Meningococcal disease, first described by Vieusseaux in 1805 as epidemic cerebrospinal fever, remains a significant health problem, particularly in the developing world. Although nasopharyngeal colonization rarely leads to disseminated disease, the fulminant, rapidly fatal course of a child with meningococcemia is not soon forgotten.
ETIOLOGY.
Neisseria meningitidis is a gram-negative diplococcus (0.6 ´0.8 mm) that is often described as biscuit shaped. It is a common commensal organism of the human nasopharynx and has not been isolated from animal or environmental sources. The meningococcus is fastidious, and growth is facilitated in a moist environment at 35–37º C in an atmosphere of 5–10% carbon dioxide. It grows well on several enriched media, including supplemented chocolate agar, Mueller-Hinton agar, blood agar base, and trypticase soy agar. On solid media, colonies are transparent, nonpigmented, and nonhemolytic. N. meningitidis is identified by its ability to ferment glucose and maltose to acid and its inability to ferment sucrose or lactose. Indole and hydrogen sulfide are not formed. The cell wall contains cytochrome oxidase, which results in the positive oxidase test result.
The meningococci have been divided into serogroups based on antigenic differences in their capsular polysaccharides. At least 13 serogroups have been identified, but groups A, B, C, W, and Y account for most meningococcal disease. The other serogroups often colonize the nasopharynx but rarely disseminate. Lipooligosaccharides (e.g., endotoxin) and proteins found in the outer membrane complex are also used to serotype meningococcal strains.
EPIDEMIOLOGY.
Meningococcal dissemination occurs as endemic disease punctuated by outbreaks of cases that are often clustered geographically. True epidemics have become rare in developed countries but remain a significant problem in much of the developing world. Endemic disease appears to be caused by a heterogeneous group of meningococcal serotypes, and epidemics are caused by a single serotype. Analysis with multilocus enzyme genetic methods has confirmed that a meningococcal epidemic is caused by strains derived from a single clonotype.
The Centers for Disease Control (CDC) reported the results of a laboratory-based surveillance for meningococcal disease in a large United States United States
Meningococcal disease, particularly group A, remains a major health problem in much of the developing world. Many areas, such as China and Africa , have an endemic rate of disease of 10–25 per 100,000 persons and major periodic epidemics (100–500 cases/100,000). Epidemic disease typically involves individuals who are older than those with endemic disease.
PATHOGENESIS.
N. meningitidis is thought to be acquired by a respiratory route. Colonization of the nasopharynx with meningococci usually leads to asymptomatic carriage, and only rarely does dissemination occur. Colonization can persist for weeks to months. Carriage rates vary from 2–30% in a normal population during nonepidemic periods but are higher among children in day-care centers and in conditions of crowding. The carriage rate can approach 100% in a closed population during an epidemic.
For colonization to take place, meningococci must evade mucosal IgA and adhere to epithelial cells in the nasopharynx. This is facilitated by the secretion of proteases that cleave the proline-rich hinge region of IgA and render it nonfunctional. Meningococci and gonococci produce this enzyme, but nonpathogenic Neisseria organisms do not. Meningococci then bind selectively to nonciliated epithelial cells. Pili appear to be of major importance in the attachment of meningococci to the human nasopharynx. The bacteria enter nonciliated epithelial cells by a parasite-directed endocytotic process and are carried across the cell in membrane-bound vacuoles.
Meningococci disseminate from the upper respiratory tract through the bloodstream. Serum antibody leading to complement-mediated bacterial lysis has been shown to block this dissemination, and a deficiency of antimeningococcal antibody is associated with the development of meningococcemia. Bactericidal antibody is directed against the capsular polysaccharide, subcapsular protein, and lipooligosaccharide antigens. Newborn infants have protective antibody that is primarily IgG of maternal origin. As this antibody wanes,infants 3–24 mo of age experience the highest incidence of meningococcal disease. By adulthood, most individuals have developed natural immunity against N. meningitidis.
The source of this immunity comes from nasopharyngeal colonization with N. meningitidis and colonization of the gastrointestinal tract with enteric bacteria that express cross-reactive antigens. Infants have a high carriage rate of an unencapsulated, nonpathogenic neisserial strain, N. lactamica, that leads to the development of bactericidal antibody against the meningococcus.
The importance of the complement system in host defense against N. meningitidis is underscored by the fact that individuals with primary or acquired complement deficiency have an increased risk of developing meningococcal disease, and 50–60% of individuals with properdin, factor D, or terminal-component deficiencies develop bacterial infections that are caused almost solely by N. meningitidis. Recurrent infection is common with terminal component deficiencies but is uncommon with properdin deficiency. Acquired complement deficiency also carries an increased risk and can be seen with systemic diseases that deplete serum complement. Examples are systemic lupus erythematosus, nephrotic syndrome, multiple myeloma, and hepatic failure.
The group B capsule is a homopolymer of sialic acid, which is known to inhibit alternative complement pathway activation. Antibody that activates the classic pathway can overcome this inhibition. The lack of specific antibody coupled with the inhibition of the alternative pathway may explain the prevalence of serogroup B meningococcal disease in young children.
PATHOLOGY. Disseminated meningococcal disease is associated with an acute inflammatory response. Hemorrhage and necrosis may be seen in any organ system and appears to be mediated by intravascular coagulation with deposition of fibrin in small vessels. The major organ systems involved in fatal cases of meningococcemia are the heart, central nervous system, skin, mucous and serous membranes, and adrenals. Myocarditis is found in more than 50% of patients who die of meningococcal disease. Cutaneous hemorrhages, ranging from petechiae to purpura, occur in most fatal infections and are associated with acute vasculitis with fibrin deposition in arterioles and capillaries. Diffuse adrenal hemorrhage may occur in patients with fulminant meningococcemia (i.e., Waterhouse-Friderichsen syndrome). Meningitis is characterized by acute inflammatory cells in the leptomeninges and perivascular spaces. Focal cerebral involvement is uncommon.
The interaction of endotoxin released by N. meningitidis and the complement system probably is key in the pathogenesis of the clinical manifestations of meningococcal disease. Complement activation correlates with the concentration of meningococcal lipooligosaccharide in the plasma. The concentration of circulating endotoxin is directly correlated with activation of the fibrinolytic system, development of disseminated intravascular coagulopathy, multiple organ system failure, septic shock, and death. The level of endotoxemia correlates with the concentration of circulating cytokines, which are released from endotoxin-stimulated monocytes and macrophages. The concentrations of tumor necrosis factor-a and interleukins have been directly associated with fatal meningococcal disease.
CLINICAL MANIFESTATIONS. The spectrum of meningococcal disease can vary widely, from fever and occult bacteremia to sepsis, shock, and death. Recognized patterns of disease are bacteremia without sepsis, meningococcemic sepsis without meningitis, meningitis with or without meningococcemia, meningoencephalitis, and infection of specific organs.
A well-recognized entity is occult bacteremia in a febrile child. Upper respiratory or gastrointestinal symptoms or a maculopapular rash can be evident. The child often is sent home on no antibiotics or oral antibiotics for a minor infection. Spontaneous recovery without antibiotics has been reported, but some children have developed meningitis.
Acute meningococcemia can mimic a viral-like illness with pharyngitis, fever, myalgias, weakness, and headache. With widespread hematogenous dissemination, the disease rapidly progresses to septic shock characterized by hypotension, disseminated intravascular coagulation, acidosis, adrenal hemorrhage, renal failure, myocardial failure, and coma. Meningitis may or may not develop. Concomitant pneumonia, myocarditis, purulent pericarditis, and septic arthritis have been described. More often, meningococcal disease manifests as acute meningitis that responds to appropriate antibiotics and supportive therapy. Seizures and focal neurologic signs occur less frequently than in patients with meningitis caused by the pneumococcus or Haemophilus. Rarely, meningoencephalitis can occur with diffuse brain involvement.
Typical rash in typical meningococcemia
rash in purpura (meningococcemia) fulminans
Infant with meningococcal endophthalmitis
Meningeal pose in meningitis
Nuchal rigidity (stiff neck) and positive upper Brudzinsky’s sign
Positive Kernig’s and lower Brudzinsky’s sign
A review of 100 children with invasive meningococcal disease revealed that 71% presented with fever, 4% with hypothermia, and 42% with shock. Skin lesions occurred in 71% of the cases with petechiae and/or purpura, and in 49% with both. Purpura fulminans developed in 16%. Other rashes described were maculopapular, pustular, and bullous lesions. Additional presenting symptoms and signs were irritability in 21%, lethargy in 30%, and emesis in 34%. Diarrhea, cough, rhinorrhea, seizure, and arthritis occurred much less frequently (6–10%). Leukopenia and low platelet counts affected 21% and 14%, respectively, and the white blood cell counts ranged from 0.9 to 46/mm3 ´{times} 103. N. meningitidis was isolated in blood culture from 48% of the children, and meningitis was diagnosed in 55%. Six children had meningococci isolated from CSF in the absence of CSF pleocytosis, hypoglycorrhachia, or organisms detected by Gram stain. Five of eight children who presented with arthritis had N. meningitidis isolated from joint aspiration fluid. Eight per cent of the children had radiographic evidence of pneumonia on presentation.
Uncommon manifestations of meningococcal disease include endocarditis, purulent pericarditis, septic arthritis, endophthalmitis, mesenteric adenitis, and osteomyelitis. Primary purulent conjunctivitis can lead to invasive disease. Sinusitis, otitis media, and periorbital cellulitis also can be caused by the meningococcus. Primary meningococcal pneumonia is a recognized clinical entity that is associated with pleural effusions or empyema in 15% of cases. N. meningitidis is a rare isolate of the genitourinary tract in asymptomatic or symptomatic individuals and has been the causal organism in urethritis, cervicitis, vaginitis, and proctitis.
Chronic meningococcemia is a rare manifestation of meningococcal disease that can occur in children and adults. It is characterized by fever, nontoxic appearance, arthralgias, headache, and rash. The rash resembles that of disseminated gonococcal infection. Symptoms are intermittent, with the rash often appearing with fever. The mean duration of illness is 6–8 wk. Blood cultures may initially be sterile. Without specific therapy, complications such as meningitis can result.
DIAGNOSIS.
Definitive diagnosis of meningococcal disease is made by the isolation of the organism from a usually sterile body fluid such as blood, CSF, or synovial fluid. Isolation of meningococci from the nasopharynx is not diagnostic for disseminated disease. Blood and CSF are the usual sources of organism isolation. The blood culture yields N. meningitidis in about one half of the cases of disseminated disease, and culture or Gram stain usually reveal the organism in those with meningitis. Culture or Gram stain of petechial or papular lesions has been variably successful in identifying meningococci. Occasionally, bacteria can be seen on Gram stain of the buffy coat layer of a spun blood sample.
In meningitis, the morphologic and clinical characteristics of CSF are those of acute bacterial meningitis. CSF cultures can be positive in patients with meningococcemia but without clinical evidence of meningitis or CSF pleocytosis. CSF cultures may be negative if the lumbar puncture has been performed early in the course of disease or if the patient has received previous antibiotic treatment.
lumbar puncture
CSF in meningococcal meningitis
Techniques of counterimmunoelectrophoresis and latex agglutination detect meningococcal capsular polysaccharide in CSF, serum, joint fluid, and urine. False-negative results occur, and specificity may be limited when organisms with cross-reactive antigens are involved, such as Escherichia coli K1, which cross reacts with the group B meningococcus. Antisera and monoclonal antibodies can be used to identify different serogroups of meningococci. These studies are useful early in infection and if the patient has received antibiotics, rendering cultures sterile.
Ancillary data may support a systemic bacterial infection and includes elevated sedimentation rate and C-reactive protein, leukocytopenia or leukocytosis, thrombocytopenia, proteinuria, and hematuria. Patients with disseminated intravascular coagulation may have decreased serum concentrations of prothrombin and fibrinogen. Screening for complement deficiency is recommended for individuals diagnosed with meningococcal disease. In one series of 20 patients with a first episode of meningococcal meningitis, meningococcemia, or meningococcal pericarditis, three had a deficiency of a terminal-pathway component and three had deficiencies of multiple complement components associated with underlying systemic diseases.
DIFFERENTIAL DIAGNOSIS. This includes acute bacterial or viral meningitis, mycoplasma infection, leptospirosis, syphilis, acute hemorrhagic encephalitis, encephalopathies, serum sickness, collagen vascular diseases, Henoch-Schö{umlaut-o}nlein purpura, hemolytic uremic syndrome, and ingestion of various poisons. The petechial or purpuric rash of meningococcemia is similar to that noted in any patient with a disease characterized by generalized vasculitis. These diseases include septicemia due to many gram-negative organisms; overwhelming septicemia with gram-positive organisms; bacterial endocarditis; Rocky Mountain spotted fever; epidemic typhus; Ehrlichia canis infection; infections with echoviruses, particularly types 6, 9, and 16; coxsackievirus infections, predominantly of types A2, A4, A9, and A16; rubella; rubeola and atypical rubeola; Henoch-Schönlein purpura; Kawasaki disease; idiopathic thrombocytopenia; and erythema multiforme or erythema nodosum due to drugs or infectious or noninfectious disease processes. The morbilliform rash occasionally observed may be confused with any macular or maculopapular viral exanthem.
COMPLICATIONS.
Acute complications are related to the inflammatory changes, vasculitis, disseminated intravascular coagulation, and hypotension of invasive meningococcal disease. These can include adrenal hemorrhage, arthritis, myocarditis, pneumonia, lung abscess, peritonitis, and renal infarcts. The vasculitis can lead to skin loss with secondary infection, tissue necrosis, and gangrene. Skin sloughing can necessitate the use of skin grafts. Bone involvement can lead to growth disturbance and late skeletal deformities secondary to epiphyseal avascular necrosis and epiphyseal-metaphyseal defects. Limb amputation has been reported for patients with purpura fulminans.
adrenal hemorrhage (Waterhouse-Frederikson syndrome)
Gangrene in a patient with purpura fulminans
Meningitis rarely is complicated by subdural effusion or empyema or by brain abscess. Deafness is the most frequent neurologic sequelae, but the reported incidence varies from 0–38%. Other rare sequelae include ataxia, seizures, blindness, cranial nerve palsies, hemiparesis or quadriparesis, and obstructive hydrocephalus.
subdural effusion
obstructive hydrocephalus
The late complications of meningococcal disease are thought to be immune complex–mediated and become apparent 4–9 days after the onset of illness. The usual manifestations are arthritis and cutaneous vasculitis. The arthritis is usually monoarticular or oligoarticular. Effusions are usually sterile and respond to nonsteroidal anti-inflammatory agents. Permanent joint deformity is uncommon. Because most patients with meningococcal meningitis are afebrile by the 7th hospital day, the persistence or recrudescence of fever after 5 days of antibiotics warrants an evaluation for immune complex-mediated complications.
PREVENTION.
Close contacts of patients with meningococcal disease are at increased risk of infection and should be carefully monitored and brought to medical attention if fever develops. Prophylaxis is indicated as soon as possible for household, day-care, and nursery school contacts. Prophylaxis is also recommended for persons who have had contact with patients' oral secretions. Prophylaxis is not routinely recommended for medical personnel except those with intimate exposure, such as with mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy was begun. Rifampin is given (10 mg/kg; maximum dose, 600 mg) orally every 12 hr for 2 days (total of four doses). The dose is reduced to 5 mg/kg for very young infants. If the isolate is known to be sensitive to sulfonamides, suflisoxazole prophylaxis is preferred. Penicillin does not eradicate nasopharyngeal carriage, and patients with meningococcal disease should receive rifampin before discharge.
A quadrivalent vaccine composed of capsular polysaccharide of meningococcal groups A, C, Y, and W-135 is licensed in the United States United States
Immunization is useful to control outbreaks of meningococcal disease of the serogroups represented in the quadravalent vaccine. It is also recommended for travelers to countries with a high incidence of meningococcal disease. Immunization of close contacts of individuals with A, C, Y, or W disease should be considered, because it has been useful in the prevention of secondary cases. Individuals with anatomic or functional asplenia and those with complement component deficiencies should be immunized.
Polysaccharide-protein conjugate vaccines are being developed for the prevention of meningococcal disease, and subcapsular proteins and detoxified lipooligosaccharides are being investigated as possible vaccines.
TREATMENT.
Aqueous penicillin G is the drug of choice and should be given in doses of 250,000 to 300,000 U/kg/24 hr, administered intravenously in six divided doses. Chloramphenicol sodium succinate (75–100 mg/kg/24 hr, intravenously in four divided doses) provides effective treatment for patients who are allergic to penicillin. Cefotaxime (200/mg/24 hr) and ceftriaxone (100 mg/kg/24 hr) are effective empirical therapy for meningococcal disease and may be useful in patients who are allergic to penicillin. Therapy is continued for 7 days.
Isolates of N. meningitidis have been reported from Spain, South Africa, and Canada as being relatively resistant to penicillin, defined as having a minimal inhibitory concentration of penicillin of 0.1–1.0 m{mu}g/mL. Moderate resistance is caused, at least in part, by altered penicillin-binding protein 2. High-level resistance due to b-lactamase production has been reported from South Africa 1991 in the United States
PROGNOSIS.
Despite the use of appropriate antibiotics, the mortality rate for disseminated meningococcal disease remains at 8–12% in the United States
Main :
References:
1. Current therapy in pediatric infectious diseases – 2 edited by John D. Nelson, M. D. – B.C. Decker inc. Toronto, Philadelphia, 1988, - P. 134-138, 285.
2. Ambulatory pediatric care (edited by Robert A. Derchewitz; - 2 nd ed. – Lippincot – Raven, 1992. – P. 570-574; 255.
3. Principles and Practice of Pediatric Infectious Diseases. / Edited by Saran S. Long, Larry K. Pickering, Charles G. Prober, Philadelphia , Pa
Additional:
1. Textbook of Pediatric Nursing. Dorothy R. Marlow; R. N., Ed. D. –London
2. Pediatrics ( 2nd edition, editor – Paul H.Dworkin, M.D.) – 1992. – 550 pp.
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