Antigenic Structure At least 13 serogroups of meningococci have been identified by immunologic specificity of capsular polysaccharides. The six most important serogroups associated with disease in humans, worldwide, are A, B, C, X, Y, and W-135. In contrast to the other capsular serogroups in which the capsule is composed of sialic acid moieties, the group A polysaccharide is a polymer of N-acetyl-mannosamine-1-phosphate. Incorporation of human sialic acid derivatives such as NANA into the meningococcal capsules allows the organism to be overlooked by the host immune system (often referred to as “molecular mimicry”). Meningococcal antigens are found in blood and cerebrospinal fluid of patients with active disease.

The outer membrane of N. meningitidis consists of proteins and LPS that play major roles in organism virulence. There are two porin proteins (Por A and Por B) that are important in controlling nutrient diffusion into the organism and also interact with host cells. These porins have been tar gets of interest in vaccine development. The opacity proteins (Opa) are comparable to Opa of the gonococci and play a role in attachment. Meningococci are piliated and these structures initiate binding to nasopharyngeal epithelial cells and other host cells such as endothelium and erythrocytes. The lipid A disaccharide of meningococcal LPS is responsible for many of the toxic effects found in meningococcal disease. The highest levels of endotoxin measured in sepsis have been found in patients with meningococcemia (50- to 100-fold greater than with other Gram-negative infections). Collectively, these structures and proteins are responsible for the devastating clinical features so characteristic of meningococcal infections.

Pathogenesis, Pathology, and Clinical Findings

 Humans are the only natural hosts for whom meningococci are pathogenic. The nasopharynx is the portal of entry. There, the organisms attach to epithelial cells with the aid of pili; they may form part of the transient microbiota without producing symptoms and/or disease. Invasive meningococcal diasease (IMD) occurs in only a small number of individuals who acquired the organism and are transient carriers; infants and adolescents have the highest incidence of IMD in developed countries. From the nasopharynx, organisms may reach the bloodstream, producing meningococcal bacteremia; the initial symptoms during this stage of the actual infection may be similar to those of an upper respiratory tract, “flu-like” infection, but IMD quickly ensues. IMD typically presents as meningitis, sepsis (ie, meningococcemia), or as a combination of both. Meningitis is the most common complication of menigococcal bacteremia. It usually begins suddenly with an intense headache, vomiting, photophobia, confusion, and stiff neck; it may progresses to coma within a few hours. Fulminant meningococcemia is more severe, presenting with a high fever and a hemorrhagic rash; the patient may also develop disseminated intravascular coagulation and ultimate circulatory collapse with bilateral hemorrhagic necrosis of the adrenal glands with subsequent adrenal failure (Waterhouse-Friderichsen syndrome).

During meningococcemia, there is thrombosis of many small blood vessels in many organs, with perivascular infiltration and petechial hemorrhages. There may be interstitial myocarditis, arthritis, and skin lesions. In meningitis, the meninges are acutely inflamed, with thrombosis of blood vessels and exudation of polymorphonuclear leukocytes, so that the surface of the brain is covered with a thick purulent exudate.

The exact mechanisms that transform an asymptomatic colonization of the nasopharynx into meningococcal bacteremia, subsequently leading to meningococcemia and meningitis, are not very well understood; however, the invasion of the bloodstream can be prevented by specific bactericidal serum antibodies against the infecting serotype. Neisseria bacteremia is favored by the absence of bactericidal antibody (IgM and IgG), inhibition of serum bactericidal action by a blocking IgA antibody, or a complement component deficiency (C5, C6, C7, or C8). Meningococci are readily phagocytosed in the presence of a specific opsonin.

Diagnostic Laboratory Tests

A. Specimens

 The typical specimens for isolation of N. meningitides include blood for culture and cerebrospinal fluid (CSF) for smear and culture. Puncture material or biopsies from petechiae may be taken for smear and culture. Nasopharyngeal swab cultures are suitable for carrier surveys.

 B. Smears

 Gram-stained smears of the sediment of centrifuged spinal fluid or of petechial aspirate often show typical neisseriae within polymorphonuclear leukocytes or extracellularly.

 C. Culture

Although neisseriae are inhibited by certain toxic factors present in media and polyanethole sulfonate (anticoagulant) present in commercial blood culture broths, this seems to be of a lesser problem for the ability to recover N. meningitis from blood cultures, compared to N. gonorrhoeae. CSF specimens are plated on sheep blood agar and chocolate agar and then incubated at 37°C in an atmosphere of 5% CO₂ . A MTM agar favors the growth of neisseriae, inhibits many other bacteria, and is used for nasopharyngeal cultures. Colonies of N. meningitidis are gray, convex, and glistening, with entire edges; a positive oxidase test together with a Gram-stain showing Gram-negative diplococci provides presumptive organism identification. Spinal fluid and blood generally typically yield pure cultures that can be further identified by carbohydrate oxidative reactions (see Table 1) and subsequent agglutination with type-specific or polyvalent serum.

Table1. Biochemical Reactions of the Neisseriae and M. catarrhalis

 D. Serology

Antibodies to meningococcal polysaccharides can be measured by latex agglutination or hemagglutination tests or by their bactericidal activity. These tests are only performed in reference laboratories.

 Immunity

Immunity to meningococcal infection is associated with the presence of specific, complement-dependent, bactericidal antibodies in the serum. These antibodies develop after subclinical infections with different strains or injection of antigens and are group specific, type specific, or both. The immunizing antigens for groups A, C, Y, and W-135 are the capsular polysaccharides. For group B, two vaccines, 4CMenB (Bexsero®) and Trumenba are licensed by the US FDA for use in the United States. Currently, there are three vaccines against serogroups A, C, Y, and W-135 and one that contains only C and Y available in the United States. A polysaccharide tetra valent vaccine (Menomune®, Sanofi Pasteur) in which each dose consists of four purified bacterial capsular polysaccharides is poorly immunogenic in children younger than age 18 months, does not confer long-lasting immunity, and does not cause a sustainable reduction in nasopharyngeal carriage. This is approved as a single dose for individuals ≥2 years. A tetravalent conjugate vaccine approved in 2005 (Menactra™, Sanofi Pasteur) is licensed for use in persons 9 months to 55 years of age. It contains capsular polysaccharide conjugated to diphtheria toxoid. In children aged 9–23 months, two doses are required. Menveo (Novartis) is another tetravalent con jugate vaccine in which A, C, Y, and W135 oligosaccharide is conjugated to diphtheria CRM197. This vaccine is approved for use in individuals 2–55 years of age. The Hib-MenCy-TT conjugate vaccine (GlaxoSmithKline) is a four-dose series vac cine approved for children 6 weeks to 18 months old. A quadrivalent meningococcal vaccine in which tetanus toxoid is the conjugate protein (MenACWY-tt; Nimenrix®) is available in Europe. The advantage of the conjugate vaccines is that a T cell-dependent response to vaccine is induced. This enhances primary response among infants and substantially reduces asymptomatic carriage.

Routine vaccination of all young adolescents (ages 11–12 years) before high school with a booster dose at age 16 years using an approved conjugate vaccine is now recommended. Vaccination is also recommended for persons 2 months of age or older who are among the following at-risk groups: persons with functional or surgical asplenia, and persons with complement deficiencies. Persons aged 9 months or older who are travelers to or residents of highly endemic areas (eg, sub-Saharan Africa), “closed populations” such as college freshman living in dorms and military personnel, populations experiencing a community outbreak, and clinical laboratory workers (microbiologists) are other at-risk groups who should routinely be vaccinated.

Treatment

Penicillin G is the drug of choice for treating patients with meningococcal disease. Either chloramphenicol or a third generation cephalosporin such as cefotaxime or ceftriaxone is used in persons who are allergic to penicillins.

Epidemiology, Prevention, and Control

Meningococcal meningitis occurs in epidemic waves (eg, in military encampments, in religious pilgrims, and in sub-Saharan Africa, the so-called “meningitis belt”); and a smaller number of sporadic interepidemic cases. Outbreaks and sporadic cases in the Western hemisphere in the past decade have been caused mainly by groups B, C, W-135, and Y; outbreaks in southern Finland and São Paulo, Brazil, were caused by groups B and C; outbreaks in New Zealand have been caused by a particular B strain; and those in Africa were mainly caused by group A. Group C and, especially, group A are associated with epidemic disease.

Serogroup A is responsible for the majority of outbreaks in sub-Saharan Africa, whereas serogroup B is most often the cause of sporadic infections. About 5–30% of the normal population may harbor meningococci (often nontypeable isolates) in the nasopharynx during interepidemic periods. During epidemics, the carrier rate goes up to 70–80%. A rise in the number of cases is preceded by an increased number of respiratory carriers. Treatment with penicillin or other antibiotics does not eradicate the carrier state. Chemoprophylaxis for household and other close contacts following exposure to an index case is recommended, using rifampin, 600 mg orally for adults, 5 mg/kg for children <1 month, or 10 mg/kg for children 1 month or older twice daily for 2 days. Ciprofloxacin in adults, 500 mg as a single dose, and ceftriaxone in children <15 15 years, 125 mg IM as a single dose, are alternative agents. While clinical cases of meningitis present only a negligible source of infection, and isolation of individual patients therefore has only limited usefulness; however, droplet and standard precautions for the first 24 hours of antimicrobial therapy are recommended by the CDC. Prevention of meningococcal disease has focused on enhancing immunity through administration of vaccines in an at risk population as discussed; another approach is the reduction of personal contacts in a population with a high carrier rate. This can be accomplished by avoidance of crowding.

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مواضيع ذات صلة

Actinomyces

The Brucellae

Diagnostic Laboratory Tests of Bordetella pertussis

Chlamydia psittaci

Laboratory Diagnosis of Chlamydia trachomatis

Spectrum of Disease of Chlamydia trachomatis

Epidemiology and Pathogenesis of Chlamydia trachomatis

Antigenic Structure, Pathogenesis, and Pathology of Bordetella pertussis

Haemophilus influenzae

Campylobacter jejuni

Conventional Phenotypic Tests for Mycobacterial Infections

Genetic Sequencing and Nucleic Acid Amplification for Mycobacterial Infections