balance of benefits and harms of screening for gonorrhea in males. [37] However, when testing a male for gonococcal infection, NAAT assay testing of urine specimens is the recommended first-line method for diagnosing gonorrheal genitourinary infections. Evidence has shown that the first catch urine specimen is as good as, if not better than, urethral swabs specimens in the detection of genitourinary gonorrheal infections. [52] Urethral swab specimen collection is recommended in patients in whom CDC-recommended initial therapy has failed based on repeat positive NAAT assay results 7 days or more days after treatment and who are not believed to have been re-exposed to gonorrhea after the treatment course. The specimen should be sent for antibiotic susceptibility to evaluate for antimicrobial resistance.

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Testing for Gonorrhea in Females

According to the USPTF recommendation, sexually active women younger than 25 years and older women at increased risk for gonococcal infection (defined by the CDC as those who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has an STI) should be screened annually. Other medical governing bodies have also suggested other risk factors for gonorrhea, including prior gonococcal infection, other concurrent sexually transmitted infections, inconsistent condom use, commercial sex work, and illicit drug use.

The preferred method to screen for genitourinary gonorrhea is collection of vaginal swab specimens sent for NAAT assay testing. Studies have shown that the sensitivity of vaginal swab specimens is equal to that of cervical swab specimens. [53] In addition, patient-collected vaginal specimens also have the same sensitivity and specificity as clinician-collected specimens. [54, 55]

If the patient needs a concurrent pelvic examination, an endocervical swab is reasonable. However, in contrast with workup in males, first catch urine specimens to detect gonorrhea may detect about 10% fewer infections when compared with vaginal and endocervical swab specimens.

In patients in whom CDC-recommended initial therapy has failed based on repeat positive NAAT assay results 7 or more days after treatment and are not believed to have been re-exposed to gonorrhea after the treatment course, an endocervical swab for N gonorrhoeae should be obtained and sent for antibiotic susceptibility to evaluate for antimicrobial resistance.

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Testing for Gonorrhea at Extragenital Sites

Extragenital gonorrheal infections (pharyngeal and rectal infections) are often asymptomatic and are not uncommon in certain populations, such as men who have sex with men (MSM). Annual screening of extragenital sites in the MSM population is recommended by the CDC. While NAAT assay is the test of choice for extragenital gonorrheal infection screening, NAAT assays have not been approved by the FDA for pharyngeal and rectal specimens. Laboratories are recommended to process extragenital NAAT assay screens in compliance with Clinical Laboratory Improvement Amendments (CLIA) guidelines. [56] It is also important to be aware that certain NAAT assays may detect commensal Neisseria species and thereby yield false-positive results. In this situation, alternative testing methods may be needed for increased accuracy. If a patient has received a CDC-recommended antibiotic course with a repeat positive NAAT assay result 7 or more days after treatment and is not believed to have been re-exposed to gonorrhea after the treatment course, a rectal and/or oropharyngeal swab specimen for N gonorrhoeae culture should be obtained and evaluated for antibiotic susceptibility.

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