Gonorrhea

The term gonorrhea has Greek origins and is credited to the great physician Galen of Pergamum, who lived in Rome in the second century AD.

The most commonly used term is “blenorrhagia” (Swediatur, 1700), which is etymologically composed of blénna, meaning “mucus”, and “rhḗgnymi”, meaning “rupture”. From this peculiarity of mucus secretion, comes the more popular term drainage, indicating a discharge of a serous fluid.

Gonorrhea caused by sexually transmitted infections (STIs) remains a major public health concern globally today.

CAUSES

The disease is caused by the bacterium Neisseria gonorrhoeae, a diplococcus transmitted in most cases by sexual contact. It generally causes mucosal infections of the urogenital tract, infecting columnar and transitional epithelia, although it can also attach to the stratified squamous epithelium of the ectocervix.

Gonococcus is thus a diplococcus, which under the microscope typically appears to be composed of two joined cells with flattened adjacent sides, with a shape resembling that of a kidney or coffee bean. The Gram-negative microorganism belongs to the bacterial class of Betaproteobacteria and the family Neisseriaceae, and has been evolving with its human host for centuries.

The genus Neisseria currently consists of at least 23 species, of which about half are human-restricted species, some are animal-restricted, and some can be isolated from mucosal surfaces in both humans and animals.

N. gonorrhoeae is also related to many other commensal Neisseria species that reside in particular in the pharynx. Although they contain many of the pathogenicity and virulence factors of N. gonorrhoeae and N. meningitidis, the commensal species of Neisseria, from which these two pathogenic species evolved, do not normally cause pathology.

The pathogenesis (the mechanism by which a morbid process is established) and pathophysiology (the scientific study of the changes presented by organ functions in a pathological condition) of N. gonorrhoeae have been studied for decades; however, detailed knowledge of many fundamental properties is lacking.

TRANSMISSION

Transmission occurs through risky sexual intercourse, by contact with infected secretions, and from the mother to the fetus during delivery. Gonorrhea also facilitates the transmission and acquisition of other sexually transmitted diseases, including HIV infection.

Gonorrhea represents the second most prevalent STD (sexually transmitted disease) of bacterial origin, after chlamydia, with 127 million new cases each year.

Reasons for the recent increase in the incidence of gonorrhea in many resource-intensive settings include changes in sexual behaviour in the era of antiretroviral treatment for HIV infection (i.e., due to the availability of antiretroviral treatment and the perception that HIV infection is no longer life-threatening in the short term, people are less cautious and engage in sexual activity with new and casual partners without using condoms), increased electronic connectivity (e.g., use of dating apps to meet sexual partners), increased number of unknown casual partners, larger sexual networks, increased travel, and variable access to services.

Another factor to consider is the increasing use of drugs in sex networks, which is particularly common among MSM and sex workers. Finally, some key populations are at higher risk and disproportionately affected by sexually transmitted diseases, including gonorrhea; these populations include MSM, migrants, youths and sex workers.

The above factors, typically in combination, have substantially contributed to the variable increases in gonorrhea case rates over the past 5-10 years, even in countries with more comprehensive health care systems. For example, in the United States and the European Union, it has been observed that both socioeconomic status and ethnic background are highly correlated with rates of gonococcal infection. In the United States in 2017, the rate of reported cases of gonorrhea was about eight times higher among black populations than white populations.

Higher rates were also noted among Native Americans and Alaska Natives, Native Hawaiians, and individuals with Hispanic ancestry, while the rate among individuals with Asian ancestry was half the rate among whites.

GEOGRAPHICAL DISTRIBUTION

The epidemiological diversity of gonorrhea is manifested in the variability of geographic distribution and prevalence among certain populations. Determinants of this variability include sexuality and sexual orientation, socioeconomics, demographics, geographic and cultural ramifications (including stigma and taboos), and access to and quality of sex education, prevention, testing and diagnostics, as well as political commitment to health service delivery.

In 2016, the WHO estimated that there were 86.9 million global cases of gonorrhea (global prevalence 0.9 percent) among adults aged 15-49 years.

The African region has experienced high incidence in both men and women, 22 million new cases per year.

In 2017, the highest incidence rates of Gonorrhea are expressed in the United Kingdom with 75 cases per 100,000 population, Ireland with 47 cases per 100,000, Norway with 27 per 100,000, and Sweden with 25 per 100,000.

However, from 2008 to 2017, the incidence of the disease in Europe more than doubled. Also in 2017, 850 cases were reported in Italy, which equates to incidence of 1.4 cases per 100,000. In the past 5 years, cases have increased about 2 times.

SYMPTOMS

The incubation period for urogenital gonorrhea ranges from 2 to 8 days. Clinical manifestations are variable and differ greatly in men and women.

In men, gonorrhea becomes evident through leaks from the urethral canal that are first serous and colorless, then purulent (yellowish-green and denser). This typical symptom picture is known as gonococcal urethritis.

Usually, this manifestation is associated in the male with burning during urination, itching, redness, and swelling at the opening of the penis. The following may also appear:

• Testicular swelling;
• Penile pain during erection;
• Pain during ejaculation.

Further complications are rare. However, if the disease is neglected and not properly treated, the infection can spread to the prostate and epididymis (small ducts located in each testicle), resulting in prostatitis, epididymitis, and vesiculitis, leading to infertility.

Unlike male gonorrhea, in women there is a greater degree of variability in the mode of presentation of infection. In the female sex, first of all, asymptomatic courses are more common: in about 30% of cases, the infection produces no major symptoms; therefore, it may go undetected for a long time. When present, the symptoms of gonorrhea in women are usually mild and difficult to distinguish from other vaginal or urinary tract infections.

The initial manifestations of female gonorrhea include:

• Burning during urination;
• Frequent and painful urination;
• Swelling of the external genitalia;
• Redness of the urinary meatus;
• Yellowish vaginal discharge;
• Blood loss between menstrual cycles.

Also in the female sex, neglecting gonorrhea can seriously affect fertility. The infection can spread upward to the cervix and tubes, causing local inflammation (cervicitis, endometritis, salpingitis) that can predispose women to pelvic inflammatory disease (PID). This syndrome can cause fever accompanied by chronic abdominal and pelvic pain. In addition, pelvic inflammatory disease is a major cause of infertility and increases the risk of miscarriage and extrauterine pregnancy.

DIAGNOSIS

Diagnosis is by Gram stain and culture or nucleic acid-based tests. Gonococci are detected by microscopic examination with gram stain, by culture or by a nucleic acid test done on genital secretions or blood or joint fluids taken with needle aspiration.

Gram staining is not useful for infections of the cervix, rectum, or pharynx, but is specific in men with urethral discharge. The culture test is specific, but the swabbed sample must be seeded quickly because of the delicacy of the bacteria.

For men with symptomatic urethritis, Gram staining can be used to support symptom assessment. In contrast, diagnostic laboratory tests play a more important role, for the detection of gonococci in men, in asymptomatic women, and in patients of all sexes for extragenital (rectal and pharyngeal) infections, which are mostly asymptomatic or present with nonspecific symptoms.

Although about 40 percent of women with gonococcal cervicitis may report abnormal vaginal discharge, this symptom is not reliable for the syndromic diagnosis of gonorrhea, as many other genitourinary infections equally or more common in women (e.g., bacterial vaginosis, trichomoniasis, and vaginal candidiasis) can cause the same symptoms.

TREATMENT

Treatment is based on specific antimicrobial therapy, given the high resistance to antibiotics that N. gonorrheae has developed over time. For uncomplicated infection, treatment is a single dose of Ceftriaxone with Azithromycin.

When the infection is disseminated with arthritis, antibiotics should be given parenterally and for longer.

It is critical to also treat sexual partners with a positive result within 2 months.

This antimicrobial resistance is of serious public health concern because the pathogen has become highly resistant to all previously recommended antimicrobials, and new resistance has emerged for extended-spectrum cephalosporin (ESC) and macrolide azithromycin.

PREVENTION

In the absence of a gonococcal vaccine, prevention, management, and control rely on effective, inexpensive, and accessible antimicrobial treatment, supported by appropriate prevention, diagnostic testing or screening, notification and management of sexual partners of infected individuals, and epidemiologic surveillance.

Behavioural prevention:

To prevent infection, it is advisable, especially when traveling abroad, to have responsible sexual behaviour based primarily if possible on a low number of partners and always if possible a knowledge of the partner's own state of health.

The risk of gonorrhea can be limited and reduced with conscious use of condoms, perhaps the most useful means of prevention compared to number of partners or targeted health information for partners.

After returning from a trip abroad when you have had casual intercourse and experience some symptoms in particular (such as burning during urination, discharge from the urethral canal, redness and swelling of the opening of the penis in the man and, again, burning, painful urination, redness and discharge in the woman) we always recommend having a specialist checkup.

The dermatologist, the leading expert on sexually transmitted diseases (STDs), should be involved in this checkup, keeping in mind reporting not only traditional sexual intercourse but also oral and anal sex even if protected with the use of condoms.

Prevention through screening:

Screening the general population for gonococcal infections is not recommended. However, screening or opportunistic testing may be considered for individuals at higher risk of gonococcal infection. These populations include sexually active youths, sexual contacts of individuals with a suspected gonococcal infection, MSM, individuals with new or multiple sexual partners, individuals with HIV infection or a history of sexually transmitted diseases, sex workers and their sexual partners, and women (≤35 years of age) and men (≤30 years of age) on first admission.

Guidelines from the U.S. Centers for Disease Control and Prevention recommend annual gonorrhea screening of all sexually active women under the age of 25 and older women at higher risk of infection, and screening should also be offered to young MSM.

In other high-income settings, there are no screening recommendations for the general population because of the low cost-effectiveness and low prevalence of gonorrhea in the population, which results in low positive predictive values of the test and increased likelihood of false positive results, which could cause considerable harm to patients and their partners. No etiology-based screening is performed in low-income settings.

Major prevention efforts include education about symptomatic and asymptomatic gonorrhea and other sexually transmitted diseases; promotion of safe sexual behaviour (e.g., increasing condom use through condom promotion and education campaigns) behavioural change communication programs (e.g., promotion of fewer unknown, casual, and unprotected sexual contacts and early health-seeking behaviour); improved sexual partner notification and treatment; and expansion of targeted interventions, including screening in certain settings for vulnerable populations (sex workers, MSM, adolescents, and patients with sexually transmitted diseases and their sexual partners).

Prevention by vaccination:

Given the threat of incurable gonorrhea due to the spread of AMR and the high load of gonorrhea worldwide, the need for a gonococcal vaccine has become increasingly urgent.

The development of the gonococcal vaccine is complicated by the biology of gonococcus. Limitations include poor adaptive immune responses to gonococcal infections, lack of known correlates of protection, antigenic variation of potential vaccine candidate antigens, production of blocking antibodies (which by binding to their target, prevent binding of other antibodies, e.g., bactericides, antibodies and to the same target or other targets in close proximity) to conserved antigens, and lack of small, robust laboratory animals for testing vaccines.

However, it has recently been noted in several countries that there has been a decline in the number of gonorrhea cases following the use of group B meningococcal vaccines against N. meningitidis.

One such vaccine, with the trade name MeNZB, was associated with reduced rates of diagnosis and hospitalization for gonorrhea and appears to provide a proof of principle to inform the development of gonococcal vaccines. Research to clarify the specific or nonspecific antigens and mechanisms involved in MeNZB-mediated protection against gonorrhea is critical. MeNZB is no longer available; however, the licensed four-component group B meningococcal vaccine 4CMenB (trade name BEXSERO; GlaxoSmithKline) includes the same OMV as MeNZB and three recombinant meningococcal antigens (Neisserial heparin-binding antigen, factor H-binding protein and Neisseria A adhesin), which are also relatively well conserved compared with their gonococcal counterparts.

Therefore, high coverage of 4CMenB in the population may also reduce the prevalence of gonorrhea.

Improved global actions and research efforts towards gonorrhea remaining an easily treatable infection are essential.

 

Bibliography & Sitography

• M Unemo, H S Seifert, E W. Hook , S Hawkes, F Ndowa, JR. Dillon. Gonorrhoea. NATURE REVIEWS | DISEASE PRIMERS Article citation ID: (2019) 5:79.
• Edward W. Hook, M.D., R D. Kirkcaldy. A Brief History of Evolving Diagnostics and Therapy for Gonorrhea: Lessons Learned. Clin Infect Dis. 2018 September 28; 67(8): 1294–1299.
•  J. Calado, R Castro, Â Lopes, M J Campos, M Rocha, F Pereira. Antimicrobial resistance and molecular characteristics of Neisseria gonorrhoeae isolates from men who have sex with men. International Journal of Infectious Diseases 79 (2019) 116–122.
• C H Rovirola, G Spiteri, Meritxell Sabidó, A Montoliu, V. Gonzalez,  J Casabona, M J Cole. Antimicrobial resistance in Neisseria gonorrhoeae isolates from foreign-born population in the European Gonococcal Antimicrobial Surveillance Programme. Sex Transm Infect 2020;96:204–210. doi:10.1136/sextrans-2018-053912.
• Moroni M., Spinello A., Vullo V. Manuale di Malattie Infettive. Edra LSWR, Masson, 2014.