1231CHAPTER 155 Meningococcal Infections

resuscitation (with replacement of the circulating volume several

times in severe cases) and inotropic support may be necessary to

maintain cardiac output. If shock persists after volume resuscitation at 40 mL/kg, the risk of pulmonary edema is high, and elective

intubation is recommended to improve oxygenation and decrease

the work of breathing. Metabolic derangements, including hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia,

hypophosphatemia, anemia, and coagulopathy, should be anticipated and corrected. However, aggressive fluid resuscitation with

unbuffered electrolyte solutions was found to increase mortality in

febrile African children. Studies of the effects of lower volumes of

buffered solutions and similar studies in resource-rich settings are

required. In the presence of raised intracranial pressure, management includes correction of coexistent shock and neurointensive

care to maintain cerebral perfusion.

Empirical antibiotic therapy for suspected meningococcal disease consists of a third-generation cephalosporin such as ceftriaxone (75–100 mg/kg per day [maximum, 4 g/d] in one or two

divided IV doses) or cefotaxime (200 mg/kg per day [maximum,

8 g/d] in four divided IV doses) to cover the various other (potentially penicillin-resistant) bacteria that may produce an indistinguishable clinical syndrome. Although unusual in most isolates,

reduced meningococcal sensitivity to penicillin (a minimal inhibitory concentration of 0.12–1.0 μg/mL) has been reported.

Both meningococcal meningitis and meningococcal septicemia

are conventionally treated for 7 days, although courses of 3–5 days

may be equally effective. Furthermore, a single dose of ceftriaxone

or an oily suspension of chloramphenicol has been used successfully in resource-poor settings. No data are available to guide the

duration of treatment for meningococcal infection at other foci

(e.g., pneumonia, arthritis); antimicrobial therapy is usually continued until clinical and laboratory evidence of infection has resolved.

Cultures usually become sterile within 24 h of initiation of appropriate antibiotic chemotherapy.

The use of glucocorticoids for adjunctive treatment of meningococcal meningitis remains controversial since no relevant studies

have had sufficient power to determine true efficacy. One large

study in adults did indicate a trend toward benefit, and in clinical

practice a decision to use glucocorticoids usually must precede a

definite microbiologic diagnosis. Therapeutic doses of glucocorticoids are not recommended in meningococcal septicemia, but

many intensivists recommend replacement glucocorticoid doses

for patients who have refractory shock in association with impaired

adrenal gland responsiveness, management that is supported by

limited evidence.

Various other adjunctive therapies for meningococcal disease

have been considered, but few have been subjected to clinical

trials and none can currently be recommended. An antibody to

LPS (HA1A) failed to confer a demonstrable benefit. Recombinant

bactericidal/permeability-increasing protein (which is not currently

available) was tested in a study that had inadequate power to show

an effect on mortality rates; however, there were trends toward

lower mortality rates among patients who received a complete infusion, and this group also had fewer amputations, fewer blood-product transfusions, and a significantly improved functional outcome.

Given that protein C concentrations are reduced in meningococcal

disease, the use of activated protein C has been considered. A

survival benefit was demonstrated in adult sepsis trials; however,

trials in pediatric sepsis (of particular relevance for meningococcal

disease) found no benefit and indicated a potential risk of bleeding

complications with use of activated protein C.

The postmeningococcal immune-complex inflammatory syndrome has been treated with nonsteroidal anti-inflammatory agents

until spontaneous resolution occurs.

■ COMPLICATIONS

About 10% of patients with meningococcal disease die despite the

availability of antimicrobial therapy and other intensive medical

interventions. The most common complication of meningococcal disease (10% of cases) is scarring after necrosis of purpuric skin lesions,

for which skin grafting may be necessary. The lower limbs are most

often affected; next in frequency are the upper limbs, the trunk, and the

face. On average, 13% of the skin surface area is involved. Amputations

are necessary in 1–2% of survivors of meningococcal disease because of

a loss of tissue viability after peripheral ischemia or compartment syndromes. Unless there is local infection, amputation should usually be

delayed to allow the demarcation between viable and nonviable tissue

to become apparent. Approximately 5% of patients with meningococcal

disease suffer hearing loss, and 7% have neurologic complications. In

one study, pain was reported by 21% of survivors, and in a recent analysis of capsular group B meningococcal disease (the MOSAIC study) as

many as one-quarter of survivors had psychological disorders. In some

investigations, the rate of complications is higher for capsular group C

disease (mostly associated with the ST11 clone) than for capsular group

B disease. In patients with severe hypovolemic shock, renal perfusion

may be impaired and prerenal failure is common, but permanent renal

replacement therapy is rarely needed.

Several studies suggest adverse psychosocial outcomes after meningococcal disease, with reduced quality of life, lowered self-esteem, and

poorer neurologic development, including increased rates of attention

deficit/hyperactivity disorder and special educational needs. Other

studies have not found evidence of such outcomes.

■ PROGNOSIS

Several prognostic scoring systems have been developed to identify

patients with meningococcal disease who are least likely to survive.

Factors associated with a poorer prognosis are shock; young age

(infancy), old age, and adolescence; coma; purpura fulminans; disseminated intravascular coagulation; thrombocytopenia; leukopenia;

absence of meningitis; metabolic acidosis; low plasma concentrations

of antithrombin and proteins S and C; high blood levels of PAI-1;

and a low erythrocyte sedimentation rate or C-reactive protein level.

The Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS)

performs well and may be clinically useful for severity assessment in

meningococcal disease. However, scoring systems do not direct the clinician to specific interventions, and the priority in management should

be recognition of compromised airways, breathing, or circulation and

direct, urgent intervention. Most patients improve rapidly with appropriate antibiotics and supportive therapy. Fulminant meningococcemia

is more likely to result in death or ischemic skin loss than is meningitis;

optimal emergency management may reduce mortality rates among

the most severely affected patients.

■ PREVENTION

Since mortality rates in meningococcal disease remain high despite

improvements in intensive care management, immunization is the

only rational approach to prevention at a population level. Secondary

cases are common among household and “kissing” contacts of cases,

and secondary prophylaxis with antibiotics is widely recommended for

these contacts (see below).

Polysaccharide Vaccines Purified meningococcal capsular polysaccharide has been used for immunization since the 1960s. Meningococcal polysaccharide vaccines are currently formulated as either

bivalent (capsular groups A and C) or quadrivalent (capsular groups A,

C, Y, and W), with 50 μg of each polysaccharide per dose. Local reactions (erythema, induration, and tenderness) may occur in up to 40%

of vaccinees, but serious adverse events (including febrile convulsions

in young children) are very rarely reported. In adults, the vaccines are

immunogenic, but immunity appears to be relatively short-lived (with

antibody levels above baseline for only 2–10 years), and booster doses

do not induce a further rise in antibody concentration. Indeed, a state

of immunologic hyporesponsiveness has been widely reported to follow booster doses of plain polysaccharide vaccines. The repeating units

of these vaccines cross-link B-cell receptors to drive specific memory

B cells to become plasma cells and produce antibody. Because meningococcal polysaccharides are T cell–independent antigens, no memory

B cells are produced after immunization, and the memory B-cell pool

1232 PART 5 Infectious Diseases

is depleted such that fewer polysaccharide-specific cells are available

to respond to a subsequent dose of vaccine (Fig. 155-6). The clinical

relevance of hyporesponsiveness is unknown. Plain polysaccharide

vaccines generally are not immunogenic in early childhood, possibly

because marginal-zone B cells are involved in polysaccharide responses

and maturation of the splenic marginal zone is not complete until

18 months to 2 years of age. The efficacy of the meningococcal capsular

group C component is >90% in young adults; no efficacy data are available for the capsular group Y and W polysaccharides in this age group.

Group A meningococcal polysaccharides are exceptional in that

they are effective in preventing disease at all ages. Two doses administered 2–3 months apart to children 3–18 months of age or a single

dose administered to older children or adults has a protective efficacy

rate of >95%. The vaccine was previously used widely in the control

of outbreaks of meningococcal disease in the African meningitis belt.

The duration of protection appears to be only 3–5 years. The plain

polysaccharide vaccines have been largely superseded by protein–

polysaccharide conjugate vaccines.

There is no meningococcal capsular group B plain polysaccharide

vaccine because α-2,8-N-acetylneuraminic acid is expressed on the

surface of neural cells in the fetus such that the B polysaccharide is

perceived as “self ” and therefore is not immunogenic in humans.

Conjugate Vaccines The poor immunogenicity of plain polysaccharide vaccines in infancy has been overcome by chemical conjugation

of the polysaccharides to a carrier protein (CRM197, tetanus toxoid,

or diphtheria toxoid). Conjugates that contain monovalent capsular

group C polysaccharide and quadrivalent vaccines with A, C, Y, and

W polysaccharides have been developed, as have vaccines including

various other antigen combinations (e.g., tetanus conjugates with capsular group C and/or Y polysaccharide and Haemophilus influenzae

type b polysaccharide). After immunization, peptides from the carrier

protein are conventionally thought to be presented by polysaccharide-specific B cells to peptide-specific T cells in association with

major histocompatibility complex (MHC) class II molecules. (Some

data suggest that carrier protein peptide may actually be presented

in association with an oligosaccharide and MHCII.) The result is a

T cell–dependent immune response that allows production of antibody

and generation of an expanded B-cell memory pool. Unlike responses

to booster doses of plain polysaccharides, responses to booster doses of

conjugate vaccines have the characteristics of memory responses. Indeed,

conjugate vaccines overcome the hyporesponsiveness induced by plain

polysaccharides by replenishing the memory pool. The reactogenicity

of conjugate vaccines is similar to that of plain polysaccharide vaccines.

The first widespread use of capsular group C meningococcal conjugate vaccine (MenC) came in 1999 in the United Kingdom after a rise

in capsular group C disease. A mass vaccination campaign involving

all individuals <19 years of age was undertaken, and the number of

laboratory-confirmed capsular group C cases fell from 955 in 1998–

1999 to just 29 in 2011–2012. The effectiveness of the immunization

program was attributed both to direct protection of immunized persons and to reduced transmission of the organism in the population

Differentiation

B cell Plasma cell

IgG2 and IgM

BCR

Polysaccharide

Depletion of

memory B-cell pool

No production of

memory B cells

Antibody

production

A

Polysaccharidespecific B cell

Polysaccharidespecific memory

B cell

CD40 CD80

or CD86

CD28 CD40L

TCR

Carrier peptide–

specific T cell

Polysaccharidespecific plasma cell IgG1 and IgG3

BCR

Polysaccharide

Carrier

protein

Antibody

production

Memory

response

Internalization

and processing

of carrier protein

T-cell

help

B

MHC Class II

FIGURE 155-6 A. Polysaccharides from the encapsulated bacteria that cause disease in early childhood stimulate B cells by cross-linking the B-cell receptor (BCR) and

driving the production of immunoglobulins. There is no production of memory B cells, and the B-cell pool may be depleted by this process such that subsequent immune

responses are decreased. B. The carrier protein from protein–polysaccharide conjugate vaccines is processed by the polysaccharide-specific B cell, and peptides are

presented to carrier peptide–specific T cells, with the consequent production of both plasma cells and memory B cells. MHC, major histocompatibility complex; TCR,

T-cell receptor. (Reproduced with permission from AJ Pollard: Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines. Nat Rev

Immunol 9:213, 2009.)

1233CHAPTER 155 Meningococcal Infections

as a result of decreased rates of colonization among the immunized

(i.e., herd immunity). Data on immunogenicity and effectiveness

have shown that the duration of protection is short when the vaccine

is administered in early childhood; thus booster doses are needed to

maintain population immunity. In contrast, immunity after a dose of

vaccine given in adolescence appears to be more prolonged.

In 2005, the first quadrivalent conjugate meningococcal vaccine

containing A, C, Y, and W polysaccharides conjugated to diphtheria

toxoid was initially recommended for all children >11 years of age in

the United States and for persons 2–55 years of age in Canada. Such

vaccines are now recommended by the Advisory Committee on Immunization Practices (ACIP) for routine administration to individuals

11–18 years of age, with a booster dose 3 years later; only a single dose

is given to persons >16 years of age. These vaccines are also recommended for high-risk persons from 2 months to 55 years of age (see

www.cdc.gov/mmwr/preview/mmwrhtml/mm6324a2.htm).

Uptake was slow initially, but current U.S. data suggest an efficacy

rate of 82% in the first year after vaccination, with waning to 59%

at 3–6 years after vaccination. Limited early data from the U.S. Vaccine Adverse Events Reporting System indicated that there might be

a short-term increase in the risk of Guillain-Barré syndrome after

immunization with the diphtheria conjugate vaccine; however, further

investigation has not confirmed this finding. Quadrivalent conjugate

vaccines with tetanus or CRM197 as carrier protein are now available

in many countries and are used for high-risk groups and in routine

programs for toddlers and adolescents.

A monovalent capsular group A vaccine, manufactured in India, was

licensed in 2010 and rolled out to countries in the sub-Saharan African

meningitis belt in a mass immunization campaign. There is strong

evidence that this vaccine has been highly effective in controlling epidemic meningococcal disease in the region, with >90% reduction in

disease in vaccinated populations. However, disease caused by capsular

groups C, X, and W persists, and new-generation vaccines with wider

coverage are being developed.

Vaccines Based on Subcapsular Antigens The lack of immunogenicity of the group B capsule has led to the development of vaccines based on subcapsular antigens. Various surface components have

been studied in early-phase clinical trials. Outer-membrane vesicles

(OMVs) containing outer-membrane proteins, phospholipid, and LPS

can be extracted from cultures of N. meningitidis by detergent treatment (Fig. 155-7). OMVs prepared in this way were used in efficacy

trials with a Norwegian outbreak strain and reduced the incidence of

group B disease among 14- to 16-year-old schoolchildren by 53%. Similarly, OMV vaccines constructed from local outbreak strains in Cuba

and New Zealand have had reported efficacy rates of >70%. These

OMV vaccines appear to produce strain-specific immune responses,

with only limited cross-protection, and are therefore best suited to

clonal outbreaks (e.g., those in Cuba and New Zealand as well as others

in Norway and the province of Normandy in France).

Several purified surface proteins have been evaluated in phase

1 clinical trials but have not yet been developed further because

of antigenic variability or poor immunogenicity (e.g., transferrinbinding proteins, neisserial surface protein A). Other vaccine candidates

have been identified since sequencing of the meningococcal genome.

The combination vaccine 4CMenB, which includes the New Zealand

OMV vaccine and three recombinant proteins (neisserial adhesin A,

factor H–binding protein, and neisserial heparin-binding antigen), is

immunogenic from infancy and has been licensed for use in the United

States, Canada, Europe, and Australia. This vaccine has been used

with apparent success in the control of several university outbreaks in

the United States and in a community outbreak in an area of Quebec,

Canada. 4CMenB vaccine has an acceptable safety profile, with fever

prominent among infants and injection-site pain frequently reported

among older children and adults. The vaccine is also being used in many

countries for immunization of high-risk groups. In September 2015,

4CMenB was recommended for routine use in the United Kingdom

for all infants born from May 2015 onward; a recent analysis reported

a 75% reduction in age groups that were fully eligible for vaccination,

with a high coverage rate of 95%. The licensed schedule is 3 priming

doses before 6 months of age and a booster dose at 12 months of age. A

non-significant vaccine effectiveness of 53% was seen after two doses,

and 59% effectiveness was found after the booster dose at 1 year of age.

Because the disease is so rare, the cost-effectiveness of capsular

group B vaccine in infant immunization programs, as assessed with

conventional thresholds, is borderline in the United Kingdom. Since

infants are not commonly colonized with capsular group B meningococci, any impact on the total population burden of carried organisms

will be small. It is therefore unlikely that an infant immunization program will provide additional value through induction of herd immunity. Rates of capsular group B carriage are higher among teenagers and

young adults than at other ages (apart from infancy). A recent large

cluster randomized trial in Australia found no effect of 4CMenB on

carriage of disease-causing meningococci, highlighting that the benefit

of this vaccine is likely to be via direct protection.

An immunogenic vaccine based on two variants of the lipoprotein

factor H–binding protein (fHbp2) has been developed for use in adolescents and is licensed in the United States and Europe. The vaccine is

immunogenic against representative indicator strains, inducing fourfold rises in bactericidal antibody titer in 50–92% of individuals. fHbp2

has an acceptable safety profile, with pain at the injection site, fatigue,

and headache commonly reported. This vaccine can be used with a

range of vaccines routinely administered in adolescence, including

Tdap (tetanus–diphtheria–acellular pertussis), human papillomavirus,

and MenACWY vaccines. fHbp2 has been used to control outbreaks of

meningococcal disease in educational institutions in the United States,

but no formal studies of its effectiveness have yet been undertaken.

Studies in the UK are currently evaluating the impact of both 4CMenB

and fHbp2 against meningococcal carriage amongst teenagers.

Both of the new capsular group B meningococcal vaccines are

licensed for use in the United States for persons 10–25 years of age.

In addition, ACIP recommends their administration to individuals

at high risk of capsular group B disease, with 4CMenB administered

as two doses (1–2 months apart) and fHbp2 as two doses (at 0 and

6 months) or three doses (at 0, 1–2, and 6 months).

■ MANAGEMENT OF CONTACTS

Close (household and kissing) contacts of individuals with meningococcal disease are at increased risk for developing secondary disease

(up to 1000 times the rate for the general population); a secondary case

FIGURE 155-7 Illustration of meningococcal outer-membrane vesicle containing

outer-membrane structures.

1234 PART 5 Infectious Diseases

■ DEFINITION

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.

■ MICROBIOLOGY

Neisseria gonorrhoeae is a gram-negative, nonmotile, non-sporeforming organism that grows singly and in pairs (i.e., as monococci

and diplococci, respectively). Exclusively a human pathogen, the gonococcus contains, on average, three genome copies per coccal unit; this

polyploidy permits a high level of antigenic variation and the survival

of the organism in its host. 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 use glucose but not

maltose, sucrose, or lactose.

■ EPIDEMIOLOGY

The incidence of gonorrhea had been declining steadily in the United

States, but in 2018, there were ~616,000 newly reported cases—up 56%

since 2015. With 87 million cases estimated by the World Health Organization to have occurred globally in 2016, gonorrhea remains a major

public health problem worldwide, is a significant cause of morbidity in

developing countries, and may play a role in enhancing transmission

of HIV.

Gonorrhea predominantly affects young, nonwhite, unmarried, less

educated members of urban populations. The number of reported cases

probably represents half of the true number of cases—a discrepancy

resulting from underreporting, self-treatment, nonspecific treatment

without a laboratory-proven diagnosis, and asymptomatic infection.

The number of reported new cases of gonorrhea in the United States

rose from ~250,000 in the early 1960s to a high of 1.01 million in 1978.

The recorded incidence of gonorrhea in modern times peaked in 1975,

with 468 reported new cases per 100,000 population in the United

States. This peak was attributable to the interaction of several variables,

including improved accuracy of diagnosis, changes in patterns of contraceptive use, and changes in sexual behavior. A decline in the overall

incidence of gonorrhea in the United States over the past quartercentury may have reflected increased condom use resulting from public

health efforts to curtail HIV transmission. Nevertheless, in 2019, 187.8

new cases per 100,000 population were reported in this country, representing a 1-year increase of 5% and a 92% increase since the historic

low in 2009; this figure is the highest among industrialized countries.

Simultaneously, antibiotic resistance is increasing in the United States

and other countries, prompting the U.S. Centers for Disease Control

and Prevention (CDC) to name antibiotic-resistant N. gonorrhoeae as

one of the three most urgent threats of its kind. At present, the attack

rate in the United States is highest among 15- to 24-year-old women

and 20- to 29-year-old men; >70% of all reported cases occur in these

two groups. From the standpoint of ethnicity, rates are highest among

African Americans and lowest among persons of Asian descent.

The incidence of gonorrhea is higher in developing countries than

in industrialized nations. The exact incidence of any STI is difficult to

ascertain in developing countries because of limited surveillance and

variable diagnostic criteria. Extremely high rates of gonorrhea have

been reported among aboriginal populations in Namibia and Australia.

Studies in Africa have clearly demonstrated that nonulcerative STIs

156 Gonococcal Infections

Sanjay Ram, Peter A. Rice

follows as many as 3% of sporadic cases. About one-fifth of secondary

cases are actually co-primary cases—i.e., cases that occur soon after the

primary case and in which transmission is presumed to have originated

from the same third party. The rate of secondary cases is highest during

the week after presentation of the index case. The risk falls rapidly but

remains above baseline for up to 1 year after the index case; 30% of secondary cases occur in the first week, 20% in the second week, and most

of the remainder over the next 6 weeks. In outbreaks of meningococcal

disease, mass prophylaxis has been used; however, limited data support

population intervention, and significant concerns have arisen about

adverse events and the development of resistance. For these reasons,

prophylaxis is usually restricted to (1) persons at greatest risk who are

intimate and/or household contacts of the index case and (2) health

care workers who have been directly exposed to respiratory secretions.

In most cases, members of wider communities (e.g., at schools or colleges) are not offered prophylaxis.

The aim of prophylaxis is to eradicate colonization of close contacts

with the strain that has caused invasive disease in the index case.

Prophylaxis should be given to all contacts at the same time to avoid

recolonization by meningococci transmitted from untreated contacts

and should also be used as soon as possible to treat early disease in

secondary cases. If the index patient is treated with an antibiotic that

does not reliably clear colonization (e.g., penicillin), he or she should

be given a prophylactic agent at the end of treatment to prevent relapse

or onward transmission. Although rifampin has been most widely

used and studied, it is not the optimal agent because it fails to eradicate

carriage in 15–20% of cases, rates of adverse events have been high,

compliance is affected by the need for four doses, and emerging resistance has been reported. Ceftriaxone as a single IM or IV injection is

highly (97%) effective in carriage eradication and can be used at all ages

and in pregnancy. Reduced susceptibility of isolates to ceftriaxone has

occasionally been reported. Ciprofloxacin or ofloxacin is preferred in

some countries; these agents are highly effective and can be administered by mouth but are not recommended in pregnancy. Resistance to

fluoroquinolones has been reported in some meningococci in North

America, Europe, and Asia.

In documented capsular group A, B, C, Y, or W disease, contacts

may be offered immunization (with either the MenACWY conjugate

vaccine or the MenB vaccine, as appropriate) in addition to chemoprophylaxis to provide protection beyond the duration of antibiotic

therapy. Mass vaccination has been used successfully to control disease

during outbreaks in closed communities (educational and military

establishments) as well as during epidemics in open communities.

■ FURTHER READING

Christensen H et al: Meningococcal carriage by age: A systematic

review and meta-analysis. Lancet Infect Dis 10:853, 2010.

Cohn AC et al: Prevention and control of meningococcal disease:

Recommendations of the Advisory Committee on Immunization

Practices (ACIP). MMWR Recomm Rep 62(RR-2):1, 2013.

Gossger N et al: Immunogenicity and tolerability of recombinant

serogroup B meningococcal vaccine administered with or without

routine infant vaccinations according to different immunization

schedules: A randomized controlled trial. JAMA 307:573, 2012.

Jafri RZ et al: Global epidemiology of invasive meningococcal disease.

Popul Health Metr 11:17, 2013.

Ladhani SN et al: Vaccination of infants with meningococcal group B

vaccine (4CMenB) in England. N Engl J Med 382:309, 2020.

Marshall HS et al: Meningococcal B vaccine and meningococcal carriage in adolescents in Australia. N Engl J Med 382:318, 2020.

Pollard AJ et al: Maintaining protection against invasive bacteria

with protein–polysaccharide conjugate vaccines. Nat Rev Immunol

9:213, 2009.

Read RC et al: Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal

carriage: An observer-blind, phase 3 randomised clinical trial. Lancet

384:2123, 2014.

Vieusseux M: Memoire sur le maladie qui a regne a Geneva au printemps de 1805. J Med Clin Pharm 11:163, 1805.

1235CHAPTER 156 Gonococcal Infections

such as gonorrhea (in addition to ulcerative STIs) are an independent

risk factor for the transmission of HIV (Chap. 202).

Gonorrhea is transmitted from males to females more efficiently

than in the opposite direction. The rate of transmission to a woman

during a single unprotected sexual encounter with an infected man is

~50–70%. Oropharyngeal gonorrhea occurs in ~20% of women who

practice fellatio with infected partners. Transmission in either direction by cunnilingus is rare.

In any population, there exists a small minority of individuals

who have high rates of new-partner acquisition. These “core-group

members” or “high-frequency transmitters” are vital in sustaining STI

transmission at the population level. Another instrumental factor in

sustaining gonorrhea in the population is the large number of infected

individuals who are asymptomatic or have minor symptoms that are

ignored. These persons, unlike symptomatic individuals, may not cease

sexual activity and therefore may continue to transmit the infection.

This situation underscores the importance of contact tracing and

empirical treatment of the sex partners of index cases.

■ PATHOGENESIS, IMMUNOLOGY, AND

ANTIMICROBIAL RESISTANCE

Outer-Membrane Proteins •  PILI Fresh clinical isolates of

N. gonorrhoeae initially form piliated (fimbriated) colonies distinguishable on translucent agar. Pilus expression is rapidly switched off with

unselected subculture because of rearrangements in pilus genes. This

change is a basis for antigenic variation of gonococci. Piliated strains

adhere better to cells derived from human mucosal surfaces and are

more virulent in organ culture models and human inoculation experiments than nonpiliated variants. In a fallopian tube explant model,

pili mediate gonococcal attachment to nonciliated columnar epithelial

cells. This event initiates gonococcal adherence, invasion and transport

through these cells to intercellular spaces near the basement membrane

or directly into the subepithelial tissue. Pili are also essential for genetic

competence and transformation of N. gonorrhoeae, which permit

horizontal transfer of genetic material between different gonococcal

lineages in vivo.

OPACITY-ASSOCIATED PROTEIN Another gonococcal surface protein

that is important in adherence to epithelial cells is opacity-associated

protein (Opa; formerly called protein II). Opa contributes to intergonococcal adhesion, which is responsible for the opaque nature of

gonococcal colonies on translucent agar and the organism’s adherence

to a variety of eukaryotic cells, including polymorphonuclear leukocytes

(PMNs). Certain Opa variants promote invasion of epithelial cells, and

this effect has been linked with the ability of Opa to bind vitronectin,

heparan sulfate proteoglycans, and several members of the carcinoembryonic antigen–related cell adhesion molecule (CEACAM) receptor

family. Epithelial CEACAM-binding gonococci prevent exfoliation

of epithelium through a mechanism that involves nitric oxide that is

produced during anaerobic bacterial metabolism and upregulation of

CD105 (a member of the transforming growth factor-beta receptor family), which may interfere with bacterial clearance. N. gonorrhoeae Opa

proteins that bind CEACAM1, which is expressed by primary CD4+ T

lymphocytes, suppress the activation and proliferation of these lymphocytes. Select Opa proteins can engage CEACAM3, which is expressed on

neutrophils, with consequent nonopsonic phagocytosis (i.e., phagocytosis independent of antibody and complement) and killing of bacteria.

PORIN Porin (previously designated protein I) is the most abundant

gonococcal surface protein. Porin molecules exist as trimers that

provide anion-transporting aqueous channels through the otherwise hydrophobic outer membrane. Porin exhibits stable interstrain

antigenic variation and forms the basis for gonococcal serotyping.

Two main serotypes have been identified; PorB.1A strains are often

associated with disseminated gonococcal infection (DGI), whereas

PorB.1B strains usually cause local genital infections only. DGI

strains are generally resistant to the killing action of normal human

serum and do not incite a significant local inflammatory response;

therefore, they may not cause symptoms at genital sites. These characteristics may be related to the ability of PorB.1A strains to bind to

complement-inhibitory molecules, resulting in a diminished inflammatory response. Porin can translocate to the cytoplasmic membrane

of host cells—a process that could initiate gonococcal endocytosis and

invasion. PorB.1B present in outer membrane vesicles shed during

bacterial growth inhibits the ability of dendritic cells to induce T-cell

proliferation and may contribute to the ability of gonococci to subvert

adaptive immunity.

OTHER OUTER-MEMBRANE PROTEINS Other notable outermembrane proteins include H.8, a lipoprotein that is present in high

concentration on the surface of all gonococcal strains and is an excellent target for antibody-based diagnostic testing. Transferrin-binding

proteins (Tbp1 and Tbp2), lactoferrin-binding proteins (LbpA and

LbpB), and hemoglobin/haptoglobin binding proteins (HpuA and

HpuB) are required for scavenging iron from transferrin, lactoferrin,

and heme in vivo. Transferrin and iron have been shown to enhance

the attachment of iron-deprived N. gonorrhoeae to human endometrial cells. TdfH and TdfJ enable gonococci to scavenge host zinc from

calprotectin and S100 calcium binding protein A7 (psoriasin). IgA1

protease is produced by N. gonorrhoeae and may protect the organism

from the action of mucosal IgA.

Lipooligosaccharide Gonococcal lipooligosaccharide (LOS) consists of a lipid A and a core oligosaccharide that lacks the repeating

O-carbohydrate antigenic side chain seen in many other gram-negative

bacteria. Gonococcal LOS possesses marked endotoxic activity and

contributes to the local cytotoxic effect in a fallopian tube model. LOS

core sugars undergo a high degree of phase variation under different

conditions of growth; this variation reflects genetic regulation and

expression of glycotransferase genes that dictate the carbohydrate

structure of LOS. These phenotypic changes may affect interactions

of N. gonorrhoeae with elements of the humoral immune system

(antibodies and complement) and may also influence direct binding

of organisms to both professional phagocytes and nonprofessional

phagocytes (epithelial cells). For example, gonococci that are sialylated

at their LOS sites inhibit the classic pathway of complement by reducing binding of IgG and also bind complement factor H to inhibit the

alternative pathway of complement. LOS sialylation may also decrease

nonopsonic Opa-mediated association with neutrophils and inhibit

the oxidative burst in PMNs. The binding of the unsialylated terminal

lactosamine residue of LOS to an asialoglycoprotein receptor on male

epithelial cells facilitates adherence and subsequent gonococcal invasion of these cells. Moreover, oligosaccharide structures in LOS can

modulate host immune responses. For example, the terminal monosaccharide expressed by LOS determines the C-type lectin receptor

on dendritic cells that is targeted by the bacteria. In turn, the specific

C-type lectin receptor engaged influences whether a TH1- or TH2-type

response is elicited; the latter response may be less favorable for clearance of gonococcal infection.

Host Factors In addition to gonococcal structures that interact

with epithelial cells, host factors seem to be important in mediating

entry of gonococci into nonphagocytic cells. Activation of phosphatidylcholine-specific phospholipase C and acidic sphingomyelinase by

N. gonorrhoeae, which results in the release of diacylglycerol and ceramide, is a requirement for the entry of N. gonorrhoeae into epithelial

cells. Ceramide accumulation within cells leads to apoptosis, which

may disrupt epithelial integrity and facilitate entry of gonococci into

subepithelial tissue. Release of chemotactic factors as a result of complement activation contributes to inflammation, as does the toxic effect

of LOS in provoking the release of inflammatory cytokines.

The importance of humoral immunity in host defenses against

neisserial infections is best illustrated by the predisposition of persons

deficient in terminal complement components (C5 through C9) to

have recurrent bacteremic gonococcal infections and recurrent meningococcal meningitis or meningococcemia. Gonococcal porin induces

T cell–proliferative responses in persons with urogenital gonococcal

disease. A significant increase in porin-specific interleukin (IL) 4–

producing CD4+ as well as CD8+ T lymphocytes is seen in individuals with mucosal gonococcal disease. A portion of these lymphocytes