Infections caused by Neisseria species are among the most frequently encountered and potentially dangerous diseases. The two major species of concern are N. meningitidis and N. gonorrhoeae. Both are gram-negative cocci that reside primarily in polymorphonuclear white blood cells and tend to cluster in pairs [see Figure 1]. No nonhuman reservoir exists for either organism. Although there is some overlap in the clinical syndromes these two species elicit, they are commonly known for distinctly different presentations.
Infections Caused by Neisseria meningitidis
The most clinically relevant classification scheme for N. meningitidis utilizes the organism’s capsular polysaccharides and includes at least 13 serogroups. The most common of these are A, B, C, X, Y, L, and W135.1 In addition to serogroup, the organism can be classified by class 1 outer-membrane proteins (OMP) (serosubtype), class 2 or 3 OMP (serotype), and lipo-oligosaccharide (immunotype).
Invasive disease caused by N. meningitidis is a significant source of morbidity and mortality worldwide. Important trends include increased recognition of the Y serogroup’s role in outbreaks, consideration of college freshmen as candidates for vaccination, and the relative increase of N. meningitidis as a pathogen in children as the success of immunization against Haemophilus influenzae type b is increasingly realized.
Epidemiology and transmission
N. meningitidis is most commonly found in the setting of asymptomatic nasopharyngeal carriage. The prevalence of na-sopharyngeal colonization in the United States is estimated at 5% to 10%.2 Duration of colonization varies from transient (days) to as long as 2 years, with a median of 9 to 10 months. Development of humoral immunity to the colonizing strain of the organism is common and may last at least 4 to 6 months after exposure.
Transmission results from direct transfer of respiratory or oral secretions and requires prolonged intimate contact. Consequently, habitation in very close quarters (e.g., military barracks, correctional facilities, and college dormitories) can facilitate colonization, the prevalence of which can reach 20% to 40% during outbreaks.3 Facilitation of transmission within close quarters is also reflected by seasonal patterns in invasive infection. Although disease occurs year-round, the incidence peaks in late winter and early spring. Transmission has also been documented through prolonged exposure to an infected person on an airplane and in laboratory technicians working with isolates on open laboratory benches.4,5
Despite longstanding availability of antibiotics and meningo-coccal vaccine, most areas of the world continue to have stable rates of endemic disease. After Streptococcus pneumoniae, N. meningitidis is the most common cause of bacterial meningitis worldwide, causing an estimated 25% of cases.6 In the United States, laboratory-based surveillance for invasive meningococ-cal disease from 1992 to 1996 revealed an average annual incidence of 1.1 cases per 100,000 population (approximately 2,454 cases a year).2,6,7 Incidence was highest in infants younger than 1 year, with a rate of 15.9/100,000 for children 4 to 5 months of age. The serogroup associated with the most cases of invasive disease was serogroup C (35%); however, significant geographic variation was seen, and the incidence of disease from serogroup Y increased during the study period.7 For reasons that are unclear, rates of invasive meningococcal disease in the United States are higher in blacks than in nonblacks.
The risk of invasive meningococcal infection in college students has been summarized by the Centers for Disease Control and Prevention (CDC),8 which initiated surveillance in this group in 1998. Whereas the incidence in undergraduates overall was lower than that in persons 18 to 23 years of age who were not enrolled in college, rates were relatively high in the approximately 590,000 freshmen who lived in dormitories (4.6/100,000).
Sporadic outbreaks of invasive meningococcal disease also continue to occur in sub-Saharan Africa, in an area extending from Senegal in the west to Ethiopia in the east, known as the meningitis belt. Outbreaks caused primarily by serogroup A occur there during the dry season, from December to June. However, serogroups B and C have caused large epidemics elsewhere, including the United States.
Pathogenesis and immunity
The cascade of events from exposure to colonization and from invasion to specific manifestations of clinical disease is complex. Most persons who develop invasive meningococcal disease do so after recent colonization.1 Concomitant upper respiratory viral infection, cigarette smoking, underlying chronic illness, and preceding Mycoplasma infection may facilitate meningococcal infection and colonization. Colonization requires attachment to nonciliated columnar mucosal cells of the nasopharynx. Meningococci secrete proteases that cleave IgA, which may disable a major mucosal defense mechanism; how this mechanism contributes to pathogenesis is unclear, however. Endocytosis and intracellular transport of meningococci-laden vacuoles mediate the organisms’ passage to the submucosa.
Figure 1 Gram stain of urethral secretions showing abundant N. gonorrhoeae as gram-negative diplococci within polymorphonuclear cells.
Immunity to meningococcus involves interactions at the nasopharyngeal mucosa, innate immune mechanisms, and acquired antibody.9,10 The importance of antibody is highlighted by several findings. Natural immunity is acquired after, and boosted by, meningococcal colonization of the nasopharynx. Immunity correlates with bactericidal antibody levels in serum, and the age-specific attack rate of meningococcal disease is reciprocally related to the presence of serogroup-specific antibod-ies.9 Further, hypogammaglobulinemia is a risk factor for invasive disease. In military recruits, risk of disease is highest in the absence of bactericidal activity against the prevalent pathogenic strain.11 Specific antibody directly binds the meningococcus and activates complement-mediated phagocytosis.
Both pathways of the complement system—classic and alternative—appear critical in controlling meningococcal infection.9 Persons with deficiencies in the terminal complement system (C5, C6, C7, C8, or C9) develop antibody to meningo-cocci, but the rates of meningococcal infection in these individuals are 1,400-fold to 10,000-fold higher than in the general population.12 Approximately 50% of affected persons have at least one episode of meningococcal infection, and 20% to 25% have more than one episode. Of note, infections in persons with complement deficiency often involve unusual serogroups and are less severe. Persons with deficiencies of properdin (an alternative-pathway component) or factor D are also at increased risk for meningococcal disease, with a case-fatality rate of over 50%. Recurrent meningococcal disease should prompt screening for complement deficiencies,13 which involves testing the serum for hemolytic whole-complement activity.
Coagulopathy and microvascular thrombosis are hallmarks of meningococcal sepsis. The most visible manifestation of these processes is purpura fulminans [see Figure 2]. Dysfunction of the activation pathway of protein C appears to play a key role in these thrombotic events. When activated by its binding to thrombomodulin and the endothelial protein C receptor, protein C normally functions to keep thrombin’s proco-agulant properties in check. In children with purpuric lesions from meningococcal sepsis, endothelial protein C activation is impaired.14
Clinical presentations
Meningococcal Bacteremia
Meningococcal bacteremia occurs across a spectrum of clinical presentations, ranging from an acute fulminant disease that is fatal within hours to asymptomatic infection. The presence of N. meningitidis in the blood is usually associated with severe illness. However, bacteremia may occasionally be found in persons who appear healthy or who have only mild systemic symptoms (usually fever and, sometimes, upper respiratory symptoms or rash resembling a viral exanthem).
Symptoms associated with so-called benign bacteremia usually resolve before the infection is identified by isolation of meningococcus from blood cultures. This syndrome differs from the so-called chronic meningococcemia associated with low-grade fever, rash, and polyarticular arthritis that can be confused with disseminated gonococcal infection (DGI).
The rash of chronic meningococcemia usually takes the form of a nonspecific maculopapular eruption, but it may be pe-techial. Unlike persons who experience recurrent meningococ-cal meningitis (see below), patients with chronic meningococ-cemia appear immunologically normal and are usually infected with typical serogroups. N. meningitidis should be considered in the evaluation of any patient with a chronic arthritis-dermatitis syndrome.
The most notorious presentations of meningococcal disease take two forms: meningococcemia and meningococcal sepsis. The two forms may occur simultaneously.
The term meningococcemia usually denotes bacteremia accompanied by signs of sepsis and frequently by the classic pur-puric or petechial rash typical of this syndrome, which occurs in 75% of patients with this disease [see Figure 2]. Although the rash of purpura fulminans is obvious, patients presenting early in the course of disease may have more subtle abnormalities of the skin and mucous membranes. These abnormalities include palpebral and conjunctival petechiae and lesions in areas subject to physical pressure, such as the waist and soles of the feet. Because these findings can herald the development of fullblown meningococcemia, they should be carefully sought in persons in whom this illness is a consideration; so that a thorough examination can be performed, the patient should be examined without clothes. Affected patients may also complain of intense, diffuse myalgias in the initial period of their illness. Evolution of individual petechiae to coalescence and eventual frank ecchymosis proceeds apace with the progression of the thrombocytopenia of disseminated intravascular coagulation (DIC).
Meningococcal sepsis is characterized by a rapid progression from general, nonspecific complaints that may resemble a viral illness to hypotension, multiorgan failure, and DIC. Despite the availability of antibiotics and advances in critical care, meningococcal sepsis still carries a mortality of up to 40%.2 Concomitant adrenal hemorrhage, known as the Waterhouse-Friderichsen syndrome, may also occur. Myocarditis has been noted on histopathologic examination in more than 70% of patients with fatal meningococcemia.15,16 Meningococcemia may also precipitate pericarditis, sometimes to the point of tampon-ade. The formation of arterial thrombi can result in peripheral gangrene.
Meningitis
Acute meningococcal meningitis results from hematogenous dissemination of the organism and is usually accompanied by classic signs of bacterial meningeal inflammation: fever, headache, and nuchal rigidity. Other findings typical of meningitis may occur, including photophobia, nausea, vomiting, focal neurologic signs, seizures, and progression to obtundation and coma.17 From 50% to 75% of patients have a petechial rash suggestive of meningococcemia.18 The cerebrospinal fluid is typically purulent, with numerous polymorphonuclear neutrophils (PMNs), low glucose (< 50 mg/dl, present in 75% of cases), and an elevated protein concentration. In contrast, the uncommon syndrome of recurrent meningococcal meningitis produces less severe clinical and CSF findings.
Bacteremic Pneumonia
Bacteremic pneumonia from N. meningitidis constituted 3% of cases of invasive meningococcal disease reported by Schuchat6 in 1997 and may be more commonly associated with serogroup Y isolates. However, meningococcal pneumonia probably occurs more frequently than is indicated by detection through positive blood cultures, and this disease has occurred in outbreaks. In a well-described outbreak involving 68 military recruits, most of the individuals had fever, rales, and pharyngitis.19 Although disease was multilobar in 40% of the patients, no deaths occurred. Diagnosis by sputum culture is problematic, given the potential confounding effect of upper airway colonization. Instead, most patients are diagnosed either at bronchoscopy or, if they have systemic infection, with positive cultures at nonpulmonary sites.
Figure 2 (a) The rash of purpura fulminans, seen here with petechiae as well as larger, coalescent hemorrhagic lesions, in a patient with meningococcal sepsis and meningitis caused by serogroup B. (b) Closer view of petechiae, some of which have coalesced into purpuric and intracutaneous hemorrhagic lesions.
Other Meningococcal Infections
Uncommonly, N. meningitidis can cause syndromes for which N. gonorrhoeae is well known, including urethritis in men and cervicitis in women. One proposed mechanism of meningococcal genital infection is acquisition through orogen-ital sex, which may transmit nasopharyngeal colonizers to genital sites.20 These syndromes respond well to the antibiotics typically used for gonococcal genital infections (see below).21 Sex partners should be treated, but no further chemoprophylaxis (e.g., treatment of household contacts) is indicated.
Cases of N. meningitidis infecting numerous other body sites have been reported, including endocarditis, cellulitis, conjunctivitis, otitis media, epiglottitis, and arthritis.
Diagnosis
N. meningitidis is a fastidious aerobic organism that grows best on chocolate agar and is distinguished from N. gonorrhoeae by its ability to ferment both maltose and glucose. The bacteria can be isolated from blood in approximately 75% of persons with invasive meningococcal disease and from the CSF in approximately 46% to 94% of persons with meningitis.17 Sepsis occurs in an estimated 5% to 20% of persons with positive blood cultures. Gram stain of CSF remains a very useful means of detecting the meningococcus; however, its sensitivity is probably no higher than 50% to 70% and, like that of culture, is reduced by recent antibiotic use. Detection assays for polysaccharide antigens using countercurrent immunoelectrophoresis or latex agglutination are frequently applied to CSF. Their advantages include rapid turnaround time, high specificity, and ability to individuate serogroups. Their major disadvantage is relatively low sensitivity (meaning that false negatives occur), particularly if serogroup B is responsible; in addition, they are not reliable when used to detect antigen in urine or serum. The poly-merase chain reaction (PCR) has been successfully applied to the detection of N. meningitidis, especially in the United Kingdom, but is not commercially available in the United States.24 Of note, the isolation of meningococci from upper respiratory secretions does not itself indicate meningococcal disease.
Complications and prognosis
Meningococcal sepsis confers a mortality of up to 40%, and 11% to 19% of survivors suffer sequelae, including hearing loss, neurologic disability, and amputation because of peripheral gangrene.25 The case-fatality rate for all invasive meningococcal disease is estimated to be 11%, and it is significantly higher in the presence of bacteremia (17%) than with meningitis alone (3%). Mortality from N. meningitidis is most profound in children: in developed countries, invasive meningococcal disease is the leading cause of death in this age group. Among 295 adolescents and young adults with invasive meningococcal disease in Maryland during the 1990s, 22.5% of those 15 through 24 years of age died.26 Clearly, this disease continues to present a major challenge to physicians, communities, and the public health system.
Differential diagnosis
In its earliest stage, the presentation of invasive meningococ-cal disease can be nonspecific, resembling a typical viral illness with fever and myalgias. Appearance of a rash should prompt consideration of common viral etiologies, including the en-teroviruses. The presence of severe systemic illness should bring to mind Rocky Mountain spotted fever (RMSF), vasculi-tides (polyarteritis nodosa, Churg-Strauss syndrome, and ana-phylactoid [Henoch-Schonlein] purpura), and toxic shock syndromes associated with staphylococcal, streptococcal, and, less commonly, clostridial infections. Less common infections that can present in similar fashion include epidemic typhus, infections caused by Streptobacillus moniliformis and Spirillum minus (rat-bite fever), gonococcemia, septicemia caused by H. influen-zae type b, typhoid fever, and acute S. aureus endocarditis. Key pieces of information can help narrow the differential diagnosis. Tick-borne diseases such as RMSF usually occur within specific geographic confines and are generally associated with outdoor exposure to animal or insect vectors during the temperate months, principally in summer. Travel history is important in consideration of typhoid fever, as is information regarding the host’s general immune status.
Table 1 Chemoprophylaxis for Meningococcal Disease1
|
Drug |
Dosage |
Relative Efficacy |
Comments |
|
Rifampin |
Children < 1 mo: 5 mg/kg p.o., q. 12 hr for 2 days Children a 1 mo: 10 mg/kg p.o., q. 12 hr for 2 days Adults: 600 mg q. 12 hr for 2 days |
First choice |
Not recommended for pregnant women, because it is teratogenic in animals; because reliability of oral contraceptives may be affected by rifampin, alternative contraceptive measures should be considered during its administration |
|
Ciprofloxacin |
Adults: 500 mg p.o. once |
Alternative |
Not generally recommended for persons < 18 yr or for pregnant and lactating women, because it causes cartilage damage in immature laboratory animals; however, ciprofloxacin has been used extensively in children with cystic fibrosis without reported adverse outcomes; CDC recommends it for chemoprophylaxis in children when no acceptable alternative is available |
|
Ceftriaxone |
Children < 15 yr: 125 mg I.M. once Adults: 250 mg I.M. once |
Alternative |
Indicated for pregnant women |
Treatment
Emergency Management
Infected patients should be isolated and droplet precautions observed until effective antimicrobial therapy has been given for at least 24 hours.27 Antibiotic therapy should be started as soon as possible. Earlier initiation of antibiotics has been demonstrated to favorably affect outcome in some, though not all, studies,28 but the disease is frequently so severe that reasonable measures to impact its early course should be undertaken.
Penicillin has constituted the mainstay of antibiotic therapy of meningococcal disease for several decades. Although |-lac-tamase-producing strains with high-level resistance (minimum inhibitory concentration [MIC] > 250 ^g/ml) exist, and strains with altered penicillin-binding proteins and intermediate resistance (MIC, 0.1 to 1.0 ^g/ml) have been isolated clinically, treatment failures with penicillin have not been report-ed.29 Similarly, isolates with high-level resistance to chloramphenicol have been reported outside the United States. Given these data, meningococcal isolates from blood and CSF should be routinely evaluated for penicillin susceptibility at a reference laboratory.
Antibiotic Therapy
Until the presence of meningococcus is confirmed, the patient should receive empirical treatment for bacterial meningitis [see 7:XXXVI Bacterial Infections of the CSF]. Once N. meningi-tidis is identified in the CSF or blood, monotherapy with penicillin G (300,000 U/kg/day I.V., up to 24 million U/day) or ceftriaxone (50 mg/kg/day, up to 2 g) may be used. For persons who cannot tolerate penicillins or cephalosporins, chlor-amphenicol is an option; however, hematologic toxicity remains a concern. These antibiotics provide adequate CSF penetration, especially in the presence of meningeal inflammation. Treatment for 10 to 14 days is commonly recommended.29 Although fluoroquinolones provide excellent activity against N. meningitidis and achieve very good CSF levels, their role in the treatment of invasive meningococcal disease requires further study.
Adjunctive Therapy
Adjunctive therapy of meningococcal infection with corticosteroids has been a subject of intense debate. Steroid therapy has not been shown to improve outcomes associated with meningococcal disease and is therefore not recommended. Another strategy under pursuit is repletion of activated protein C, which is severely depleted in severe meningococcemia.30 One small open-label study showed that compared with predicted outcomes, there were reductions in morbidity and mortality from severe meningococcemia in patients treated with activated protein C.31 In a large, randomized, placebo-controlled study of patients with sepsis, recombinant protein C reduced mortality but also increased bleeding events.32 None of the patients in this study had sepsis from N. meningitidis. However, protein C depletion appears to be more severe in meningococ-cal disease than in related conditions that commonly cause sepsis, suggesting that further study is warranted. Recombinant protein C is commercially available, and its use in patients with sepsis from N. meningitidis should be considered.
