Pediatrics

Disseminated gonococcal infection

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Disseminated Gonococcal Infection (DGI)? What are the typical findings for this disease?

The most common presentation of disseminated gonococcal infection (DGI) is acute arthritis, tenosyovitis, and dermatitis (Arthritis-Dermatitis Syndrome). Patients may present with infectious arthritis wthout associated skin findings. Complications include meningitis or endocarditis resulting from DGI (rare).

History

A detailed medical and sexual history is critical to making the correct diagnosis of DGI. Clinical interview of the parent with the child/adolescent patient may provide important details regarding the course of clinical findings, past medical history, and family history to aid with diagnosis. It is equally important that the clinician request to interview the adolescent alone to fully assess lifestyle factors that may be contributing to the disease process.

Important historical details include:

-history of present illness including clinical manifestations timing, course, and review of systems (e.g., fever, rash, arthralgias, joint swelling, vaginal or urethral discharge, dysuria, abdominal pain, sore throat, headache, vomiting, confusion, neck stiffness, fatigue, shortness of breath, chest pain)

-sexual history with most recent sexual intercourse, types of sexual contact (vaginal, anal, oral), number of partners, partner symptoms

-past medical history including chronic medical problems and sexually transmitted infections

-last menstrual period (female patients) to assess menstrual timing (50% of patients with DGI are diagnosed within 7 days of last period) and pregnancy risk assessment (female patients)

-immunization history

-family history to determine risk for other diseases

-social history including query for sexual abuse

Key Components of the Physical Examination

In addition to a thorough general clinical examination with vital signs, particular attention should be paid to:

Skin Examination: (See Figure 1.)

Figure 1.

DGI skin lesion of the hand, Courtesy: Dr.Jonathan Zenilman, Department of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore Maryland

Assess for classic finding-

Less than 30 painful, necrotic pustules on a base of erythema

Distal parts of extremities

Alternate presentations seen as lesions progress:

Macules

Papules

Petchiae

Bullae

Ecchymoses

Joint examination: (See Figure 2 and Figure 3.)

Figure 2.

Patient with gonococcal arthritis of the hand. Centers for Disease Control and Prevention, Public Health Image Library, Image 6843, http://cdc.gov/phil/details.asp. Last accessed, 4/12/11

Figure 3.

Gonococcal arthritis with inflammation of the skin of the right arm. Centers for Disease Control and Prevention, Public Health Image Library, http://phil.cdc.gov/phil/details.asp, Last accessed: 4/12/11

Swelling

Erythema

Effusions

Cardiac examination:

New or worsening murmur

Neurological examination:

General status (alert versus sleepy; oriented versus confused)

Light sensitivity (particularly with headache)

Signs of meningeal irritation

Abdominal examination:

Lower abdominal pain (to assess for pelvic inflammatory disease (PID) in female patients)

Genintourinary:

Vaginal discharge/cervical motion tenderness on bimanual examination to assess for concurrent PID (female)

Urethral discharge/scrotal enlargement or pain to assess for concurrent epidymitis (male)

Anal discharge

Pharyngitis

What other disease/condition shares some of these symptoms?

The differential diagnosis for DGI includes a number of other clinical disorders as outlined below.

Other forms of infectious and non-infectious arthritis (synovial fluid analysis and cultures for Neisseria gonorrhoeae (GC) should distinguish DGI from other arthritis syndromes).

Viral Infections (acute HIV infection, parvovirus B19, measles, and rubella).

Hepatitis B (synovial fluid analysis is non-inflammatory and rash appears uticarial).

Connective tissue disease (rheumatoid, psoriatic, and reactive arthritis).

Acute rheumatic fever (post-streptococcal arthritis can usually be distinguished by the rash and evidence of recent streptococcal infection).

Secondary syphilis (note that the rash of secondary syphilis usually involves palms and soles).

Lyme disease characteristic rash (erythema chronicum migricans) and other clinical findings will distinguish from DGI.

Endocarditis caused by another organism if cardiac symptoms present.

What caused this disease to develop at this time?

Individuals who develop DGI are typically adolescents or young adults (15-24 years) who are sexually active and reside in areas with a high incidence of sexually transmitted infections. Women have a slightly higher risk than men (female patients often have asymptomatic infections), and the rate of DGI is disproportionately high among underrepresented minorities and those living in poverty. DGI often develops after a period of asymptomatic gonococcal infection, and 50% of DGI in women occurs within 7 days of the menstrual period or during pregnancy or the post-partum period.

Individuals with a defect in the terminal complement deficiency (C5-C9) are more likely to develop severe disease.

Newborns whose mothers have active gonococcal infection at delivery, with or without a scalp electrode used for fetal monitoring, are at risk for DGI. GC infection of the newborn is usually apparent within 5 days of birth.

GC infection, including DGI, can occur following sexual abuse.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Urinalysis may be positive if tested for leucocyte esterase. WBC may be elevated with a shift to the left, and the erythrocyte sedimentation rate may be elevated.

Evaluation for genitourinary gonococcal infection should be performed. Gram stain of urethral discharge (99% specific, 95% sensitive) may expedite the clinical decision-making process. Unfortunately, gram stain of anal, cervical, pharyngeal, and synovial fluid are often non-diagnostic. Urethral (male) or cervical (female) culture, nucleic acid hybidization testing, or nucleic acid amplification testing should be performed. Vaginal specimens (female) and urine samples may also be tested for GC using nucleic acid amplification testing. Pharyngeal culture is indicated for patients with history of oral sexual contact.

Blood cultures are positive in 30-40% of patients with DGI. Susceptibility testing should be performed.

Culture of pustular material within skin lesions is typically negative, but should be obtained for gram stain and culture.

Synovial fluid cultures are positive in 20-30% of patients with DGI. In addition to the culture, evaluation of the synovial fluid can aid in diagnosis and management of patients who have a septic joint versus aseptic joint in the context of DGI. In patients with a true septic joint synovial fluid will have a white blood-cell count = 50,000 or greater and positive cultures. DGI is presumed among individuals who have an elevated white blood cell count of the synovial fluid, evidence of GC elsewhere (e.g. cervical, urethral, or skin infection), but have negative synovial fluid cultures.

Testing for other sexually transmitted infections is important to identify coexistent STIs and also eliminate STIs which may present with similar clinical findings (noted above) from the differential diagnoses. All individuals should be tested for Chlamydia trachomatis (CT) (urethral, anal, vaginal, cervical specimens), syphilis (RPR), human immunodeficiency virus (ELISA), hepatitis B in unimmunized patients.

Echocardiogram and additional cardiac procedures may be indicated for patients with suspected endocarditis (rare).

Goncooccal meningitis is extremely rare. Few cases have been reported in the literature since the first case was described in 1922. Since that time, access to highly effective antibiotics in the context of asymptomatic screening have further reduced the incidence. CSF, however, should be obtained for cell count, protein, glucose, culture, and susceptibility testing if the patient has meningeal signs or in febrile infants with suspected DGI.

Complement testing should be reserved for individuals with recurrent DGI. Individuals with low CD50, but normal CD 3 and 4 will need additional testing of terminal components (C5-9).

Would imaging studies be helpful? If so, which ones?

The primary clinical syndrome associated with DGI is diagnosed based on the clinical examination and detection of the organisms using culture and/or PCR. A small subset of patients may require additional radiological procedures if other issues such as DGI related osteomyelitis are suspected or if the patient does not have substantial improvement while being treated with appropriate antibiotic coverage for DGI.

Confirming the diagnosis

The best guide for management of DGI and uncomplicated GC infection are the most recent CDC STD Treatment Guidelines which incorporate the best evidence available and expert opinion to create standards of care for diagnosis, management, and treatment of GC infection.

If you are able to confirm that the patient has Disseminated Gonococcal Infection, what treatment should be initiated?

The patient should be hospitalized for initiation of treatment. This is particularly important for neonates, patients for whom adherence is uncertain, the diagnosis is uncertain, and for those with evidence of complications.

Sexual partners and mothers of infected neonates should be notified for testing and possible antibiotic therapy ( Table I).

Table I.

Antibiotic Regimens for DGI Therapy
Disease Manifestations Antibiotic Regimen Duration of Cephalosporin Treatment
Arthritis-Dermatitis Syndrome* Recommended: Ceftriaxone 1 g intravenously (IV) or intramuscularly (IM) every 24 hoursAlternative regimens include: Cefotaxime 1g IV every 8 hours or Ceftizoxime 1g IV every 8 hours) 24-48 hours of IV therapy (or until 24 hours after clinical improvement) followed by oral cefixime 400 mg (oral) daily to complete 7 days of therapy
Purulent Arthritis* Recommended: Ceftriaxone 1 g intravenously (IV) or intramuscularly (IM) every 24 hoursAlternative regimens include: Cefotaxime 1g IV every 8 hours or Ceftizoxime 1g IV every 8 hours) 7-14 days of IV therapyPatient may require drainage by orthopedic surgery
Meningitis* Ceftriaxone 1-2 g IV every 12 hours 10-14 days IV therapy
Endocarditis* Ceftriaxone 1-2 g IV every 12 hours 4 weeks IV therapy
Children with bacteremia/DGI Children > 45kg: Ceftriaxone 50 mg/kg IM or IV in a single dose daily f (max dose: 1 g)Children:≤ 45kg:Ceftriaxone 50 mg/kg IM or IV in a single dose daily 7 days
Neonatal DGI Ceftriaxone 25–50 mg/kg/day IV or IM 7 days DGI10-14 days if meningitis documented

What are the adverse effects associated with each treatment option?

Clinicians should always conduct a detailed assessment regarding medication allergies that will influence antibiotic choices. Alternative regimens can be prescribed for treatment of DGI, but closer follow-up may be indicated if the patient is unable to tolerate one of the cephalosporin regimens as outlined above.

Patient should also be aware that some strains of GC may be resistant to various treatment regimens. As an example, fluroquinolones are no longer recommended for treatment of GC infections because surveillance data has revealed pockets of resistance throughout the country, particularly among men who have sex with men.

What are the possible outcomes of Disseminated Gonococcal Infection?

Most patients have substantial improvement within 24-48 hours on IV antibiotic therapy because of the effectiveness of the above antibiotic regimens against GC infection. Patients who do not improve substantially may require additional evaluation to determine the extent of disease. Complications may occur and patients may also rarely present with meningitis or endocarditis resulting from DGI.

What causes this disease and how frequent is it?

DGI is caused by GC infection. Clinical symptoms related to gonococcal infection have been reported since ancient times. The organism was first described in the scientific literature in the 1879 by (Neisser) and cultivated in 1882 (Leistikow and Lõffler).

Infection with GC is common worldwide. Among notifiable diseases in the United States, GC is the second most commonly reported. In 2009, there were 301,174 cases of GC reported in the United States for a rate of 99.1 cases per 100,000. in the population.

Centers for Disease Control and Prevention (CDC) surveillance data indicates that while the rates of gonococcal infection have decreased in the United States over the last 10 years across ethnic and age groups; adolescents and young adults and individuals residing the South, Midwest, and dense metropolitan areas appear to be at highest risk for infection. Recent trends show slightly lower rates of infection among men compared with women. Disproportionate rates of disease exist among under-represented minority groups.

Among those who acquire a GC infection, approximately 0.5-3% of patients will acquire disseminated disease.

Individuals who engage in high risk sexual behaviors (multiple partners, commercial sex work) or are a part of a sexual network in a high GC prevalence community are at risk for infection.

How do these pathogens/genes/exposures cause the disease?

GC is a robust gram-negative diplodocus with a propensity for infection through mucosal surfaces of human species and is primarily transmitted through sexual contact with an infected person. Through a combination of auxotyping and serotyping, over 70 different strains of the gonococcus have been identified. Strains can be further defined by their antimicrobial susceptibilities and opacity-associated protein (Opa) genotyping.

The organism's survival has been primarily due to its ability evade host defenses through antigenic variation and the associated structural changes involved in pathogenesis.

Key GC structures that are subject to variability but are associated with pathogenesis because they enhance the organism's ability to evade host defenses include: porin proteins (aid with host cell insertion), Opa (adherence), pili, (adherence), lipooligosaccharide (tissue toxin), and peptidoglycan (tissue toxin).

Individuals who develop DGI are thought to have infection with gonococcal strains that express the PI.A porin and Opa proteins and /or short lipooligosaccharides.

GC strains that are able to resist destruction by antibodies and complement, thus limiting the cellular immune response, may allow for a longer period of asymptomatic infection leading to DGI.

What complications might you expect from the disease or treatment of the disease?

Disease complications may include:

Perihepatitis

Endocarditis

Meningitis

Delivery of an infant with localized (ophthalmia neonatorum) or DGI (pregnant women)

Are additional laboratory studies available; even some that are not widely available?

Patients who are suspected of having gonococcal meningitis should have a lumbar puncture and evaluation of the cerebrospinal fluid with culture. Individuals who develop endocarditis should have an echocardiogram and consultation by a cardiologist and infectious disease specialist who can aid in clinical management.

How can Disseminated Gonococcal Infection be prevented?

The only way that DGI can be prevented is by preventing acquisition of GC infection. Since GC is a sexually transmitted infection, DGI can be prevented by:

Condom use during sexual intercourse.

Routine asymptomatic screening for sexually transmitted infections every 6-12 months (depending on age and disease prevalence).

Testing for symptomatic genitourinary findings.

Adequate treatment of diagnosed infection.

Notification and treatment of all sexual partners/exposed individuals.

What is the evidence?

Epidemiology:

"Sexually Transmitted Disease Surveillance 2009". US Department of Health and Human Services. 2010. http://www.cdc.gove/std/stats09/surv2009-Complete.pdf.

Gorgos, L, Newman, L, Satterwhite, C, Berman, S, Weinstock, H. "Gonorrhea positivity among women aged 15-24 years in the USA, 2005-2007". Sex Transm Infect. vol. 87. 2011. pp. 202-4.

Pathogenesis:

Ghosh, SK, Zhao, J, Philogene, MC, Alzaharani, A, Rane, S, Banerjee, A. "Pathogenic consequences of Neisseria gonorrhoeae pilin glycan variation". Microbes Infect. vol. 6. 2004. pp. 693-701.

Holmes, KK, Sparling, PF. "Sexually Transmitted Diseases". The McGraw-Hill Companies. 2008. pp. 607-626.

Clinical Manifestations and Predisposing Risk Factors for DGI:

Akkinepally, S, Douglass, E, Moreno, A. "Triscuspid valve gonococcal endocarditis: fourth case report". International Journal of Infectious Disease. vol. S3. 2010. pp. e196-7.

Alexander, ER. "Gonorrhea in the newborn". Annals of the New York Academy of Sciences,. vol. 549. 1988. pp. 180-6.

Black, JR, Cohen, MS. "Gonococcal osteomyelitis: a case report and review of the literature". Sex Transm Dis. vol. 11. 1984 Apr-Jun. pp. 96-9.

Burgis, JT, Nawaz, H. "Disseminated gonococcal infection in pregnancy presenting as meningitis and dermatis". Obstetrics and Gynecology. vol. 108. 2006. pp. 798-801.

Holmes, KK, Counts, GW, Beaty, HN. "Disseminated gonococcal infection". Annals of Internal Medicine. vol. 74. 1979. pp. 979-93.

Khoo, CL, Davies, AJ, Dobson, CM, Cheesbrough, J, Edwards, J, Sweeney, J. "Disseminated gonococcal infection in pregnancy". J Obstetrics and Gynaecology. vol. 29. 2009. pp. 550-1.

Petersen, BH, Lee, TJ, Snyderman, R, Brooks, GF. "Neisseria meningitis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency". Annals of Internal Medicine. vol. 90. 1979. pp. 917-20.

Raychaudhuri, M, Peall, A, Page, C, Browing, M. "A case of duplicitous diplococci". Sexually Transmitted Diseases. vol. 85. 2009. pp. 441-2.

Rosenthal, L, Olhagen, B, Ek, S. "Aseptic arthritis after gonorrhea". Annals of Rheumatic disease. vol. 39. 1980. pp. 141-6.

Russ, S, Wrenn, K. "Images in clinical medicine. Disseminated gonococcal infection". The New England Journal of Medicine. vol. 352. 2005. pp. e15.

Walters, N, Butani, L.A. "16-year-old girl with recent disseminated gonococcemia now presenting with a facial rash". Annals of Allergy, Asthma, and Immunology. vol. 94. 2005. pp. 224-227.

Wiggers, M.N.L., Oudesluys-Murphy, A.M.. "A child presenting with fever and arthritis due to disseminated gonorrhoea". Nederlands Tijdschrift voor Geneeskunde. vol. 150. 2006. pp. 1462-1465.

Types of GC testing:

http://www.aphl.org/aphlprograms/infectious/std/Pages/stdtestingguidelines.aspx.

Chernesky, M, Freund, GG, Hook, E. "Detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in North American women by testing SurePath liquid-based Pap specimens in APTIMA assays". J Clin Microbiol. vol. 45. 2007. pp. 2434-8.

Kimmitt, P.T., Kirby, A., Perera, N., Nicholson, K.G., Schober, P.C., Rajakumar, K., Chapman, C.A. "Identification of Neisseria gonorrhoeae as the causative agent in a case of culture-negative dermatitis-arthritis syndrome using real-time PCR". Journal of Travel Medicine. vol. 15. 2008. pp. 369-371.

Read, P, Abbott, R., Pantelidis, P., Peters, B.S., White, J.A. "Disseminated gonococcal Infection in a homosexual man diagnosed by nucleic amplification testing from a skin lesion swab". Sexually Transmitted infections. vol. 84. 2008. pp. 348-49.

Schachter, J, Moncada, J, Liska, S. "Nucleic acid amplification tests in the diagnosis of chlamydial and gonococcal infections of the oropharynx and rectum in men who have sex with men". Sex Transm Dis. vol. 35. 2008. pp. 637-42.

Leukocyte Esterase Screening in for GC/CT Infection in Males:

Obrien, SF, Bell, TA, Farrow, JA. "Use of a leukocyte esterase dipstick to detect Chlamydia trachomatis and Neisseria gonorhoeae urethritis in asymptomatic male detainees". American Journal of Public Health. vol. 78. 1988. pp. 1583-1584.

Shafer, MA, Schacter, J, Mosiciki, AB, Weiss, A, Shalwitz, J, Vaughan, E, Millstein, SG. "Urinary leukocyte esterase screening test for asymptomatic chlamydial and gonococcal infections in males". JAMA. vol. 262. 1989. pp. 2562-6.

Management:

Matthews, CJ, Kingsley, G, Field, M, Jones, A, Weston, VC, Phillips, M, Walker, D, Coakley, G. "Management of septic arthritis: a systemic review". Annals of Rheumatic Disease,. vol. 66. 2007. pp. 440-5.

Workowski, KA, Berman, S. "Centers for Disease Control and Prevention". MMWR Recomm Rep. vol. 59. 2010. pp. 1-110.

Necessity of Concurrent CT Treatment with DGI:

Lyss, SB, Kamb, ML, Peterman, TA, Moran, JS, Newman, DR, Bolan, G. "Project RESPECT Study Group.Chlamydia trachomatis among patients infected with and treated for Neisseria gonorrhoeae in sexually transmitted disease clinics in the United States". Annals of Internal Medicine. vol. 139. 2003. pp. 178-85.

Antimicrobial Resistance and Primary management with Cephalosporins:

Dal Conte, I., Starnino, S., Di Perri, G., Stefanelli, P. "Disseminated gonococcal infection in an immunocompetent patient caused by an imported Neisseria gonorrhoeae multidrug-resistant strain". Journal of Clinical Microbiology. vol. 44. 2006. pp. 3833-34.

Workowski, KA, Berman, SM, Douglas, JM. "Emerging antimicrobial resistance in Neisseria gonorrhoeae: urgent need to strengthen prevention strategies". Ann Int Med,. vol. 148. 2008. pp. 606-13.

Ongoing controversies regarding etiology, diagnosis, treatment

The routine use of radiologic studies for diagnosis of septic arthritis remains unsupported in systematic reviews in the literature.

Use of arthroscopy and open drainage of GC arthritis is rarely necessary and of limited value given the effectiveness of antibiotic regimens available for treatment.

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