OVERVIEW: What every practitioner needs to know
Are you sure your patient has meningococcal infection? What are the typical findings for this disease?
Neisseria meningitidis (NMn), the cause of meningococcal infection, colonizes the upper respiratory tract of approximately 10% of the population; the prevalence of carriage increases with age throughout childhood and adolescence. The most common clinical findings associated with invasive meningococcal infection are fever, chills, malaise and rash. The rash begins as macules, maculopapules, or urticaria, but petechiae and purpura develop rapidly.
Meningitis is the most common focal complication of meningococcemia. Symptoms may include headache, photophobia, neck stiffness, and vomiting. Meningitis due to NMn is accompanied by seizures in approximately 20% of patients. Meningococcal meningitis may develop without or prior to development of rash.
Meningococcal septicemia may progress rapidly to fulminant disease, leading to shock, coagulopathy, purpura, limb ischemia, and pulmonary edema. The mortality rate is approximately 10%. Less common manifestations of meningococcal septicemia include pneumonia, septic arthritis, osteomyelitis, purulent pericarditis, peritonitis, conjunctivitis, and endophalmitis.
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What other disease/condition shares some of these symptoms?
Fever and lethargy may be associated with infection caused by many bacteria and viruses. Septicemia due to other Gram negative bacteria, Streptococcus pneumoniae, group A streptococcus, and Staphylococcus aureus, and Haemophilus influenzae may lead to hypotension, prostration, and focal complications similar to those caused by NMn.
Fever and petechial rash are common presentations of many childhood infections, including those due to enterovirus, parvovirus B19, Epstein-Barr virus, influenza and other respiratory tract viruses, and cytomegalovirus. Rickettsial infection, especially Rocky Mountain spotted fever, characteristically manifests with fever, headache, and petechial or purpuric rash, predominantly on the extremities, including palms and soles.
Rat-bite fever, caused by Streptobacillus moniliformisor Spirillum minus, causes fever, chills, muscle pain, headache, and vomiting, and is associated with a maculopapular or petechial rash, predominantly on the extremities, including the palms and soles. Henoch-Schonlein purpura, collagen vascular disorders, idiopathic thrombocytopenic purpura and other coagulation abnormalities, and drug reactions are other conditions that may present with petechial or purpuric rash, with or without fever.
The signs and symptoms of meningitis due to NMn cannot be distinguished from those due to other causes of infectious meningitis, particularly in the absence of the typical petechial or purpuric rash.
What caused this disease to develop at this time?
NMn is transmitted from asymptomatic carriers to non-immune individuals via respiratory droplets. Close contact, such as occurs in households, is required. Susceptibility to infection occurs when there is a lack of bactericidal antibody to the relevant strain, and absence or deficiency of the terminal components of complement (C5-C9) or properdin increases the risk of that invasive disease will develop even in the presence of specific antibody. Natural immunity develops as a result of asymptomatic colonization or of colonization with other organisms that provoke cross-reacting antibody.
Epidemiologic factors that increase risk of developing invasive infection include age less than 1 year or 14-25 years, crowding, exposure to tobacco smoke, preceding viral respiratory infection, especially influenza, and being a household contact of an individual with meningococcal disease.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Culture of the blood and CSF prior to initiation of antibiotics are the most likely to provide a definitive diagnosis. Blood cultures are positive in 40% to 75% of untreated patients, and CSF results are positive in 90%. Taken together, blood culture and culture and Gram stain of CSF yields a positive identification in 94%. Culture and Gram stain of other apparently affected, usually sterile body sites, such as pleural or pericardial fluid or synovial fluid may also be positive. Scraping of petechial or purpuric lesions are sometimes positive by Gram stain and may be helpful if antibiotic therapy has been initiated prior to the diagnostic evaluation.
CSF should be sent for cell count, protein, and glucose analysis in addition to culture and Gram stain. Elevated CSF WBC count, elevated CSF protein, and reduced CSF protein are indicative of bacterial meningitis.
Because of the importance of treating NMn disease as quickly as possible, prompt initiation of antibiotics is recommended in patients with suspected meningococcal disease, even if appropriate diagnostic samples cannot be obtained prior to their initiation. In these situations, however, prior antibiotic therapy reduces the likelihood of a positive blood culture to approximately 10% and of a positive CSF culture to approximately 50% in patients with meningitis. Antigen detection methods have been used to detect the organism treated patients, but these assays lack both specificity and sensitivity.
Polymerase chain reaction testing to detect serogroup specific NMn is available in Great Britain and in research and public health laboratories in the United States. This test has proven useful in patients who have received antibiotics before samples are obtained.
Laboratory testing to detect metabolic derangements, such as hypoglycemia, electrolyte abnormalities, and coagulopathies are indicated in children suspected of NMn septicemia and/or meningitis. CBC may demonstrate anemia and either leukocytosis or leukopenia.
Would imaging studies be helpful? If so, which ones?
Appropriate diagnostic imaging should be determined based on the clinical presentation and course. For patients presenting with seizure and/or coma, computed tomography (CT) of the brain may be indicated, both to exclude trauma, hemorrhage, and other non-infectious causes, and to exclude cerebral edema in anticipation of planned lumbar puncture. Chest radiograph (x-ray) may be indicated if pulmonary edema or pneumonia is suspected.
Confirming the diagnosis
N/A
If you are able to confirm that the patient has meningococcal infection, what treatment should be initiated?
Treatment of a child with suspected invasive meningococcal infection should not await the results of diagnostic testing. Because the differential diagnosis includes other invasive bacteria, including S. pneumoniae, S. aureus, group A streptococcus, Gram negative enteric organisms, and, in the unimmunized or immunodeficient child, H. influenzae, broad spectrum antibiotics should be initiated promptly.
Antibiotic therapy should include a third generation cephalosporin, usually ceftriaxone (100 mg/kg every 12-24hours), and vancomycin (60 mg/kg/day administered every 6 hours). If NMn infection is confirmed, penicillin G (250,000-300,000 units/kg/day [maximum 12 million units] divided every 4-6 hours) should be administered and other antibiotics may be discontinued. NMn with reduced susceptibility to penicillin have been found in some parts of the United States and Canada, as well as in Spain, Italy, and parts of Africa. Isolates with moderate susceptibility (0.12 micrograms/mL to1.0 micrograms/mL) may be successfully treated with recommended doses of penicillin. Isolates with higher level resistance are rare.
Ceftriaxone (100 mg/kg/day, maximum 4 g/day, divided every 12-24 hours) or cefotaxime (200 mg/kg/day, maximum 8 g/day, divided every 6 hours) are alternate and equally effective options for treatment of invasive NMn disease, including meningitis.
Appropriate antimicrobial therapy should be continued for 7 days for patients with meningitis, septicemia, or both. There are no data supporting the need for longer therapy, and a shorter course (4-5 days) is recommended by some authors. Appropriate duration of therapy for other sites of infection, including osteomyelitis, septic arthritis, pericarditis, or pneumonia, has not been established but should be at least until clinical symptoms have resolved.
There are no studies in pediatric patients to support use of adjunctive therapies such as activated protein C or recombinant bactericidal permeability-increasing protein (rBPI) in children with invasive NMn disease. Corticosteroid therapy is often used in children with shock presumed to be a result of impaired adrenal gland function due to meningococcemia, but no controlled pediatric studies support its use for prevention of neurologic sequelae due to meningococcal meningitis.
Volume resuscitation and administration of inotropic agents are critical components of resuscitation and management in children with fulminant meningococcal infection, and increased intracranial pressure should be reduced in the setting of a pediatric intensive care unit. Identification and correction of coagulopathies are also critical aspects of management, and intubation and mechanical ventilation may be necessary for some patients.
What are the adverse effects associated with each treatment option?
Allergic reaction manifest by rash and/or fever may occur in patients treated with antibiotics. Diarrhea is a common side effect, particularly during treatment with third generation cephalosporins. Aggressive volume resuscitation may result in fluid overload and pulmonary edema. Management of increased intracranial pressure may require placement of a monitoring device and the risk of bacterial infection.
What are the possible outcomes of meningococcal infection?
Overall case fatality rate for patients with invasive meningococcal infection is 10%. The majority of patients who are diagnosed and managed promptly and appropriately survive without sequelae, but complications may include ischemic damage to limbs resulting in disability or need for amputation and neurologic sequelae, including hearing loss and neurologic disability. Tissue gangrene and ischemia of digits and limbs are all potential complications of fulminant shock. Hearing loss, motor dysfunction, and other neurologic deficits occur in approximately 5% of pediatric survivors of meningococcal meningitis, considerably lower than the rates of such sequelae in patients with bacterial meningitis due to other bacterial pathogens.
What causes this disease and how frequent is it?
Neisseria meningitidis is a pleomorphic Gram negative coccus with a lipopolysaccharide-containing outer membrane and a polysaccharide capsule. Thirteen serogroups have been identified, but only 5 are commonly associated with human disease. Those include serogroups A, B, C, W-135, and Y. Invasiveness is enhanced by the polysaccharide capsule, which allows the organism to resist phagocytosis. Colonization of humans by NMn is common, occuring in about 10% of the population.
The factors that lead to invasion are not clearly understood, but appear to involve variation in the bacterial surface structure leading to invasion across the nasopharyngeal mucosa into the bloodstream and subsequent release of endotoxin (in the case of NMn, this is the lipopolysaccharide). Endotoxin release triggers a cascade of inflammatory proteins, including tumor necrosis factor alpha (TNF-alpha), intraleukin 1 (IL-`) and other intraleukins, plasminogen activator inhibitor (PAI-1), and leukemia-inhibitory factor.
Invasion of the meninges by NMn results in similar release of inflammatory cytokines, and it is thought that the resulting inflammation is the cause of neurologic injury.
NMn infection occurs in endemic and epidemic patterns of human disease, and the prevalence of individual serogroups found in various regions varies over time. Epidemics due to serogroup A have occurred in recent years across sub-Saharan Africa, and serogroup W-135 led to epidemic disease among Hajj pilgrims in Saudi Arabia during the past decade. The serogroups associated with endemic infection leading to individual cases or small outbreaks also varies from region to region and from time to time.
Currently in the United States serogroups B, C, and Y each account for approximately 30% of cases, but serogroup B is a more common cause of disease among infants, and serogroup C is more common among adolescents. These serogroup distinctions are important because the available vaccines provide protection against serogroups A, C, Y, and W-135, but not against serogroup B.
Overall, NMn is the cause of invasive disease in approximately 1/100,000 people in the United States. Variation in serogroups and in incidence occur in specific regions. A particularly virulent serogroup C strain led to increased rates of disease in Great Britain in the 1990’s, with 5/100,000 individuals affected.
Non-epidemic invasive meningococcal infection is most common in infants less than 2 years of age. Adolescents between the ages of 15-18 years are also at particular risk, and recruits in military boot camps and freshman college students living in dormatories are at greater risk of infection than other adolescents of the same age.
Introduction of vaccines that protect against H. influenzae and the majority of disease-causing serotypes of S. pneumoniae has left NMn as the most common cause of bacterial meningitis in the United States and in many developed countries.
Individual susceptibility is increased in situations that lead to crowding, among those exposed to tobacco smoke, those with prior respiratory tract infection (especially influenza), and among those with a history of contact with a patient with meningococcal disease. In addition, inherited or acquired deficiencies in antibody production and deficiencies in the terminal components of complement (C5-C9) and properdin enhance susceptibility to invasive disease and to recurrent disease.
Other clinical manifestations that might help with diagnosis and management
A rare form of meningococcemia, chronic meningococcal disease, is associated with repeated episodes of fever, rash, arthralgia, and arthritis which occur over a period of months. Patients with chronic meningococcemia are well between episodes, and the infection often clears without specific antibiotic therapy. Diagnosis depends on obtaining blood cultures during febrile episodes. The condition can eventually lead to invasive disease, including meningitis if not recognized and treated. This form of meningococcal infection may be mistaken for bacterial endocarditis, rheumatic fever, immune-mediated vasculitis, or mononucleosis.
How can meningococcal infection be prevented?
Vaccines: Two types of vaccines that protect against NMn infection are available in the United States. Both contain antigens that provoke an antibody response to 4 serogroups of NMn: serogroups A, C, Y, and W-135.
Polysaccharide vaccine (MPSV4) is composed of 50 micrograms of purified capsular polysaccharide from NMn serogroups A, C, Y, and W-135 and is licensed for use in children > 2 years of age. It is administered subcutaneously in a single 0.5 mL dose. This vaccine is no longer the preferred vaccine for children over 2 years of age, because of the superior immunogenicity and duration of protection of protein conjugate vaccines.
Two quadrivalent protein-conjugated vaccines are available in the United States, and both are recommended for the prevention of invasive NMn disease. Protein conjugate vaccines provoke an enhanced immunologic response and induce immunologic memory, in contrast to polysaccharide vaccine. Recommendations for use of the conjugate vaccines vary by age, but there is no known advantage for the use of one product over the other except for infants < 2 years of age.
Infants 9-23 months of age who are at increased risk of meningococcal infection by virtue of complement component deficiencies or who are traveling to or reside in a country where meningococcal infection is hyperendemic or epidemic should receive two doses of MenACWY-D (Menactra, Sanofi-Pasteur) separated by 3 months. For children with functional or anatomic asplenia, meningococcal immunization should be deferred until 2 years of age.
Children 2-10 years of age who are at increased risk of invasive meningococcal infection because of functional or anatomic asplenia or because of complement component deficiency should receive a two-dose series of either MenACWY-D or MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics). Children 2-10 years of age who are at increased risk because of travel to or residence in a country in which meningococcal infection is hyperendemic or epidemic should receive one dose.
No meningococcal vaccine is recommended for children who are not at increased risk of meningococcal infection.
All children and adolescents 11-12 years of age should receive a single dose of conjugate meningococcal vaccine with a booster dose at age 16. If the first dose is administered at 13-15 years of age a second dose should be administered at age 16-18 or at least 8 weeks after the first dose. If the first dose is administered at 16 years of age a second dose is not recommended.
Two doses of conjugate vaccine should be administered at least 8 weeks apart to anyone 11-18 years of age who is infected with HIV. Teens who are 11-18 years of age and who have a complement component deficiency or anatomic or functional asplenia should also receive two doses administered at least 8 weeks apart, and these individuals should receive booster doses every 5 years.
Chemoprophylaxis: Antibiotic chemoprophylaxis is indicated for individuals who are close contacts with a patient who develops invasive meningococcal infection. Close contacts include those who have been exposed to the patient’s oral secretions through close social contact, including kissing, sharing of toothbrushes or eating utensils, and child care or preschool contacts. In addition, anyone who frequently slept in the same dwelling as the infected person within the 7 days prior to development of infection and anyone who spent more than 8 hours on the same airplane and was seated next to the infected person should receive prophylaxis.
Routine prophylaxis is NOT recommended for health care professionals unless they have intimate contact with respiratory secretions from the infected patient, such would occur during unprotected mouth-to-mouth resuscitation, intubation, or suctioning before or <24 hours after initiation of appropriate antibiotic therapy.
Antimicrobial agents recommended as prophylaxis include the following: rifampin (10 mg/kg orally every 12 hours for 2 days, 5 mg/kg orally every 12 hours for infants < 1 month); ceftriaxone IM (125 mg in a single dose for those <15 years old and 250 mg in a single dose for those ≥ 15 years; ciprofloxicin (20 mg/kg, maximum 500 mg, orally in a single dose; or azithromycin (10 mg//kg, maximum 500 mg, orally in a single dose).
Immunoprophylaxis: Post-exposure immunoprophylaxis can be used as an adjunct to chemoprophylaxis to prevent late secondary cases if the case patient’s infection was caused by a serogroup that is prevented by the vaccine. Conjugate vaccine is preferred.
What is the evidence?
An algorithm for the emergency department (pre-pediatric ICU) management of patients with meningococcal sepsis created by the Guideline Development Group of the Meningitis Research Foundation of the Republic of Ireland (accessed 03/10/2012)
www.meningitis.org/assets/x/50150
Pollard, AJ, Finn, A, Long, SS, Pickering, LK, Prober, CG. “Neiserria meningitidis”. 2008. pp. 734-743. (This is a very comprehensive chapter which reviews pathophysiology as well as clinical presentation and management of this infection in infants and children.)
Rosenstein, N, Perkins, B, Stevens, D. “The changing epidemiology of meningococcal disease in the United States, 1992-1996”. J Infect Dis. vol. 180. 1999. pp. 1894-1901. (This article provides an example of the variable nature of serogroups causing invasive meningococcal infection over time.)
Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. “Meningococcal Infections”. Red Book: 2009 Report of the Committee on Infectious Diseases. 2009. pp. 455-463. (This website, hosted by the Centers for Disease Control and Prevention, provides up-to-date information about meningococcal infection.)
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