One of the most serious and life-threatening infectious diseases during childhood is bacteremia; a consequence of which is septic shock where inadequate perfusion of tissues occur due to endotoxemia. Neisseria meningitidis (Meningococcus) is an important bacterial infection manifesting as meningitis or septicemia, or more often a combination of both. Asymptomatic pharyngeal colonization is the initial step of infection with humans being the natural reservoirs. From the nasopharynx, the coccus reaches the meninges translocating across the nasopharyngeal mucosa and along the perineural sheath of the olfactory nerve, through the cribriform plate of the ethmoid. Bloodstream spread to the meninges will cause meningitis. In some children, the predominant feature is cardiovascular collapse leading to septic shock.
Transmission occurs by respiratory droplets and requires close direct contact. Children younger than 5 years do not have adequate immunity against the polysaccharide antigens of N. meningitidis. The risk factors for infectious disease in child care facilities include immunologic susceptibility, lack of awareness and practice of good hygiene, a natural tendency to intimacy, frequent oral contact with objects in the environment.
The invasive meningococcal disease is seen in 2 age groups: infants who are vulnerable due to disappearance in the early life of the maternal antibodies and adolescents with a high rate of colonization of the nasopharynx.
N. meningitidis is a gram-negative coccus, in pairs with adjacent sides flattened. It is non-motile, aerobic, and facultative anaerobic. It produces catalase and is oxidase positive. It produces acid from glucose and maltose. Fresh isolates require enriched media like blood or chocolate agar. Incubation in a humidified 10% carbon dioxide (CO2) environment enhances growth.
Virulence factors include the polysaccharide capsule which enhances invasiveness by inhibiting phagocytosis and enhancing organism survival during bloodstream and central nervous system (CNS) invasion. Pili mediate attachment, colonization, and invasion of the organisms to the mucosal cells of the nasopharynx. Antigenic variation of pili by a cassette mechanism allows the bacterium to escape the host's immune system.
Outer Membrane Proteins
Porin proteins can insert themselves into membranes of target cells, and phagolysosomes can induce apoptosis. OPC protein functions in mucosal adherence and invasion of endothelial cells. IgA1 protease hydrolyzes IgA1 molecules at the hinge regions. The enzyme inactivates IgA1 at mucosal surfaces, enabling initial attachment and subsequent invasion. Pathogenic Neisseria survives and multiplies by their ability to extract iron from high-affinity iron-binding proteins. N. meningitidis can acquire penicillin resistance from commensal Neisseria species in the nasopharynx through DNA fragments by transformation. Meningococcus also exhibit a phase variation of surface antigens, thus evading the host immune response.
The capsular polysaccharides are antigenic and form the basis of serogroups. Twelve serogroups are A, B, C, H, I, K, L, X, Y, Z, W-135, and 29F. Serogroups A, B, C, W-135, X, and Y are the most common causes of invasive disease worldwide.
Invasive infections caused by N. meningitidis are reported through the National Notifiable surveillance system in the United States. The number of cases reported to the Centers for Disease Control and Prevention (CDC) in 2013 and 2014 was 556 and 564, respectively. These are the lowest numbers reported in the United States.
In 2014, the overall incidence of invasive meningococcal disease for the United States was 0.14/100,000 population. Of the cases reported, 25% of cases were bacteremia with a fatality of 20%. The serogroup distribution was 26% serogroup B, 36% serogroup C, 9% serogroup Y, and 28% other serogroups. In the United States, serogroup B is responsible for 65% of infant disease, and serogroups C and Y are responsible for adolescent disease. Among the unvaccinated, outbreaks are due to serogroup C.
Meningococcal disease in the United States peaks during the months of November through March. A progressive increase in the protective antibodies against meningococci is seen between 2 and 12 years. Passive in utero IgG antibodies transfer occurs in neonates if the mother has the anti-meningococcal antibody.
In developing countries, the incidence rate of invasive meningococcal disease is 10 to 25 per 100,000 inhabitants per year. The highest rate of 10 to 1000 per 100,000 per year is seen in a belt across sub-Saharan Africa, termed the meningitis belt, with recurrent epidemics of group A. Death occurs in 6% to 10% of cases and complications in 4.3 to 11.2% of cases. Group A was predominant during 2007 through 2009, while serogroup W135 predominated in 2010 through 2011. In 2013 and 2014, 2 outbreaks of meningococcal serogroup C, a strain relatively rare in Africa, occurred in Nigeria and Kebbi.
International outbreaks of N. meningitidis infections occurred in 1987 and 2000 associated with the Hajj pilgrimage to Mecca. 1987 outbreak was due to serogroup A and 2000 outbreak due to serogroup W-135. Serogroup W has emerged in other regions, including South America and England. In European countries, invasive serogroup C disease has declined and serogroup B is causing 60% to 72% of cases of invasive disease. In Asia, large epidemics caused by serogroup A occurred historically in China, India, Nepal and Russia, more recently serogroup B and C emerged as the cause in this area.
An increase in the serogroup Y has been reported in the Nordic European countries.
The primary cause of cardiovascular collapse from sepsis is a peripheral circulatory failure. Cardiac dysfunction due to myocardial failure plays a prominent role in meningococcal disease. Higher endotoxin (LOS) concentrations were associated with shock, renal failure, and respiratory distress. High concentrations of IL-6 and IL-8 are seen in those with meningococcal shock.
TNF and IL-1 activate endothelial cells by increasing their permeability and adhesiveness for white cells. Overproduction of nitric oxide lowers arterial pressure due to vasodilation. It also impairs cardiac contractility.
Endothelial cell retraction on interaction with bacterial endothelial cells leads to a loss of integrity causing capillary hemorrhages and formation of thrombi in purpuric lesions. When a large number of bacteria colonize the blood vessels and leads to the corresponding signaling, this is responsible for the extensive purpuric lesions and severity of shock in Purpura fulminans.
Histology of skin lesions shows endothelial necrosis of capillaries and small veins in the dermis and subcutaneous tissue. Neutrophil infiltration and occlusion of vessels with WBCs, platelets, fibrin thrombi, and hemorrhage are seen. Meningococci are seen within the endothelium and thrombi.
The disease spectrum caused by N. meningitidis ranges from asymptomatic carriage to death due to fulminant meningococcemia. Meningococcal meningitis and septicemia are the common syndromes reported although both clinical pictures present in some cases.
The signs and symptoms of meningococcemia include an early upper respiratory tract infection with coryza, pharyngitis, tonsillitis, and laryngitis. Patients are febrile with a headache, vomiting, and lethargy. Typically, patients with meningococcemia have a fever and hemorrhagic rash, followed by signs of severe circulatory collapse. Purpura and shock often develop within hours. Diffuse mottling to extensive purpuric lesions are the skin manifestations. Petechiae or purpura are seen in 50% to 60% of patients. Twenty percent to 30% of children may not have a rash on presentation.
Chronic meningococcemia is defined as meningococcal septicemia with fever for at least a week before antibiotic therapy and with no meningeal symptoms. In chronic meningococcemia, bacteria are never found by biopsy or culture of skin lesions. Researchers postulate that the skin changes and arthritis may result from antigen-antibody complexes. The diagnosis is established by identifying the organism in blood cultures. Recovery is prompt following antibiotic therapy.
Diagnosis should be clinically made, and broad-spectrum antibiotic therapy started with pending organism identification.
Cerebrospinal fluid (CSF) in meningitis shows gram-negative intracellular and extracellular diplococci.
Hematologic and Metabolic Abnormalities
In meningococcal meningitis, CSF, WBC count, peripheral blood leucocyte count and C-reactive protein, procalcitonin, and ESR are elevated. CSF has raised protein, low glucose, and gram-negative Diplococcus.
Third-generation cephalosporin-ceftriaxone or cefotaxime are used for initial therapy.
Recommended duration of therapy is 7 days for both meningitis and meningococcemia.
Adjunctive and Experimental Therapies
Corticosteroid therapy: Replacement doses (25 mg/m3 hydrocortisone 4 times) daily is useful in children with refractory shock associated with impaired adrenal gland response.
Monovalent capsular group C meningococcal conjugate vaccines (MenC) are used in Europe, Australia, and Canada for routine immunization of infants and toddlers. They are highly effective; although a booster at adolescence is advocated.
Quadrivalent meningococcal A, C, Y, W conjugate vaccines (Men ACYW) are used for adolescent immunization in North America. It is being used as a vaccine for high-risk groups and travelers in many countries. It is also replacing Men C as an adolescent booster outside the United States.
Booster doses of Men ACYW are advocated in the United States for high-risk children and person immunized at younger than 15 years of age. Capsular group B outer membrane vesicle (OMV) vaccines are used for outbreaks involving single clones.
Two capsular group B vaccines (Men B-4C, 2 doses, and Men B-FHbp, 3 doses) are licensed for people older than 10 years of age. In the United States, it is recommended for at-risk patients and outbreaks and can be given at 16 to 23 years of age at clinical discretion.
Chemoprophylaxis for Contacts of Patients of Meningococcal Disease
Rifampin: 10 mg/kg per dose; Orally every 12 hours for 4 doses (for infants younger than 1 month of age, 5 mg/kg per dose)
Ceftriaxone: Single injection of 125 mg for less than 15 years and 250 mg for older than 15 years*
Ciprofloxacin: 20 mg/kg (max 500 mg) older than 1 month of age*
* From American Academy of Pediatrics Committee on Infectious Disease. Red book 2015 Report of the Committee on Infectious Diseases, 30th edition. Elk Grove, IL, American Academy of Pediatrics 2015.
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