1224 PART 5 Infectious Diseases

well as a protease and a neuraminidase. Unlike the α toxin of C. perfringens, that of C. septicum does not possess phospholipase activity. The

mechanisms remain to be fully elucidated, but it is likely that each of

these toxins contributes uniquely to C. septicum gas gangrene.

TREATMENT

Gas Gangrene

Patients with suspected gas gangrene (either traumatic or spontaneous) should undergo prompt surgical inspection of the infected site.

Direct examination of a Gram-stained smear of the involved tissues

is of major importance. Characteristic histologic findings in clostridial gas gangrene include widespread tissue destruction, a paucity

of leukocytes in infected tissues in conjunction with an accumulation of leukocytes in adjacent vessels (Fig. 154-4), and the presence

of gram-positive rods (with or without spores). CT and MRI are

invaluable for determining whether the infection is localized or

is spreading along fascial planes, and needle aspiration or punch

biopsy may provide an etiologic diagnosis in at least 20% of cases.

However, these techniques should not replace surgical exploration,

Gram’s staining, and histopathologic examination. When spontaneous gas gangrene is suspected, blood should be cultured since bacteremia usually precedes cutaneous manifestations by several hours.

For patients with evidence of clostridial gas gangrene, thorough emergent surgical debridement is of extreme importance. All

devitalized tissue should be widely resected back to healthy viable

muscle and skin so as to remove conditions that allow anaerobic

organisms to continue proliferating. Closure of traumatic wounds

or compound fractures should be delayed for 5–6 days until it is

certain that these sites are free of infection.

Except for infection caused by C. tertium (see below), antibiotic

treatment of traumatic or spontaneous gas gangrene (Table 154-1)

consists of the administration of penicillin and clindamycin for

10–14 days. Penicillin is recommended on the basis of in vitro

sensitivity data; clindamycin is recommended because of its superior efficacy over penicillin in animal models of C. perfringens gas

gangrene and in some clinical reports. Controlled clinical trials

comparing the efficacy of these agents in humans have not been

performed. In the penicillin-allergic patient, clindamycin may be

used alone. The superior efficacy of clindamycin is probably due to

its ability to inhibit bacterial protein toxin production, its insensitivity to the size of the bacterial load or the stage of bacterial growth,

and its ability to modulate the host’s immune response.

Although C. perfringens remains largely susceptible to first-line

antibiotics, antibiotic resistance has been reported. Case reports

from the United Kingdom and from Spain found clindamycin-resistant C. perfringens in cellulitis and in a spontaneous abscess,

respectively. Larger studies from Canada and Taiwan also showed

increasing resistance to clindamycin among bloodstream isolates.

In 2014, Marchand-Austin et al published a 2-year prospective

Canadian study that examined antimicrobial susceptibility of anaerobic bacteria isolated from blood, body fluids, and abscesses. Of

1412 isolates submitted for susceptibility testing, 68 were C. perfringens. Of these, all were universally susceptible to penicillin but 3.8%

were clindamycin-resistant. Notably, for Clostridium species other

than C. perfringens (n = 289), 14.2% were penicillin-resistant and

21.6% clindamycin-resistant. A more recent study from Iran found

that 21.2% of C. perfringens isolates were resistant to penicillin.

Lastly, a 2019 study from Hungary found resistance to penicillin

(2.6%) and clindamycin (3.8%) among C. perfringens isolates (n =

313) from tissues with gas gangrene. Among the non-perfringens

gas gangrene isolates (n = 59), higher resistance to penicillin and

clindamycin was observed (6.8% and 8.5%, respectively). These

findings, though not universal, highlight the importance of good

anaerobic microbiology susceptibility testing to provide up-to-date

information to guide optimal clinical management decisions for

clostridial infections.

C. tertium is resistant to penicillin, cephalosporins, and clindamycin. Appropriate antibiotic therapy for C. tertium infection is vancomycin (1 g every 12 h IV) or metronidazole (500 mg every 8 h IV).

The value of adjunctive treatment with hyperbaric oxygen (HBO)

for gas gangrene remains controversial. Basic-science studies suggest

that HBO can inhibit the growth of C. perfringens but not that of the

more aerotolerant C. septicum. In vitro, blood and macerated muscle

inhibit the bactericidal potential of HBO. Numerous studies in animals demonstrate little efficacy of HBO alone, whereas antibiotics

alone—especially those that inhibit bacterial protein synthesis—

confer marked benefits. Addition of HBO to the therapeutic regimen provides some additional benefit, but only if surgery and

antibiotic administration precede HBO treatment.

In conclusion, gas gangrene is a rapidly progressive infection

whose outcome depends on prompt recognition, emergent surgery,

and timely administration of antibiotics that inhibit toxin production. Gas gangrene associated with bacteremia probably represents

a later stage of illness and is associated with the worst outcomes.

Emergent surgical debridement is crucial to ensure survival, and

ancillary procedures (e.g., CT or MRI) or transport to HBO units

should not delay this intervention. Some trauma centers associated

with HBO units may have special expertise in managing these

aggressive infections, but proximity and speed of transfer must be

carefully weighed against the need for haste.

PROGNOSIS OF GAS GANGRENE The prognosis for patients with gas

gangrene is more favorable when the infection involves an extremity

rather than the trunk or visceral organs, since debridement of the latter

sites is more difficult. Gas gangrene is most likely to progress to shock

and death in patients with associated bacteremia and intravascular

hemolysis. Mortality rates are highest for patients in shock at the time

of diagnosis. Mortality rates are relatively high among patients with

spontaneous gas gangrene, especially that due to C. septicum. Survivors

of gas gangrene may undergo multiple debridements and face long

periods of hospitalization and rehabilitation.

PREVENTION OF GAS GANGRENE Initial aggressive debridement of

devitalized tissue can reduce the risk of gas gangrene in contaminated

deep wounds. Interventions to be avoided include prolonged application of tourniquets and surgical closure of traumatic wounds; patients

with compound fractures are at significant risk for gas gangrene if the

wound is closed surgically. Vaccination against α toxin is protective in

experimental animal models of C. perfringens gas gangrene but has not

been investigated in humans. In addition, as mentioned above, a hyperimmune globulin would represent a significant advance for prophylaxis

in victims of acute traumatic injury or for attenuation of the spread of

infection in patients with established gas gangrene.

FIGURE 154-4 Histopathology of experimental gas gangrene due to C. perfringens,

demonstrating widespread muscle necrosis, a paucity of leukocytes in infected

tissues, and accumulation of leukocytes in adjacent vessels (arrows). These

features are due to the effects of α and θ toxins on muscle cells, platelets,

leukocytes, and endothelial cells.

1225CHAPTER 155 Meningococcal Infections

Toxic Shock Syndrome Clostridial infection of the endometrium,

particularly that due to C. sordellii, can develop after gynecologic

procedures, childbirth, or abortion (spontaneous or elective, surgical or medical) and, once established, proceeds rapidly to TSS

and death. Systemic manifestations, including edema, effusions,

profound leukocytosis, and hemoconcentration, are followed by the

rapid onset of hypotension and multiple-organ failure. Elevation of

the hematocrit to 75–80% and leukocytosis of 50,000–200,000 cells/

μL, with a left shift, are characteristic of C. sordellii infection. Pain

may not be a prominent feature, and fever is typically absent. In one

series, 18% of 45 cases of C. sordellii infection were associated with

normal childbirth, 11% with medically induced abortion, and 0.4%

with spontaneous abortion; the case–fatality rate was 100% in these

groups. Of the infections in this series that were not related to gynecologic procedures or childbirth, 22% occurred in injection drug users,

and 50% of these patients died. Other infections followed trauma or

surgery (42%), mostly in healthy persons, and 53% of these patients

died. Overall, the mortality rate was 69% (31 of 45 cases). Of patients

who succumbed, 85% died within 2–6 days after infection onset or

following procedures. Rapidly fatal, spontaneous C. bifermentans

necrotizing endometritis with toxic shock, leukemoid reaction, and

capillary leak has also been described.

Early diagnosis of C. sordellii infections often proves difficult

for several reasons. First, the prevalence of these infections is low.

Second, the initial symptoms are nonspecific and frankly misleading.

Early in the course, the illness resembles any number of infectious

diseases, including viral syndromes. Given these vague symptoms

and an absence of fever, physicians usually do not aggressively pursue

additional diagnostic tests. The absence of local evidence of infection

and the lack of fever make early diagnosis of C. sordellii infection particularly problematic in patients who develop deep-seated infection

following childbirth, therapeutic abortion, gastrointestinal surgery, or

trauma. Such patients are frequently evaluated for pulmonary embolization, gastrointestinal bleeding, pyelonephritis, or cholecystitis.

Unfortunately, such delays in diagnosis increase the risk of death, and,

as in most necrotizing soft tissue infections, patients are hypotensive

with evidence of organ dysfunction by the time local signs and symptoms become apparent. In contrast, infection is more readily suspected

in injection drug users presenting with local swelling, pain, and redness

at injection sites; early recognition probably contributes to the lower

mortality rates in this group.

Physicians should suspect C. sordellii infection in patients who present within 2–7 days after injury, surgery, drug injection, childbirth, or

abortion and who report pain, nausea, vomiting, and diarrhea but are

afebrile. There is little information regarding appropriate treatment for

C. sordellii infections. In fact, the interval between onset of symptoms

and death is often so short that there is little time to initiate empirical

antimicrobial therapy. Indeed, anaerobic cultures of blood and wound

aspirates are time-consuming, and many hospital laboratories do not

routinely perform antimicrobial sensitivity testing on anaerobes. Antibiotic susceptibility data from older studies suggest that C. sordellii,

like most clostridia, is susceptible to β-lactam antibiotics, clindamycin,

tetracycline, and chloramphenicol but is resistant to aminoglycosides

and sulfonamides. Antibiotics that suppress toxin synthesis (e.g., clindamycin) may possibly prove useful as therapeutic adjuncts since they

are effective in necrotizing infections due to other toxin-producing

gram-positive organisms.

Other Clostridial Skin and Soft Tissue Infections Crepitant

cellulitis (also called anaerobic cellulitis) occurs principally in diabetic

patients and characteristically involves subcutaneous tissues or retroperitoneal tissues, whereas the muscle and fascia are not involved. This

infection can progress to fulminant systemic disease.

Cases of C. histolyticum infection with cellulitis, abscess formation, or endocarditis have also been documented in injection drug

users. Endophthalmitis due to C. sordellii or C. perfringens has been

described. C. ramosum is also isolated frequently from clinical specimens, including blood and both intraabdominal and soft tissues. This

species may be resistant to clindamycin and multiple cephalosporins.

■ FURTHER READING

Aldape MJ et al: Clostridium sordellii infection: Epidemiology, clinical

findings, and current perspectives on diagnosis and treatment. Clin

Infect Dis 43:1436, 2006.

Bodey GP et al: Clostridial bacteremia in cancer patients. A 12-year

experience. Cancer 67:1928, 1991.

Bos J et al: Fatal necrotizing colitis following a foodborne outbreak of

enterotoxigenic Clostridium perfringens type A infection. Clin Infect

Dis 40:e78, 2005.

Bryant AE et al: Clostridial gas gangrene II: Phospholipase C–induced

activation of platelet gpIIb/IIIa mediates vascular occlusion and myonecrosis in C. perfringens gas gangrene. J Infect Dis 182:808, 2000.

Leong HN et al: Management of complicated skin and soft tissue

infections with a special focus on the role of newer antibiotics. Infect

Drug Resist 11:1959, 2018.

Marchand-Austin A et al: Antimicrobial susceptibility of clinical

isolates of anaerobic bacteria in Ontario, 2010-2011. Anaerobe

28:120-125, 2014.

Obladen M: Necrotizing enterocolitis—150 years of fruitless search

for the cause. Neonatology 96:203, 2009.

Peetermans M et al: Necrotizing skin and soft-tissue infections in the

intensive care unit. Clin Microbiol Infect 26:8, 2020.

Sayeed S et al: Beta toxin is essential for the intestinal virulence of

Clostridium perfringens type C disease isolate CN3685 in a rabbit ileal

loop model. Mol Microbiol 67:15, 2008.

Stevens DL, Bryant AE: Necrotizing soft tissue infections. N Engl J

Med 377:2253, 2017.

Stevens DL et al: Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious

Diseases Society of America. Clin Infect Dis 59:e10, 2014.

Stevens DL et al: Clostridium, in Manual of Clinical Microbiology,

11th ed, JH Jorgensen et al (eds). Washington, DC, ASM Press, 2015,

pp 940–966.

Wang C et al: Hyperbaric oxygen for treating wounds: A systematic

review of the literature. Arch Surg 138:272, 2003.

Section 6 Diseases Caused by

Gram-Negative Bacteria

155

■ DEFINITION

Infection with Neisseria meningitidis most commonly manifests as

asymptomatic colonization in the nasopharynx of healthy adolescents

and adults. Invasive disease occurs rarely, usually presenting as either

bacterial meningitis or meningococcal septicemia. Patients may also

present with occult bacteremia, pneumonia, septic arthritis, conjunctivitis, and chronic meningococcemia.

■ ETIOLOGY AND MICROBIOLOGY

N. meningitidis is a gram-negative aerobic diplococcus that colonizes

humans only and that causes disease after transmission to a susceptible

individual. Several related neisserial organisms have been recognized,

including the pathogen N. gonorrhoeae and the commensals N. lactamica, N. flavescens, N. mucosa, N. sicca, and N. subflava. N. meningitidis

is a catalase- and oxidase-positive organism that utilizes glucose and

maltose to produce acid.

Meningococcal

Infections

Manish Sadarangani,

Andrew J. Pollard

1226 PART 5 Infectious Diseases

for typing of meningococci are restricted by the limited availability of

serologic reagents that can distinguish among the organisms’ highly

variable surface proteins. Where available, high-throughput antigen

gene sequencing has superseded serology for meningococcal typing. A

large database of antigen gene sequences for the outer-membrane proteins PorA, PorB, FetA, Opa, NadA, Neisserial heparin binding antigen

(NHBA), and factor H–binding protein (fHbp) is available online

(pubmlst.org/organisms/neisseria-spp). The number of specialized

iron-regulated proteins found in the meningococcal outer membrane

(e.g., FetA and transferrin-binding proteins) highlights the organisms’

dependence on iron from human sources. A thin peptidoglycan cell

wall separates the outer membrane from the cytoplasmic membrane.

The structure of meningococcal populations involved in local and

global spread has been studied with multilocus enzyme electrophoresis (MLEE), which characterizes isolates according to differences in the electrophoretic mobility of cytoplasmic enzymes. However,

this technique was replaced by multilocus sequence typing (MLST), in

which meningococci are characterized by sequence types assigned on

the basis of sequences of internal fragments of 7 housekeeping genes.

The online MLST database currently includes more than 15,000 unique

Neisseria sequence types. A limited number of hyperinvasive lineages

of N. meningitidis have been recognized and are responsible for the

majority of cases of invasive meningococcal disease worldwide. Hyperinvasive lineages may be associated with more than one capsular group.

The apparent genetic stability of these meningococcal clones over

decades and during wide geographic spread indicates that they are well

adapted to the nasopharyngeal environment of the host and to efficient

transmission. While MLST has become established as the main method

for meningococcal genotyping in many reference laboratories over the

past 15 years, whole-genome sequencing is gradually replacing this

approach, with more than 4500 genomes already available in the

United Kingdom’s national library.

The group B meningococcal genome is >2 megabases in length and

contains 2158 coding regions. Many genes undergo phase variation

that makes it possible to control their expression; this capacity is likely

to be important in meningococcal adaptation to the host environment

and evasion of the immune response. Meningococci can obtain DNA

from their environment and can acquire new genes—including the

capsular operon—such that capsule switching from one capsular group

to another can occur.

■ EPIDEMIOLOGY

Patterns of Disease Up to 500,000 cases of meningococcal disease

are thought to occur worldwide each year, although the numbers have

been declining recently as a result of both immunization programs and

secular trends. About 10% of affected individuals die. There are several

patterns of disease: epidemic, outbreak (small clusters of cases), hyperendemic, and sporadic or endemic.

Epidemics have continued since the original descriptions of meningococcal disease, especially affecting the sub-Saharan meningitis belt

of Africa, where tens to hundreds of thousands of cases (caused mainly

by capsular group A but also by capsular groups C, W, and X) may

be reported over a season and rates may be as high as 1000 cases per

100,000 population. Capsular group A epidemics took place in Europe

and North America after the First and Second World Wars, and capsular group A outbreaks have been documented over the past 30 years

in New Zealand, China, Nepal, Mongolia, India, Pakistan, Poland, and

Russia. However, 65% of outbreaks reported in the meningitis belt

between 2010 and 2017 were caused by capsular group C and 35% by

capsular group W meningococci, following an immunization campaign to control capsular group A outbreaks.

Clusters of cases occur where there is an opportunity for increased

transmission—i.e., in closed or semi-closed communities such as

schools, colleges, universities, military training centers, and refugee

camps. Recently, such clusters have been especially strongly linked

with a particular clone (sequence type 11) that is mainly associated

with capsular group C or W but was first described in association with

capsular group B. Clusters of capsular group W disease associated with

TABLE 155-1 Structure of the Polysaccharide Capsule of Common

Disease-Causing Meningococci

MENINGOCOCCAL

CAPSULAR GROUP

CHEMICAL STRUCTURE OF

OLIGOSACCHARIDE

CURRENT DISEASE

EPIDEMIOLOGY

A 2-Acetamido-2-deoxyD-mannopyranosyl

phosphate

Epidemic disease mainly in

sub-Saharan Africa; sporadic

cases worldwide

B α-2,8-N-acetylneuraminic

acid

Sporadic cases worldwide;

propensity to cause

hyperendemic disease

C α-2,9-O-acetylneuraminic

acid

Small outbreaks and

sporadic disease

Y 4-O-α-D-glucopyranosylN-acetylneuraminic acid

Sporadic disease and

occasional small institutional

outbreaks

W 4-O-α-D-galactopyranosylN-acetylneuraminic acid

Sporadic disease; outbreaks

of disease associated with

mass gatherings; epidemics

in sub-Saharan Africa

X (α1→4) N-acetyl-Dglucosamine-1-phosphate

Sporadic disease and large

outbreaks in the meningitis

belt of Africa

FIGURE 155-1 Electron micrograph of Neisseria meningitidis. Black dots are

gold-labeled polyclonal antibodies binding surface opacity proteins. Blebs of outer

membrane can be seen being released from the bacterial surface (arrow). (Photo

courtesy of D. Ferguson, Oxford University.)

Meningococci associated with invasive disease are usually encapsulated with polysaccharide, and the antigenic nature of the capsule

determines an organism’s capsular group (serogroup) (Table 155-1).

In total, 12 capsular groups have been identified (A–C, X–Z, E, W,

H–J, and L), but just six of these—A, B, C, X, Y, and W (formerly

W135)—account for the majority of cases of invasive disease. Group

D is often listed as the thirteenth capsular group but has recently been

identified as an unencapsulated variant of group C. Meningococci are

commonly isolated from the nasopharynx in studies of carriage; the

lack of capsule often is a result of phase variation of capsule expression,

but as many as 16% of isolates lack the genes for capsule synthesis and

assembly. These “capsule-null” meningococci and those that express

capsules other than A, B, C, X, Y, and W are only rarely associated with

invasive disease and are most commonly identified in the nasopharynx

of asymptomatic carriers.

Beneath the capsule, meningococci are surrounded by an outer phospholipid membrane containing lipopolysaccharide (LPS, endotoxin)

and multiple outer-membrane proteins (Figs. 155-1 and 155-2). Antigenic variability in porins expressed in the outer membrane defines the

serotype (PorB) and serosubtype (PorA) of the organism, and structural differences in LPS determine the immunotype. Serologic methods

1227CHAPTER 155 Meningococcal Infections

Iron-binding

proteins

e.g., FetA RmpM

LPS NadA PorA

Outer

membrane

Polysaccharide

capsule

Cytoplasmic

membrane

Periplasmic

space

Phospholipid

bilayer

Transporter protein

e.g., FbpA, SodC

Inner membrane

transporter complex

e.g., FbpB, FbpC

Pilus assembly

apparatus

Pilus

Opa PorB fHbp

FIGURE 155-2 Cross-section through surface structures of Neisseria meningitidis. LPS, lipopolysaccharide.

(Reproduced with permission from M Sadarangani, AJ Pollard: Serogroup B meningococcal vaccines–an unfinished

story. Lancet Infect Dis 10:112, 2010.)

the Hajj pilgrimage in 2000/2001 led to a requirement for vaccination

against meningococcal disease for travel to Saudi Arabia. Wider and

more prolonged community outbreaks (hyperendemic disease) due

to single clones of capsular group B meningococci account for ≥10

cases per 100,000. Regions affected in the past decade include the U.S.

Pacific Northwest, New Zealand (both islands), and the province of

Normandy in France.

Most countries now experience predominantly sporadic cases

(0.3–5 cases per 100,000 population), with many different diseasecausing clones involved and usually no clear epidemiologic link

between one case and another. The disease rate and the distribution

of meningococcal strains vary in different regions of the world and

also in any one location over time. For example, in the United States,

the rate of meningococcal disease fell from 1.2 cases per 100,000

population in 1997 to 0.10 cases per 100,000 in 2018 (Fig. 155-3).

Meningococcal disease in the United States was previously dominated

by capsular groups B and C; however, capsular group Y emerged during the 1990s and in 2018 group B was predominant in children age

<5 years, whereas adults 45 years and older were infected with groups

B, C, and Y (Fig. 155-4). In contrast, rates of disease in England and

Wales rose to >5 cases per 100,000 during the 1990s because of an

increase in cases caused by the ST11 capsular group C clone. As a result

of a mass immunization program against capsular group C in 1999,

capsular group B then became predominant. Introduction of a MenB

vaccine since 2015 has led to a significant reduction in group B cases, with an

increase in recent years of capsular group

W infections (Fig. 155-4). Over the last

decade, most industrialized nations have

seen a general decrease in meningococcal disease; this decrease is linked to

immunization against capsular group C

meningococci in Europe, Canada, and

Australia and to adolescent immunization programs for capsular groups A, C,

Y, and W in the United States. However,

other factors, including changes in population immunity and prevalent clones of

meningococci (factors that, in combination, probably explain the cyclic nature

of meningococcal disease rates) as well

as a reduction in smoking and passive

exposure to tobacco smoke (driven by

bans on smoking in buildings and public spaces) across wealthy countries, are

likely to have contributed to the fall in

cases. Over the past decade, a hyperinvasive ST11 clone bearing a W capsule has

emerged in South America and spread to the United Kingdom and has

also emerged in other countries in Europe and in Australia, leading to a

considerable increase in capsular group W cases. Increases in capsular

group Y disease have also been noted in various countries in Europe,

Canada, and South Africa.

Factors Associated with Disease Risk and Susceptibility The

principal determinant of disease susceptibility is age, with the peak

incidence in the first year of life (Fig. 155-5). The susceptibility of the

very young presumably results from an absence of specific adaptive

immunity in combination with very close contact with colonized individuals, including parents. Compared with other age groups, infants

appear to be particularly susceptible to capsular group B disease: >30%

of capsular group B cases in the United States occur during the first

year of life. In the early 1990s in North America, the median ages for

patients with disease due to capsular groups B, C, Y, and W were 6, 17,

24, and 33 years, respectively.

After early childhood, a second peak of disease occurs among adolescents and young adults (15–25 years of age) in Europe and North

America. It is thought that this peak relates to social behaviors and

environmental exposures in this age group, as discussed below. Most

cases of infection with N. meningitidis in developed countries today

are sporadic, and the rarity of the disease suggests that individual susceptibility may be important. A number of factors probably contribute

to individual susceptibility, including the host’s genetic constitution,

environment, and contact with a carrier or a case.

The best-documented genetic association with meningococcal

disease is complement deficiency, chiefly of the terminal complement

components (C5–9), properdin, or factor D; such a deficiency increases

the risk of disease by up to 600-fold and may result in recurrent

attacks. Complement components are believed to be important for the

bactericidal activity of serum, which is considered the principal mechanism of immunity against invasive meningococcal disease. However,

when investigated, complement deficiency is found in only a very

small proportion of individuals with meningococcal disease (0.3%).

Conversely, 7–20% of persons whose disease is caused by the less common capsular groups (W, X, Y, Z, E) have a complement deficiency.

Complement deficiency appears to be associated with capsular group

B disease only rarely. Individuals with recurrences of meningococcal

disease, particularly those caused by non-B capsular groups, should be

assessed for complement deficiency by measurement of total hemolytic

complement activity. There is also limited evidence that hyposplenism

(through reduction in phagocytic capacity) and hypogammaglobulinemia (through absence of specific antibody) increase the risk

of meningococcal disease. Genetic studies have revealed various

Cases per 100,000 population

1997

1.4

1.2

1

0.8

0.6

0.4

0.2

Meningococcal disease rates in ABCs surveillance area

Year

0

1998

1999

2000 2001

2002

2003 2004

2005 2006 2007 2008 200920102011

2012

2013

2014

2015

2016

2017

Other Y C B

FIGURE 155-3 Meningococcal disease in the United States, 1997–2017. ABCs,

active bacterial cores. (Adapted from ABC Surveillance data, Centers for Disease

Control and Prevention; www.cdc.gov.)

1228 PART 5 Infectious Diseases

B,C,Y

B,C

B

B,C

B,C

B,C A,B,C

B,W

A

W,A

B,C

A,W

(X)

A,W,C

FIGURE 155-4 Global distribution of meningococcal capsular groups, 1999–2009. Incidence / 100,000

1

0.8

0.6

0.4

0.2

0

Meningococcal disease by age and capsular group, USA, 2009-2018

<1 year 1-4

years

5-10

years

11-14

years

15-18

years

Age in years

19-22

years

23-26

years

27-64

years

65+

years

B ACYW

FIGURE 155-5 Age distribution of capsular groups B and ACWY meningococcal disease USA, 2009-

2018. (Adapted from www.cdc.gov/meningococcal/surveillance/surveillance-data.html#figure01.)

associations with disease susceptibility, including complement and

mannose-binding lectin deficiency, single-nucleotide polymorphisms

in Toll-like receptor (TLR) 4 and complement factor H, and variants

of Fc gamma receptors.

Factors that increase the chance of a susceptible individual’s acquiring N. meningitidis via the respiratory route also increase the risk of

meningococcal disease. Acquisition occurs through close contact with

carriers as a result of overcrowding (e.g., in poor socioeconomic settings, in refugee camps, during the Hajj pilgrimage to Mecca, during

freshman-year residence in college dormitories) and certain social

behaviors (e.g., attendance at bars and nightclubs, kissing). Secondary

cases may occur in close contacts of an index case (e.g., household

members, persons kissing the infected individual); the risk to these

contacts may be as high as 1000 times the background rate in the

population. Factors that damage the nasopharyngeal epithelium also

increase the risk of both colonization with N. meningitidis and invasive disease. The most important of these factors are tobacco smoking

(odds ratio, 4.1) and passive exposure to tobacco smoke. In addition,

recent viral respiratory tract infection, infection with Mycoplasma

species, and winter or the dry season have been associated with meningococcal disease; all of these factors presumably either increase the

expression of adhesion molecules in the nasopharynx, thus enhancing

meningococcal adhesion, or facilitate meningococcal invasion of the

bloodstream.

■ PATHOGENESIS

N. meningitidis has evolved as an effective colonizer of the human

nasopharynx, with asymptomatic infection rates of >25% described

in some series of adolescents and young adults and among residents

of crowded communities. Point-prevalence studies reveal widely

divergent rates of carriage for different types of meningococci. This

variation suggests that some types may be adapted to a short duration

of carriage with frequent transmission to maintain the population,

while others may be less efficiently transmitted but may overcome this

disadvantage by colonizing for a long period. Despite the high rates

of carriage among adolescents and young adults, only ~10% of adults

carry meningococci, and colonization is very rare in early childhood.

Many of the same factors that increase the risk of meningococcal disease also increase the risk of carriage. Colonization of the nasopharynx

involves a series of interactions of meningococcal adhesins (e.g., Opa

proteins and pili) with their ligands on the epithelial mucosa. N. meningitidis produces an IgA1 protease that is likely to reduce interruption

of colonization by mucosal IgA.

Colonization should be considered the normal state of meningococcal infection, with an increased risk of invasion being the unfortunate consequence (for both host and organism) of

adaptations of hyperinvasive meningococcal lineages.

The meningococcal capsule is an important virulence

factor: acapsular strains only very rarely cause invasive

disease. The capsule provides resistance to phagocytosis

and may be important in preventing desiccation during transmission between hosts. Antigenic diversity in

surface structures and an ability to vary levels of their

expression probably have evolved as important factors

in maintaining meningococcal populations within and

between individual hosts.

Invasion through the mucosa into the bloodstream

occurs rarely, usually within a few days of acquisition

of an invasive strain by a susceptible individual. Only

occasional cases of prolonged colonization prior to

invasion have been documented. Once the organism

1229CHAPTER 155 Meningococcal Infections

is in the bloodstream, its growth may be limited if the individual is

partially immune, although bacteremia may allow seeding of another

site, such as the meninges or the joints. Alternatively, unchecked proliferation may continue, resulting in high bacterial counts in the circulation. During growth, meningococci release blebs of outer membrane

(Fig. 155-1) containing outer-membrane proteins and LPS. Endotoxin binds cell-bound CD14 in association with TLR4 to initiate an

inflammatory cascade with the release of high levels of various mediators, including tumor necrosis factor (TNF) α, soluble TNF receptor,

interleukin (IL) 1, IL-1 receptor antagonist, IL-1β, IL-6, IL-8, IL-10,

plasminogen-activator inhibitor 1 (PAI-1), and leukemia inhibitory

factor. Soluble CD14-bound endotoxin acts as a mediator of endothelial activation. The severity of meningococcal disease is related

both to the levels of endotoxin in the blood and to the magnitude of

the inflammatory response. The latter is determined to some extent

by polymorphisms in the inflammatory response genes (and their

inhibitors), and the release of the inflammatory cascade heralds the

development of meningococcal septicemia (meningococcemia). Endothelial injury is central to many clinical features of meningococcemia,

including increased vascular permeability, pathologic changes in vascular tone, loss of thromboresistance, intravascular coagulation, and

myocardial dysfunction. Endothelial injury leads to increased vascular

permeability (attributed to loss of glycosaminoglycans and endothelial

proteins), with subsequent gross proteinuria. Leakage of fluid and

electrolytes into the tissues from capillaries (“capillary leak syndrome”)

leads to hypovolemia, tissue edema, and pulmonary edema. Initial

compensation results in vasoconstriction and tachycardia, although

cardiac output eventually falls. While resuscitation fluids may restore

circulating volume, tissue edema will continue to increase, and, in the

lung, the consequence may be respiratory failure.

Intravascular thrombosis (caused by activation of procoagulant

pathways in association with upregulation of tissue factor on the

endothelium) occurs in some patients with meningococcal disease and

results in purpura fulminans and infarction of areas of skin or even

of whole limbs. At the same time, multiple anticoagulant pathways

are downregulated through loss of endothelial thrombomodulin and

protein C receptors and decreases in levels of antithrombin III, protein

C, protein S, and tissue factor pathway inhibitor. Thrombolysis is also

profoundly impaired in meningococcal sepsis through the release of

high levels of PAI-1.

Shock in meningococcal septicemia appears to be attributable to

a combination of factors, including hypovolemia, which results from

the capillary leak syndrome secondary to endothelial injury, and

myocardial depression, which is driven by hypovolemia, hypoxia, metabolic derangements (e.g., hypocalcemia), and cytokines (e.g., IL-6).

Decreased perfusion of tissues as a result of intravascular thrombosis,

vasoconstriction, tissue edema, and reduced cardiac output in meningococcal septicemia can cause widespread organ dysfunction, including renal impairment and—later in the disease—a decreased level of

consciousness due to central nervous system involvement.

Bacteria that reach the meninges cause a local inflammatory

response—with release of a spectrum of cytokines similar to that seen

in septicemia—that presents clinically as meningitis and is thought to

determine the severity of neuronal injury. Local endothelial injury may

result in cerebral edema and rapid onset of raised intracranial pressure

in some cases.

■ CLINICAL MANIFESTATIONS

As discussed above, the most common form of infection with N. meningitidis is asymptomatic carriage of the organism in the nasopharynx.

Despite the location of infection in the upper airway, meningococcal

pharyngitis is rarely reported; however, upper respiratory tract symptoms are common prior to presentation with invasive disease. It is

not clear whether these symptoms relate to preceding viral infection

(which may promote meningococcal acquisition and/or invasion)

or to meningococcal acquisition itself. After acquiring the organism, susceptible individuals develop disease manifestations in 1–10

days (usually <4 days, although colonization for 11 weeks has been

documented).

Along the spectrum of presentations of meningococcal disease,

the most common clinical syndromes are meningitis and meningococcal septicemia. In fulminant cases, death may occur within hours

of the first symptoms. Occult bacteremia is also recognized and, if

untreated, progresses in two-thirds of cases to focal infection, including

meningitis or septicemia. Meningococcal disease may also present as

pneumonia, pyogenic arthritis or osteomyelitis, purulent pericarditis, endophthalmitis, conjunctivitis, primary peritonitis, or (rarely)

urethritis. Perhaps because it is difficult to diagnose, meningococcal

pneumonia is not commonly reported but is associated with capsular groups Y, W, and Z and appears most often to affect individuals

>10 years of age.

Rash A nonblanching rash (petechial or purpuric) develops in >80%

of cases of meningococcal disease; however, the rash is often absent

early in the illness. Usually initially blanching in nature (macules, maculopapules, or urticaria) and indistinguishable from more common

viral rashes, the rash of meningococcal infection becomes petechial or

frankly purpuric over the hours after onset. In the most severe cases,

large purpuric lesions develop (purpura fulminans; Fig. A1-41). Some

patients (including those with overwhelming sepsis) may have no rash.

While petechial rash and fever are important signs of meningococcal

disease, fewer than 10% of children (and, in some clinical settings,

fewer than 1% of patients) with this presentation are found to have

meningococcal disease. Most patients presenting with a petechial or

purpuric rash have a viral infection (Table 155-2). The skin lesions

exhibit widespread endothelial necrosis and occlusion of small vessels

in the dermis and subcutaneous tissues, with a neutrophilic infiltrate.

Meningitis Meningococcal meningitis commonly presents as nonspecific manifestations, including fever, vomiting, and (especially in

infants and young children) irritability, and is indistinguishable from

other forms of bacterial meningitis unless there is an associated petechial or purpuric rash, which occurs in two-thirds of cases. Headache

is rarely reported in early childhood but is more common in later childhood and adulthood. When headache is present, the following features,

in association with fever or a history of fever, are suggestive of bacterial

meningitis: neck stiffness, photophobia, decreased level of consciousness, seizures or status epilepticus, and focal neurologic signs. Classic

signs of meningitis, such as neck stiffness and photophobia, are often

absent in infants and young children with bacterial meningitis, who

more usually present with fever and irritability and may have a bulging

fontanelle.

While 30–50% of patients present with a meningitis syndrome

alone, up to 40% of meningitis patients also present with some features

of septicemia. Most deaths from meningococcal meningitis alone (i.e.,

without septicemia) are associated with raised intracranial pressure

presenting as a reduced level of consciousness, relative bradycardia

and hypertension, focal neurologic signs, abnormal posturing, and

signs of brainstem involvement—e.g., unequal, dilated, or poorly reactive pupils; abnormal eye movement; and impaired corneal responses

(Chap. 28).

TABLE 155-2 Common Causes of Petechial or Purpuric Rashes

Enteroviruses

Influenza and other respiratory viruses

Measles virus

Epstein-Barr virus

Cytomegalovirus

Parvovirus

Deficiency of protein C or S (including postvaricella protein S deficiency)

Platelet disorders (e.g., idiopathic thrombocytopenic purpura, drug effects, bone

marrow infiltration)

Henoch-Schönlein purpura, connective tissue disorders, trauma (including

nonaccidental injuries in children)

Pneumococcal, streptococcal, staphylococcal, or gram-negative bacterial

sepsis

1230 PART 5 Infectious Diseases

Septicemia Meningococcal septicemia alone accounts for up to

20% of cases of meningococcal disease. The condition may progress

from early nonspecific symptoms to death within hours. Mortality

rates among children with this syndrome have been high (25–40%),

but early aggressive management (as discussed below) may reduce the

figure to <10%. Early symptoms are nonspecific and suggest an influenza-like illness with fever, headache, and myalgia accompanied by

vomiting and abdominal pain. As discussed above, the rash, if present,

may appear to be viral early in the course until petechiae or purpuric

lesions develop. Purpura fulminans occurs in severe cases (Fig. A1-41),

with multiple large purpuric lesions and signs of peripheral ischemia.

Surveys of patients have indicated that limb pain, pallor (including a

mottled appearance and cyanosis), and cold hands and feet may be

prominent. Shock is manifested by tachycardia, poor peripheral perfusion, tachypnea, and oliguria. Decreased cerebral perfusion leads

to confusion, agitation, or decreased level of consciousness. With

progressive shock, multiorgan failure ensues; hypotension is a late sign

in children, who more commonly present with compensated shock

(tachycardia, poor peripheral perfusion, and normal blood pressure).

Poor outcome is associated with an absence of meningism, hypotension, young age, coma, relatively low temperature (<38°C), leukopenia,

and thrombocytopenia. Spontaneous hemorrhage (pulmonary, gastric,

or cerebral) may result from consumption of coagulation factors and

thrombocytopenia.

Chronic Meningococcemia Chronic meningococcemia, which

is rarely recognized, presents as repeated episodes of petechial rash

(Fig. A1-42) associated with fever, joint pain, features of arthritis, and

splenomegaly that may progress to acute meningococcal septicemia if

untreated. During the relapsing course, bacteremia characteristically

clears without treatment and then recurs. The differential diagnosis

includes bacterial endocarditis, acute rheumatic fever, Henoch-Schönlein purpura, infectious mononucleosis, disseminated gonococcal

infection, and immune-mediated vasculitis. This condition has been

associated with complement deficiencies in some cases and with inadequate sulfonamide therapy in others.

A study from the Netherlands found that half of isolates from

patients with chronic meningococcemia had an underacylated

lipid A (part of the surface LPS molecule) due to an lpxL1 gene

mutation, which markedly reduces the inflammatory response to

endotoxin.

Postmeningococcal Reactive Disease In a small proportion

of patients, an immune complex disease develops ~4–10 days after

the onset of meningococcal disease, with manifestations that include

a maculopapular or vasculitic rash (2% of cases), arthritis (up to 8%

of cases), iritis (1%), pericarditis, and/or polyserositis associated with

fever. The immune complexes involve meningococcal polysaccharide

antigen and result in immunoglobulin and complement deposition

with an inflammatory infiltrate. These features resolve spontaneously

without sequelae. It is important to recognize this condition since a

new onset of fever and rash, and/or arthritis, can lead to concerns

about relapse of meningococcal disease and unnecessarily prolonged

antibiotic treatment.

■ DIAGNOSIS

Like other invasive bacterial infections, meningococcal disease may

produce elevations of the white blood cell (WBC) count and of values

for inflammatory markers (e.g., C-reactive protein and procalcitonin

levels or the erythrocyte sedimentation rate). Values may be normal or

low in rapidly progressive disease, and a lack of rise in these laboratory

test values does not exclude the diagnosis. However, in the presence

of fever and a petechial rash, these elevations are suggestive of meningococcal disease. In patients with severe meningococcal septicemia,

common laboratory findings include hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia,

and coagulopathy.

Although meningococcal disease is often diagnosed on clinical

grounds, in suspected meningococcal meningitis or meningococcemia,

blood should routinely be sent for culture to confirm the diagnosis and

to facilitate public health investigations; blood cultures are positive in

up to 75% of cases. Culture media containing sodium polyanethol sulfonate, which may inhibit meningococcal growth, should be avoided.

Meningococcal viability is reduced if there is a delay in transport of the

specimen to the microbiology laboratory for culture or in plating of

cerebrospinal fluid (CSF) samples. In countries where treatment with

antibiotics before hospitalization is recommended for meningococcal

disease, the majority of clinically suspected cases are culture negative.

Real-time polymerase chain reaction (PCR) analysis of whole-blood

samples increases the diagnostic yield by >40%, and results obtained

with this method may remain positive for several days after administration of antibiotics. Indeed, in the United Kingdom, more than half of

clinically suspected cases are currently identified by PCR.

Unless contraindications exist (raised intracranial pressure, uncorrected shock, disordered coagulation, thrombocytopenia, respiratory

insufficiency, local infection, ongoing convulsions), lumbar puncture

should be undertaken to identify and confirm the etiology of suspected

meningococcal meningitis, whose presentation cannot be distinguished

from that of meningitis of other bacterial causes. Some authorities have

recommended a CT brain scan prior to lumbar puncture because of the

risk of cerebral herniation in patients with raised intracranial pressure.

However, a normal CT scan is not uncommon in the presence of raised

intracranial pressure in meningococcal meningitis, and the decision to

perform a lumbar puncture should be made on clinical grounds. CSF

features of meningococcal meningitis (elevated protein level and WBC

count, decreased glucose level) are indistinguishable from those of

other types of bacterial meningitis unless a gram-negative diplococcus

is identified. (Gram’s staining is up to 80% sensitive for meningococcal

meningitis.) CSF should be submitted for culture (sensitivity, 90%) and

(where available) PCR analysis. CSF antigen testing with latex agglutination is insensitive and should be replaced by molecular diagnosis

when possible.

Lumbar puncture should generally be avoided in meningococcal

septicemia, as positioning for the procedure may critically compromise

the patient’s circulation in the context of hypovolemic shock. Delayed

lumbar puncture may still be useful when the diagnosis is uncertain,

particularly if molecular diagnostic technology is available.

In other types of focal infection, culture and PCR analysis of normally sterile body fluids (e.g., synovial fluid) may aid in the diagnosis.

Although some authorities have recommended cultures of scrapings or

aspirates from skin lesions, this procedure adds little to the diagnostic

yield when compared with a combination of blood culture and PCR

analysis. Urinary antigen testing also is insensitive, and serologic testing

for meningococcal infection has not been adequately studied. Because

N. meningitidis is a component of the normal human nasopharyngeal

flora, identification of the organism on throat swabs has limited diagnostic value, but strains identified in the nasopharynx in the context of

a probable case are likely to be those responsible for disease.

TREATMENT

Meningococcal Infections

Death from meningococcal disease is associated most commonly

with hypovolemic shock (meningococcemia) and occasionally with

raised intracranial pressure (meningococcal meningitis). Therefore,

management should focus on the treatment of these urgent clinical

issues in addition to the administration of specific antibiotic therapy. Delayed recognition of meningococcal disease or its associated

physiologic derangements, together with inadequate emergency

management, is associated with poor outcome. Since the disease

is rare, protocols for emergency management have been developed

(see www.meningitis.org).

Airway patency may be compromised if the level of consciousness is depressed as a result of shock (impaired cerebral perfusion)

or raised intracranial pressure; this situation may require intervention. In meningococcemia, pulmonary edema and pulmonary

oligemia (presenting as hypoxia) require oxygen therapy or elective endotracheal intubation. In cases with shock, aggressive fluid