Meningococcemia

Practice Essentials

Meningococcemia is a bloodstream infection (BSI) caused by Neisseria meningitidis. Its wide variety of acute presentations result from its ability to produce diffuse endovascular damage. Chronic meningococcemia is an infrequent presentation with skin and joint findings, without any meningeal involvement. [1] The most commonly affected age groups are 6 months-5 years and 15-24 years.

A 9-month-old baby in septic shock with purpuric Neisseria meningitis skin lesions. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.

Signs and symptoms Patients with acute meningococcemia may present with meningitis, meningitis with meningococcemia, or meningococcemia without apparent meningitis. The clinical presentation of meningococcemia may include any of the following:

• A nonspecific prodrome of cough, headache, and sore throat

• The above, followed by a few days of upper respiratory symptoms, increasing temperature, and chills

• Subsequent malaise, weakness, myalgias, headache, nausea, vomiting, and arthralgias

• The characteristic petechial skin rash usually is located on the trunk and legs and rapidly may evolve into purpura.

Scattered petechiae in a patient with acute meningococcemia. In fulminant meningococcemia, a hemorrhagic eruption, hypotension, cardiac depression, and rapid enlargement of petechiae and purpuric lesions may be seen.

Child with severe meningococcal disease and purpura fulminans. Serogroup W disease may be associated with atypical presentations, including septic arthritis, pneumonia, endocarditis, and epiglottitis. The meningitis of meningococcemia is associated with the following [2] :

• Headache

• Fever

• Vomiting

• Photophobia

• Lethargy

• Neck stiffness

• Rash (more than 50% of cases)

• Seizures (20% of patients at presentation and an additional 10% of patients within 72 hours)

• Early nonspecific symptoms

Meningococcemia is characterized by the following [3] :

• Fever

• Initial rash that may be erythematous or maculopapular and is short-lived, followed by petechiae and purpura

• Vomiting

• Headache

• Myalgias that may be quite severe

• Sore throat

• Abdominal pain

• Tachycardia/tachypnea

• Hypotension

• Cool extremities

• An initially normal level of consciousness

• Early symptoms are similar to those of viral illness such as influenza or streptococcal pharyngitis; however, this infection accelerates at a rate matched by few other infections

• Mild cases may be associated with transient BSI and limited skin lesions. These may become more aggressive but usually resolve

• The presentation may be that of urethritis when the pathogen is transmitted during sex.

The physical findings may include the following:

• Dermatologic manifestations: Petechiae, rash, ecchymoses, purpura

• Meningococcal meningitis: Pain and resistance to neck flexion, other signs of meningeal irritation, petechiae, fever (of variable intensity)

• Fulminant meningococcemia: Purpuric eruption, hemorrhages on buccal mucosa and conjunctivae, cyanosis, hypotension, profound shock, high fever, pulmonary insufficiency, no signs of meningitis

• Meningococcal septicemia: Fever, rash, tachycardia, hypotension, cool extremities, initially normal level of consciousness

Diagnosis The laboratory findings in the early stages of meningococcal disease often are nonspecific. A definitive diagnosis requires retrieval of meningococci from blood, cerebrospinal fluid, joint fluid, or skin lesions. Studies may include the following:

• Complete blood count

• Blood urea nitrogen and creatinine

• Fibrinogen and C-reactive protein

• Coagulation studies

• Electrolytes

• Tests for end-organ damage

• Blood and throat cultures

• Imaging studies: chest radiography, echocardiography, CT scan

• Needle aspiration and skin biopsy

• Lumbar puncture and CSF analysis

• Serogrouping/serotyping

• Singleplex real-time PCR assays

• Multiplex real-time PCR assays [4]

Management Clinical guideline summaries related to meningococcal disease include the following:

• Infectious Disease and Therapeutics [5]

• Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) [6]

Patients with a rash consistent with meningococcemia should be started on parenteral antibiotics within 1 hour of presentation. [7] Conditions associated with poor outcomes include the following:

• Shock

• Absence of meningitis

• Rapidly extending rash

• Low WBC count

• Coagulopathy

• Deteriorating level of consciousness

• Increased intracranial pressure (ICP)

• Immunodeficiencies

Antibiotics recommended for the treatment of meningococcemia include the following:

• Third-generation cephalosporins such as ceftriaxone (2 g IV q24h) or cefotaxime (2 g IV q4-6h) are the preferred antibiotics

• Alternative agents include (1) ampicillin 12 g/d either by continuous infusion or by divided dosing q4h or Penicillin G 18-24 million units IV continuously or by divided dose q 4 hr. These beta-lactams only should be started if the isolate is found to be susceptible

• Moxifloxacin 400mg /day IV

• The course of therapy is generally 7-10 days

• Chloramphenicol may be considered in patients who are allergic to beta-lactam antibiotics. There have been reports of increasing worldwide

Background

N meningitidis is an encapsulated gram-negative diplococcus. There are at least 12 serogroups of the bacterium based on capsular polysaccharide antigenic differences. Serogroups A, B, C, Y, and W-135 cause 90% of human disease. See Pathophysiology, Etiology, and Workup for more detail. Humans are the only reservoir of N meningitidis, which is transiently part of the oropharyngeal flora of up to 10% of the population. These individuals remain asymptomatic. N meningitidis is transmitted by respiratory secretions or by close contact, which facilitates the exchange of secretions. The incubation period ranges from 2-10 days. Epidemics most commonly are due to A, B, or C serotypes. Risk groups include the following:

• Asplenia

• Sickle cell disease

• Terminal complement deficiencies

• Use of eculizumab [8]

• Smoking

• MSM usually serotype C with symptoms of urethritis [9, 10, 11]

• Travel to endemic areas such as the African meningitis belt

• Overcrowded, stressful living conditions such as military barracks or college dormitories

• HIV

Thirty percent to 50% of cases of acute meningococcemia present with meningitis alone, 40% with meningitis and BSI, and 7-10% with BSI alone. [12] See Presentation and Workup for more detail. N meningitides remains a major infectious cause of childhood death in developed countries. The mortality rate remains around 5-10%. There has been little improvement in morbidity and mortality since the beginning of the antibiotic era because of the inability of antimicrobials to prevent the cardiovascular collapse brought about by the organism’s endotoxin. [13] Dorsum of the hand showing petechiae. Courtesy of Professor Chien Liu.View Media Gallery Carriers Approximately 2% of children younger than 2 years, 5% of children up to 17 years, and 20-40% of young adults are carriers of N meningitidis. Overcrowded conditions (eg, schools, military camps) can significantly increase the carrier rate. Screening of military recruits performed during recent epidemics demonstrated that, although as many as 95% of recruits were oropharyngeal carriers, only 1% developed systemic disease. Because very few of those infected had ever been in contact with another patient with a similar history, asymptomatic carriage is thought to be the major source of transmission of pathogenic strains. Immunity to N meningitidis appears to be acquired through the intermittent nasal carriage of meningococci and by antigenic cross-reaction with enteric flora during the first 2 decades of life. See Pathophysiology, Etiology, and Epidemiology for more detail.

Pathophysiology

Meningococcemia results in widespread vascular injury characterized by endothelial necrosis, intraluminal thrombosis, and perivascular hemorrhage. Endotoxin, cytokines, and free radicals damage the vascular endothelium, producing platelet deposition and vasculitis. Cytokines play a major role in its pathogenesis by causing severe hypotension, reduced cardiac output, and increased endothelial permeability. [14] The clinical picture of meningococcemia is the product of compartmental intravascular infection and intracranial bacterial growth and inflammation. The pathogen binds tightly to the endothelial cells by type IV pili. From this arises microcolonies on the apical portion of the endothelial cell. [15] These bacteria invade the subarachnoid space with resultant meningitis in 50-70% of cases. In a study of 862 patients, 37-49% developed meningitis without shock, 10-18% developed shock without meningitis, 7-12% developed both, and 10-18% with mild meningococcemia developed neither meningitis nor shock. [16] Multiple organ failure, shock, and death may ensue as a result of anoxia in vital organs and massive disseminated intravascular coagulation (DIC). Patients with fulminant meningococcemia develop thrombosis and hemorrhage in the skin, the mucous membranes, the serosal surfaces, the adrenal sinusoids, and the renal glomeruli. Adrenal hemorrhage may occur and rarely may be extensive enough to lead to adrenal necrosis (Waterhouse-Friderichsen syndrome). Thrombosis of the glomerular capillaries may cause renal cortical necrosis, the chief characteristic of the generalized Shwartzman reaction, which is a model for disseminated intravascular coagulation (DIC). [17] Similar thrombi containing numerous leukocytes may be found in the lungs and myocardium. Primary meningococcal septic arthritis has been described. [18] Virulence factors Meningococci have 3 important virulence factors, as follows [19] :

• Polysaccharide capsule - Individuals with immunity against meningococcal infections have bactericidal antibodies against cell wall antigens and capsular polysaccharide; a deficiency of circulating antimeningococcal antibodies is associated with disease.

• Lipo-oligosaccharide endotoxin (LOS)

• Immunoglobulin A1 (IgA1)

A polysaccharide capsule (which also determines the serogroup) enables the organism to resist phagocytosis. [14] An LOS can be shed in large amounts by a process called blebbing, causing fever, shock, and other pathophysiology. This is considered the principal factor that produces the high endotoxin levels in meningococcal sepsis. Meningococcal LOS interacts with human cells, producing proinflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF). LOS is one of the important structures that mediate meningococcal attachment to and invasion into epithelial cells. [20] LOS triggers the innate immune system by activating the Toll-like receptor 4MD2 cell surface receptor complex and myeloid in non-myeloid human sounds. The degree of activation of complement then coagulation system is directly related to the bacterial load. [21] IgA1 protease cleaves lysosomal membrane glycoprotein-1 (LAMP1), helping the organism to survive intracellularly. Septicemia The clinical syndrome results from the activation and continued stimulation of the immune system by proinflammatory cytokines. This process is directly caused by bacterial components, such as endotoxins released from the bacterial cell wall, and is indirectly caused by the activation of inflammatory cells. The clinical spectrum of meningococcal septicemia is produced by 4 basic processes (ie, capillary leak, coagulopathy, metabolic derangement, and myocardial failure). Combined, the processes produce multiorgan failure that usually causes cardiorespiratory depression and, possibly, renal, neurologic, and gastrointestinal (GI) failure. [22] Capillary leak From presentation until 2-4 days after illness onset, vascular permeability massively increases. Albumin and other plasma proteins leak into the intravascular space and urine, causing severe hypovolemia. This initially is compensated for by homeostatic mechanisms, including vasoconstriction. However, progression of the leak results in decreased venous return to the heart and a significantly reduced cardiac output. Hypovolemia that is resistant to volume replacement is associated with increased mortality due to meningococcal sepsis. Children with severe disease often require fluid resuscitation involving volumes several times their blood volume in the first 24 hours of the illness, mostly in the first few hours. Pulmonary edema is common and occurs after 40-60 mL/kg of fluid has been given; it is treated with artificial ventilation. Although capillary leak is the most important clinical event, the underlying pathophysiology is unclear. Some evidence suggests that meningococci and neutrophils cause the loss of negatively charged glycosaminoglycans, which are normally present on the endothelium. Also, the repulsive effect of albumin may be reduced in meningococcal infection; this change allows the protein leak. Albumin is normally confined to the vasculature because of its large size and negative charge, which repels the endothelial negative charge. Coagulopathy In meningococcemia, a severe bleeding tendency often is simultaneously present with severe thrombosis in the microvasculature of the skin, often in a glove-and-stocking distribution that can necessitate amputation of digits or limbs. Clinicians face a dilemma because supplying platelets, coagulation factors, and fibrinogen may worsen the process. Meningococcal infection affects the main pathways of coagulation. Endothelial injury results in platelet-release reactions. Along with stagnant circulation due to local vasoconstriction, platelet plugs form to start the process of intravascular thrombosis. In the plasma, soluble coagulation factors are consumed, and the natural inhibitors of coagulation (eg, the tissue factor pathway inhibitor antithrombin III) are down-regulated; this process further encourages thrombosis. The protein C pathway probably plays a key role in the pathogenesis of purpura fulminans. A very similar rash occurs in neonates with congenital protein C deficiency and in older children who develop antibodies to protein S following varicella infection. Many patients with meningococcal infection are unable to activate protein C in the microvasculature due to endothelial downregulation of thrombomodulin. [23] Protein C and S levels are low in children with meningococcal disease. However, low levels may occur in patients with septic shock without purpura fulminans. Plasma anticoagulants (tissue factor pathway inhibitor and antithrombin) also are down-regulated in meningococcal sepsis. The fibrinolytic system in meningococcal disease is down-regulated as well, reducing plasmin generation and removing an aspect of endogenous negative feedback to clot formation. In addition, plasminogen activator inhibitor levels are dramatically increased, further reducing the efficacy of the endogenous tissue plasminogen activator. Metabolic derangement Severe electrolyte abnormalities, including hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia, may occur in the setting of severe acidosis. Myocardial failure Myocardial function remains impaired even after circulating blood volume is restored and metabolic abnormalities are corrected. Reduced ejection fractions and elevated plasma troponin I levels indicate myocardial damage. A gallop rhythm often is audible, with elevated central venous pressure and hepatomegaly. Hemodynamic studies in patients with meningococcal sepsis have shown that the severity of disease is related to the degree of myocardial dysfunction. Myocardial failure in meningococcal sepsis is undoubtedly multifactorial, but various proinflammatory mediators (eg, nitric oxide, TNF-alpha, IL-1B) released in sepsis appear to have a direct negative inotropic effect on the heart, depressing myocardial function. A study using new microarray technology showed that IL-6 is the key factor that causes myocardial depression in meningococcemia. [24, 25] It recently has been demonstrated that meningococcal infection leads to human coronary microvascular thrombosis, vasculitis, and vascular leakage. [26] Other factors that reduce myocardial function, such as acidosis, hypoxia, hypoglycemia, and electrolyte disturbances, all are common in severe meningococcal disease. Meningitis Meningococcal meningitis generally has a better prognosis than septicemia. After bacteria enter the meninges, they multiply in the CSF and pia arachnoid. In the early stages of infection, the tight junctions between the endothelial cells that form the blood-brain barrier isolate the CSF from the immune system; this isolation allows bacterial multiplication. Eventually, inflammatory cells enter the CSF and release cytokines that play a central role in the pathophysiology of meningeal inflammation. [2, 22] Neurologic damage is a consequence of the following 3 main processes:

• Direct bacterial toxicity

• Indirect inflammatory processes, such as cytokine release, ischemia, vasculitis, and edema

• Systemic effects, including shock, seizures, and cerebral hypoperfusion

Cerebral edema may be caused by increased secretion of CSF, diminished reabsorption of CSF, and/or breakdown of the blood-brain barrier. Obstructive hydrocephalus may cause increased accumulation of CSF between cells. Increased ICP secondary to cerebral edema, loss of cerebrovascular autoregulation, and reduced arterial perfusion pressure secondary to shock reduce cerebral blood flow in bacterial meningitis. Reduced cerebral blood flow with vasculitis and thrombosis of cerebral vessels may cause ischemia and neuronal injury.

Etiology

N meningitidis is a gram-negative diplococcus that grows well on blood or chocolate agar supplemented or on selective media, such as Martin-Lewis or Thayer Martin blood and incubated in a moist atmosphere enriched with carbon dioxide.

Gram-negative intracellular diplococci. Courtesy Professor Chien Liu. Oxidase and catalase are biochemical markers for preliminary identification of N meningitidis. Sugar fermentations are required for final identification of the species. N meningitidis ferments glucose and maltose but not sucrose or lactose. Agglutination reactions with immune serum are used to segregate meningococci into 13 serogroups: A, B, C, D, X, Y, Z, E, W-135, H, I, K, and L, depending on the group-specific capsular polysaccharide antigen. Ninety-eight percent of infections are caused by encapsulated serogroups A, B, C, Y, and W-135, although of these groups, A, B, and C most frequently occur in meningococcal disease. The cell wall of pathogenic meningococci contains a toxic lipopolysaccharide or endotoxin that is chemically identical to enteric bacilli endotoxin. Transmission The human nasopharynx is the only known reservoir for N meningitidis. At any given time, up to 10% of the population may be asymptomatic, nasopharyngeal carriers. In China, the weighted carriage rate between 2005-2022 was 2.86% varying between provinces from 0 to 15.5%. The organism is transmitted via aerosols and nasopharyngeal secretions. Attachment to the nasopharyngeal epithelial cells is aided by meningococci-expressed pili, such as the type IV pilus encoded by pilC, which binds to human cell surface protein CD46. Meningococci may enter the bloodstream and spread to specific sites, such as the meninges or joints, or disseminate throughout the body. Five percent of individuals become long-term carriers, most of whom are asymptomatic. In outbreaks, the carriage rate of an epidemic strain can reach 90%. The likelihood of acquiring infection is increased 100 to 1000 times in intimate contacts of individuals with meningococcemia. A study of 14,000 teenagers in the United Kingdom found that attendance at pubs or clubs, intimate kissing, and cigarette smoking each were independently and strongly associated with an increased risk of meningococcal carriage. [27] Immunity Passively transferred maternal antibody provides temporary protection to infants for the first 3 to 6 months of life. As the child grows older, asymptomatic exposure to a variety of encapsulated and nonencapsulated N meningitidis strains increases protective bacterial immunity. Most individuals acquire immunity to meningococcal disease by age 20 years; protective IgM and IgG are found in up to 95% of young adults. An episode of meningococcal disease confers group-specific immunity, but a second episode may be caused by another meningococcal serogroup. Susceptibility Complement deficiency A genetic component to host susceptibility to meningococcemia is becoming more established. IgG antibodies that have specificity for meningococcal polysaccharides mediate bactericidal activity. Complement is needed for the expression of this activity. Terminal complement deficiency is well known to predispose individuals to meningococcemia. Recurrent meningococcemia can occur. [28] Genetic variants of mannose-binding lectin, a plasma opsonin that initiates another pathway of complement activation, may account for nearly one third of the cases of invasive meningococcal disease. Meningococcemia is particularly common among individuals with deficiencies of terminal complement components C5-C9 or properdin. These late complement components are required for the bacteriolysis of meningococci. An estimated 50-60% of individuals with late complement component deficiencies develop at least 1 episode of meningococcal disease. Many of these patients experience multiple episodes of infection. Acquired complement deficiencies that occur in association with systemic lupus erythematosus, multiple myeloma, severe liver disease, enteropathies, and nephrotic syndrome also predispose to meningococcal infection. Interleukin abnormalities Specific genetic polymorphisms likely predispose individuals to mortality in severe sepsis. An association has been described between increased risk for mortality in children with meningococcal disease and polymorphisms in the IL-1 cluster. An innate anti-inflammatory cytokine profile (low level of TNF and high level of IL-10) also is associated with fatal meningococcal disease. Coagulation pathway abnormalities Polymorphisms in the genes that control the coagulation pathways are being evaluated. Patients with the prothrombotic factor V Leiden mutation are at higher risk for thrombotic complications, such as amputations and skin grafting, but do not have increased mortality in meningococcemia. Other An increased type-1 plasminogen activator inhibitor response to TNF meningococcal septicemia has been demonstrated to result from a polymorphism in the PAI-1 gene. Another study reported that a toll-like receptor 4 variant genotype was associated with increased mortality in children with invasive meningococcal disease. [29] Risk factors Most patients with meningococcal disease are previously healthy; however, patients with certain medical conditions are at increased risk of developing a meningococcal infection. Risk factors include the following:

• Close contact with a patient with primary invasive disease: Epidemics among new recruits (eg, in military basic training [boot camp] and college freshmen in dormitories are classic examples of meningococcal spread (see Epidemiology).

• Recent viral respiratory illness (eg, influenza): A study showed increased rates of meningococcal disease in children during periods of increased influenza and respiratory syncytial virus activity. [30]

• Smoking or exposure to secondary smoke

• Host susceptibility: Individuals with a deficiency of complement components C5-C9 and abnormal complement factor H [31]

• Socioeconomic deprivation

• Household overcrowding

• HIV infection (see Epidemiology)

• It is identified as a sexually transmitted disease in gay men due to prolonged close contact and exchange of secretions, usually serogroup C

Patients with anatomic (splenectomy) or functional asplenia also are at increased risk for invasive meningococcal disease. Particularly severe cases have occurred during eculizumab therapy. [32]

Epidemiology

Serogroups A, B, and C account for most cases of meningococcal disease worldwide. Serogroups A and C predominate in Asia and Africa, while serogroups B and C predominate in Europe, North America, and South America. An international outbreak of meningococcal disease associated with serogroup W-135 occurred following the return of travelers who participated in the annual hajj (pilgrimage) to Mecca, Saudi Arabia in 2000 and 2001. [50, 51, 52] Outbreaks also have occurred in Africa, parts of Asia, South America, and the former Soviet republics. Serogroup A usually is implicated in these epidemics. Indeed, for more than a century, serogroup A meningococcal disease has been endemic in the African meningitis belt, which extends from Ethiopia in eastern Africa to Senegal in West Africa. Large-scale outbreaks occur at cyclic intervals of 7-10 years through these central African countries, with attack rates as high as 400-500 cases per 100,000 population. [53]

Areas with frequent epidemics of meningococcal disease. This is known as the meningitis belt of Africa; visitors to these locales may benefit from meningitis vaccine. Image courtesy of CDC Meningococcal disease also may be a significant, but underreported, problem in developing Asian countries. [54] Europe and the United Kingdom In Europe, invasive meningococcal disease predominantly is caused by serogroup B. Based on data from 2017-2018, serogroup B remains the most important cause of invasive meningococcal disease in England (54%; 404/755), followed by serogroup W disease (26%), serogroup Y disease (12%), and serogroup C disease (8%). [55] Climate-related demographics Meningococcal infections in the United States and Northern Europe are most common in the winter, whereas cases of meningococcal disease in the African meningitis belt increase at the end of the dry season. Race- and sex-related demographics Mortality rates may be significantly higher in Blacks than in Whites and Asians. [56] Meningococcal disease is somewhat more prevalent in males (1.2 cases per 100,000) than in females (1 case per 100,000). Age-related demographics In epidemics of meningococcal disease, people of any age may be affected, with the case distribution shifted toward older individuals. [57] Endemic meningococcal disease is most common in children aged 6-36 months. Children younger than 6 months are protected by maternal antibodies (although occult meningococcemia, an uncommon form of infection, affects children aged 3-24 months). It is rare in neonates, but the incidence in that age group is not known. [58]

Lesions caused by Neisseria meningitis bacteremia on the palm of the hand of a 9-month-old infant. Photo by D. Scott Smith, MD, taken at Stanford University Hospital. A second, less dramatic peak in incidence occurs among teenagers and college students; this may be due to changes in social behavior and increases in close interpersonal contact in these populations. About one third of meningococcal disease cases occur in adults. In New York City from 1989-2000, the overall incidence rates of meningococcal disease decreased. The median age of patients with meningococcal disease increased from 15 years in 1989-1991 to 30 years in 1998-2000. [59]

Prognosis

Meningococcal disease can progress very quickly and can result in loss of life, neurologic impairment, or peripheral gangrene. Patients with terminal complement component deficiency have a more favorable prognosis. A fatal outcome is highly associated with properdin deficiencies. Coagulopathy with a partial thromboplastin time of greater than 50 seconds or a fibrinogen concentration of less than 150 µg/dL also are markers of poor prognosis. A multicenter study published in 2006 evaluated the serogroups in children with N meningitidis infection. The researchers found that meningococcal disease continues to result in substantial morbidity and mortality in children. Overall, 55 (44%) of isolates were serogroup B, 32 (26%) were serogroup C, and 27 (22%) were serogroup Y. All but 1 of the isolates (intermediate) were susceptible to penicillin. The overall mortality rate in this pediatric population was 8%. [60] Cases of meningococcal meningitis without coma or focal neurological deficits have markedly better outcomes. Most of these patients recover completely when appropriate antimicrobial therapy is administered promptly upon presentation. Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). Patients with higher bacterial loads on polymerase chain reaction (PCR) testing are more likely to die or have permanent disease sequelae and experience longer hospital stays. [61] Morbidity Complications of meningococcal infection include the following:

• DIC

• Vasomotor collapse and shock

• Adrenal hemorrhage and insufficiency

• Meningitis

• Cranial nerve dysfunction, particularly involving the sixth, seventh, and eighth cranial nerves

• Seizures or deafness in the acute stages of meningitis

• Postmeningitic epilepsy (rare)

• Coma

• Thrombocytopenia

• Septic arthritis

• Herpes labialis (5-20% of patients with meningococcal disease)

• Immune complex arthritis involving multiple joints

• Pericarditis due to immunologic reaction or toxin

• Cardiorespiratory failure that requires tracheal intubation and inotropic support

• Renal failure that requires hemofiltration, hemodialysis, or peritoneal dialysis

• Peritoneal compartment syndrome due to severe abdominal capillary leak that requires placement of a tap

• Psychological disturbance after intensive care or complications

• Tamponade due to pericarditis

• Bacterial endocarditis

• Myocarditis [62, 63]

• Gangrene

• Urethritis and endometritis

• Osteomyelitis

• Purulent conjunctivitis and sinusitis

Complications of meningococcemia may occur at the time of acute disease or during the recovery phase. Patients with fulminant meningococcemia may develop respiratory insufficiency and require mechanical ventilation. Those with severe DIC may bleed into their lungs, urinary tract, and gastrointestinal tract. Ischemic complications of DIC have been reported in up to 50% of survivors of fulminant meningococcemia. Complications of meningococcal infection include immune complex disease leading to arthritis, pericarditis, myocarditis, and pneumonitis 10-14 days after the primary infection. Up to 5% of patients with meningococcemia develop a nonpurulent pericarditis with substernal chest pain and dyspnea approximately 1 week after the onset of illness. Involvement of the pericardium in meningococcal disease is a well-recognized, but rare, complication. It has been described with N meningitidis serotypes C, B, W-135, and Y. [64] Meningococcal meningitis may progress to mental obtundation, stupor, or coma, which may be related to increased ICP, and such patients are prone to herniation. Other rare complications of meningitis include acute and delayed venous thrombosis, which usually manifests as a focal neurologic deficit. Meningococcal infection may spread through the bloodstream and localize in other parts of the body, where it can cause suppurative complications. Septic arthritis, purulent pericarditis, [65] and endophthalmitis [66] can occur but are uncommon. Meningococcal pneumonia has been described and probably results from aspiration of N meningitidis. The W-135, Y, and B serogroups of meningococci are more likely to cause this form of meningococcal disease, as well as pericarditis and septic arthritis. [67] Approximately 10% of patients with meningococcal disease develop nonsuppurative arthritis, usually of the knee joints. The nonsuppurative arthritis of meningococcal disease may result from tenosynovitis due to meningococcemia or a postinfectious immunologic process. Recurrent meningococcal disease has been associated with hereditary deficiencies of various terminal components of the complement system. Myocarditis is a complication with a high mortality risk. The frequency may be more common than is clinically recognized. [68] Sequelae A case-control study examined outcomes in patients who had survived meningococcal disease in adolescence and found that they had poorer mental health, social support, quality of life, and educational outcomes, as well as greater fatigue, than did well-matched control individuals. [69] A European study found that approximately 4% of survivors of meningococcal infection had sequelae. In the United Kingdom, approximately 5% of survivors have neurologic sequelae, mainly sensorineural deafness. Amputation or skin grafting due to digital or limb ischemia and severe skin necrosis is required in 2-5% of survivors in the United Kingdom. In the United States in 2005, 11-19% of survivors of meningococcal infection had serious health sequelae, including sensorineural hearing loss, amputations, and cognitive impairment.

Presentation

History

Individuals with meningococcal disease may present with a nonspecific prodrome of cough, headache, and sore throat. After a few days of upper respiratory symptoms, the temperature rises abruptly, often after a chill. Malaise, weakness, myalgias, headache, nausea, vomiting, and arthralgias are common presenting symptoms. The skin rash of meningococcemia may advance from a few ill-defined lesions to a widespread petechial eruption within a few hours. In fulminant meningococcemia, a hemorrhagic eruption, hypotension, and cardiac depression, as well as rapid enlargement of petechiae and purpuric lesions, may be apparent within hours of the initial presentation.

Purpura in a young adult with fulminant meningococcemia. Meningitis Meningitis is associated with the following [2] :

• Headache

• Fever

• Vomiting

• Photophobia

• Lethargy

• Neck stiffness

• Rash - In more than 50% of cases

• Seizures - In 20% of patients at presentation and in an additional 10% of patients within 72 hours

• Early nonspecific symptoms - especially in infants

In adults, bacterial meningitis has a characteristic clinical pattern, although the progression of symptoms varies somewhat. Symptoms of meningitis may accompany the petechiae of meningococcemia and may produce the predominant features on presentation. Bacterial meningitis is a febrile illness of short duration; the major symptoms include headache and a stiff neck. Lethargy or drowsiness are common. Confusion, agitated delirium, and stupor are rarer; however, coma is an ominous prognostic sign. The clinical pattern of bacterial meningitis often is atypical in young children because headache and nuchal rigidity frequently are absent. Irritability, especially upon movement, is a common presenting manifestation of meningitis in a young child. Convulsions may signal the onset of meningitis at this age. Progression of the illness results in the development of lassitude and a more constant fever, often accompanied by abdominal discomfort. Projectile vomiting may occur. Septicemia Septicemia may be confused with influenza, particularly when myalgia is prominent. Meningococcal septicemia is characterized by the following [3] :

• Fever

• Rash: An early short-lived maculopapular rash may precede the classic erythematous one that may evolve into petechiae and purpura. This may be mistaken for a viral exanthema. [74]

• Vomiting

• Headache

• Myalgia that may be diffuse and severe

• Abdominal pain

• Tachycardia/tachypnea

• Hypotension

• Cool extremities

• Initially normal level of consciousness

• Early symptoms indistinguishable from those associated with viral illness, including leg pain

Symptoms of meningitis and septicemia may occur together and may complicate the distinction between an acute decreased level of consciousness due to hypotension and that caused by elevated ICP. Chronic meningococcemia Chronic meningococcemia is an intermittent bacteremic illness that lasts from at least 1 week to as long as several months. The fever tends to be intermittent, with afebrile periods ranging from 2-10 days, during which the patient seems completely healthy. As the disease progresses, the febrile periods become more common, and the fever may become continuous. [75] It may present with joint symptoms. [76] Cutaneous manifestations are variable and can consist of rose-colored macules and papules, indurated nodules, petechiae, purpura, or large hemorrhagic areas. Chronic meningococcemia may mimic the dermatitis-arthritis syndrome of subacute gonococcemia. Patients may recover spontaneously or progress to systemic complications such as meningitis. The prognosis for treated patients is excellent, with a cure rate of nearly 100% with appropriate antibiotic therapy. Penicillin G at 6-12 million U/day in divided doses for a minimum of 7 days is effective therapy.

Physical Examination Patients are severely ill. Tachycardia and mild hypotension are present. Patients with acute meningococcemia usually present with moderate fever (average, 39.5°C). High fever (average, 40.6°C) is present in fulminant meningococcemia. Rapidly developing signs and symptoms of congestive heart failure, hypotension, pulmonary edema, and respiratory failure may be present and mark the progression to fulminant meningococcemia. Laboratory or imaging evidence of end-organ damage such as pericarditis often appear concurrently. Dermatologic manifestations Petechiae develop in 50-80% of patients with meningococcal disease and involve the axillae, flanks, wrists, and ankles, although they can progress to any part of the body. Lesions commonly begin on the trunk and legs in areas where pressure is applied.

Hand showing petechiae.

Petechiae on lower extremities. Courtesy of Professor Chien Liu.View Media Gallery

Scattered petechiae in a patient with acute meningococcemia.View Media Gallery

Petechiae often are located in the center of lighter-colored macules. They are discrete lesions 1-2mm in diameter. Confluence of lesions results in hemorrhagic patches, often with central necrosis. In some cases, a transient maculopapular rash develops, usually lasting for less than 48 hours. Rash may be missed early in an individual with dark skin. [77] Critically ill patients with sepsis may develop rapidly progressing petechiae, ecchymoses, and extensive, palpable purpura or retiform purpura, accompanied by DIC and vascular collapse. Skin lesions tend to occur in crops on any part of the body, occasionally presenting on the conjunctivae and the mucous membranes (see the first image below). The face usually is spared, and involvement of the palms and the soles is less common (see the second image below).

Conjunctival petechiae. Courtesy of Professor Chien Liu Fulminant meningococcemia Fulminant meningococcemia is associated with a purpuric eruption, as shown in the image below. Lesions generally are characterized by maplike purpuric or necrotic areas. Hemorrhages may appear on the buccal mucosa and the conjunctivae. Less frequently, fulminant meningococcemia presents as purpura fulminans. In rare cases, no skin lesions develop. Symmetrical, peripheral gangrene has been described in this form. Amputation may be required in severe cases of necrosis.

Child with severe meningococcal disease and purpura fulminans. Signs of meningitis The characteristic physical examination findings of meningitis include pain and resistance to neck flexion. Other signs of meningeal irritation also can be elicited. Children with meningitis may have none of these findings. The Kernig sign is positive when the leg cannot be extended more than 135° on the thigh when flexed 90° at the hip. The Brudzinski sign is positive when neck flexion causes involuntary flexion of the thighs and the legs. Focal neurologic signs are uncommon presenting findings of bacterial meningitis. However, nuchal rigidity may not be elicited in patients who are comatose and who may have signs of focal or diffuse neurologic deficits. Papilledema is not a presenting feature of bacterial meningitis and suggests the presence of an accompanying process.

Differential diagnosis

The differential diagnosis of acute meningococcemia encompasses multiple entities, including other infectious processes. Although only 2-11% of children with petechiae and fever have invasive meningococcal disease, antibiotic therapy should be started in children and most adults without awaiting confirmatory evidence. Distinguishing meningococcal disease from other causes in these cases is difficult, and the fatality rate is high. Other causes may include the following:

• Bacterial infections - Pneumococcal septicemia, group A streptococcal septicemia, other gram-positive or gram-negative sepsis, and syphilis

• Viral infections - Epstein-Barr virus infection, enterovirus infection, measles, rubella, herpes simplex virus infection, cytomegalovirus infection, hemorrhagic viral fevers (eg, dengue)

• Other infections - Mycoplasma infection (usually maculopapular), Rocky Mountain spotted fever, epidemic typhus, ehrlichiosis, leptospirosis, and Candida infection

• Platelet disorders - Immune thrombocytopenia, leukemia, other causes of bone marrow failure, Bernard-Soulier disease, and Glanzmann disease

• Clotting disorders - Hemophilia, von Willebrand disease, vitamin K deficiency, and congenital or acquired protein C or S deficiency

• Autoantibody-mediated causes - After varicella, rubella, group A hemolytic, Streptococcus, coumarin drugs, cholestasis, renal dialysis, nephrotic syndrome, and bone marrow transplantation

• Vasculitis - Henoch-Schönlein purpura, polyarteritis, antiphospholipid syndrome, other vasculitides, and Kawasaki disease,

• Trauma - Injury and violent coughing or emesis

• Connective tissue disease - Osteogenesis imperfecta, Marfan syndrome, and vitamin C deficiency

• Miscellaneous - Cushing syndrome, hemolytic uremic syndrome, drug ingestion, erythema nodosum, erythema multiforme, and spider and snake bites

• Enteroviruses

• Infective endocarditis

• Influenza

• Leptospirosis

• Malaria

• Antiphospholipid antibody syndrome

• Bernard-Soulier syndrome

• Bone marrow transplantation

• Cholestasis

• Enterococcal infection

• Hemophilia A, B, and C

• Kawasaki disease

• Marfan syndrome

• Nephrotic syndrome

• Polyarteritis nodosa

• Bacterial sepsis - Gonococcemia, Haemophilus influenzae, and Streptococcus pneumoniae infection

• Anaphylactoid purpura

• Arboviral infections

• Capnocytophaga canimorsus infection

• Marburg virus infection

• Acute febrile neutrophilic dermatosis (Sweet syndrome)

• H influenzae meningitis - The H influenzae type B vaccine caused the decline of meningitis related to this bacteria; half of all childhood cases of bacterial meningitis are caused by N meningitidis. Most other cases are due to S pneumoniae.

• Staphylococcal endocarditis with meningitis [78]

Workup

Approach Considerations Definitive diagnosis of meningococcal infection requires culture of meningococci from blood, spinal fluid, joint fluid, or, occasionally, from skin lesions. The laboratory findings in the early stages of meningococcal disease are nonspecific and often unremarkable. For example, patients with fulminant meningococcemia may present with a normal white blood cell (WBC) count or leukopenia. A study of adults with fulminant meningococcemia found that the following 4 variables at the time of admission portend a fatal outcome:

• Plasma fibrinogen level of 1.5 g/L or less (sole adverse prognostic variable)

• Factor V concentration of 0.2 or less

• Platelet count lower than 80 X 10 9/L

• Cerebrospinal fluid (CSF) leukocyte count of 20 X 10 6/L or greater

Blood culture Cultures in meningococcal infection produce transparent, nonpigmented colonies that are oxidase positive and nonhemolytic. Overall, the sensitivity of blood culture is 50-60% in untreated patients. [79] In meningococcemia, organisms have been isolated by blood culture in almost 100% of patients. The results are not available for 12-24 hours. Obtain blood cultures before administering antibiotics. These can be drawn in rapid succession so as not to delay the institution of appropriate antibiotics. Throat culture A throat culture should be obtained; however, the diagnosis of meningococcemia cannot be made solely from a positive result from throat culture, because asymptomatic colonization is not uncommon. Complement deficiencies should be sought for complicated infections and recurrent or familial disease. Diagnosis of chronic meningococcemia The diagnosis of chronic meningococcemia is confirmed with the identification of N meningitidis from blood cultures. Multiple (3-6 sets) blood cultures are necessary to confirm BSI because of the high rate of false-negative test results. This may be due to recent use of oral antibiotics that were given before the seriousness of the patient's clinical state was recognized. Alternatively, a novel N meningitidis–specific polymerase chain reaction assay performed on skin biopsy specimens may prove to be helpful for this diagnostic challenge. [80] Chronic meningococcemia significantly differs histopathologically from acute meningococcemia. The patient is not in shock /thrombi do not occlude the capillaries orvenules, and endothelial swelling does not occur. The most common finding in a person with chronic meningococcemia is a leukocytoclastic angiitis. Imaging studies Chest radiography is useful to evaluate for pneumonia and acute respiratory distress syndrome. Echocardiography can be used to evaluate for myocardial dysfunction and pericarditis. Deep muscle and bone involvement can be evaluated with magnetic resonance imaging (MRI).

Hematologic Studies Collect blood cultures (2 sets, with at least 10 mL per bottle) in any febrile patient with petechiae. A complete blood count (CBC), platelet count, blood urea nitrogen (BUN) study, and creatinine clearance evaluation, as well as a series of coagulation studies, can be used to evaluate a consumptive coagulopathy. Gram stain of the peripheral blood buffy coat may reveal gram-negative diplococci in fulminant meningococcemia. Rapid latex antigen tests may assist with diagnosis. The latex agglutination test has 50-100% sensitivity and high specificity. However, it has a high rate of false-negative results. Coagulation tests DIC is a laboratory diagnosis, but no single laboratory test is diagnostic. Instead, DIC is recognized clinically by a pattern of changes in numerous coagulation tests. Typically, these changes include lowered platelet count, prolonged prothrombin time, prolonged partial thromboplastin time, lowered fibrinogen levels, and the presence of fibrin-split products in the circulation. Not all of these changes are found in all patients. Fibrinogen, an acute-phase reactant, may be elevated in patients with DIC. White blood cell count In patients with meningococcal infections, the WBC count and C-reactive protein level may be elevated at presentation or may increase during the subsequent 24 hours. However, these values are not reliable markers of infection. In a study of 128 consecutive children with meningococcal sepsis who were admitted to a pediatric intensive care unit, only 14% had a WBC count of more than 20 X 109/L, and 71% had a WBC count of less than 15 X 109/L. A low WBC count is a poor prognostic finding and should raise concerns about rapid disease progression. Metabolic abnormalities Biochemical disturbance is common in children who have shock with or without impaired renal function. The following abnormalities frequently occur:

• Hypokalemia despite acidosis

• Hypocalcemia

• Hypomagnesemia

• Metabolic acidosis

Other Evaluate for evidence of end-organ damage (eg, kidney or hepatic failure) with appropriate blood tests.

Needle Aspirates and Skin Biopsy Gram-negative diplococci may be observed in punch biopsy and needle aspiration specimens of skin lesions or buffy coat preparations. Gram-negative diplococci also may be recovered from joint fluid. Findings on Gram stains of skin lesions remain positive for up to 2 days after the start of antibiotics and form a rapid means of diagnosis, including when meningitis is not present and when spinal fluid culture findings are negative, owing to the administration of antibiotics. In one study, needle aspirates or skin biopsy specimens from patients with meningococcal sepsis tested using Gram stain yielded a 72% sensitivity; in another study, sensitivity was reportedly 80% using scraped material from petechiae. [81] However, a later prospective, controlled study combining Gram stain and culture of skin biopsy specimens, reported a sensitivity of 56%. [82]

Histology Leukocytoclastic vasculitis, thrombosis, and organisms often are demonstrated in biopsy specimens collected from patients with acute meningococcemia. Cutaneous petechiae and purpura correspond to thrombi in the dermal vessels composed of neutrophils, platelets, and fibrin. Acute vasculitis with neutrophils and nuclear "dust" is present within and around vessels. This process leads to hemorrhage into the surrounding tissue. Meningococci often can be seen in the luminal thrombi and vessel walls. Intraepidermal and subepidermal neutrophilic pustules also may be present. Perivascular lymphocytic infiltrate with few neutrophils characterize chronic meningococcemia, although leukocytoclastic vasculitis may be seen in biopsies of petechiae.

Serogrouping-Serotyping Meningococcal polymerase chain reaction assay Meningococcal PCR is a rapid method for diagnosing CSF infection. [83] PCR of spinal fluid has a sensitivity and specificity of more than 90% in the diagnosis of meningococcal meningitis. It is useful when antibiotics have been administered and can be used to rapidly type strains in developing epidemics. [61, 80, 84, 85, 86, 87, 88, 89] Diagnosis and serogrouping of N meningitidis infection also can be performed on formalin-fixed tissue samples using immunohistochemical analysis and PCR. [84, 85] Slide agglutination test With serogrouping, polysaccharide antigens on the capsule are identified by a slide agglutination test using polyclonal antibodies. Enzyme-linked immunosorbent assay With serotyping and serosubtyping, outer membrane proteins (PorB and PorA) can be identified by an enzyme-linked immunosorbent assay (ELISA) using monoclonal antibodies.

Lumbar Puncture Brain imaging studies before a lumbar puncture (LP) are unnecessary unless the patient is obtunded, has focal neurologic signs, has experienced a seizure within the previous week, or presents with papilledema. Perform LP for CSF evaluation. Immediately stain and culture the spinal fluid. (CSF culture yields a sensitivity of up to 70% in untreated patients.) Gram stain of the CSF should be performed immediately and examined microscopically. Organisms can be observed in the CSF in approximately half of patients who present with meningococcal meningitis. (Gram stain can have a higher yield than blood cultures.) Send the CSF for a WBC count, a WBC differential, total protein content, and glucose studies. Send additional tests as indicated for ruling out other diagnoses. Bacterial meningitis produces various inflammatory changes in the CSF. The CSF becomes turbid with more than 1000 WBC/µL, and the cells predominantly are predominantly polymorphonuclear. The intracranial pressure (ICP) may be elevated. The total protein content is increased, and the glucose level, which is normally 60% of the simultaneous blood glucose level, becomes lowered (hypoglycorrhachia). Detection of N meningitidis capsular polysaccharide antigen in CSF and urine with rapid serologic tests based on latex particle agglutination is commercially available. Contraindications for lumbar puncture In the presence of purpura or petechiae, LP may be hazardous and may add few data to aid in the diagnosis. In a patient with a depressed level of consciousness, shock, or any of the features listed below, lumbar puncture can be delayed, and treatment can immediately begin. The following are contraindications to lumber puncture (unless increased intracranial pressure [ICP] is ruled out):

• Prolonged or focal seizures

• Focal neurologic signs

• Widespread purpura or petechiae

• Glasgow Coma Scale score of less than 13

• Pupillary dilatation or asymmetry

• Impaired oculocephalic reflexes - ie, doll's eye reflexes

• Abnormal posture or movement, decerebrate or decorticate movement or cycling

• Coagulation disorder

• Papilledema

• Hypertension

• Signs of impending brain herniation - Inappropriately low pulse, increased blood pressure, irregular respiration)

Treatment & Management

Approach Considerations As mortality may be reduced with early antibiotic therapy, patients with a meningococcal rash should receive parenteral antibiotics by means of an intravenous (IV) or intramuscular (IM) route as soon as the diagnosis is suspected. [90] The IM administration of medications should be avoided in cases with shock because decreased tissue perfusion severely limits their delivery to the infected sites. Other than antimicrobial treatment, supportive measures in meningococcal disease may be required to correct circulatory collapse. Severe adrenal insufficiency requires corticosteroid replacement. [3] Chemoprophylaxis for meningococcal infection should be administered to intimate household, daycare center, and nursery school contacts of cases. Vaccinate household and other intimate contacts. Although increasingly well recognized and managed in children, meningococcal disease often is not diagnosed and treated in adults in medical settings. Fluid resuscitation may not be sufficiently aggressive, early intubation often is not considered, and the rapidity of disease progression in an adult often is not understood. Treatment of complications Arthritis has been found in about 10% of patients with meningococcal disease. This complication usually occurs within the first few days of treatment and manifests as effusion of a large joint, often the knee. Occasionally, repeated arthrocentesis is needed to control symptoms. Other possible complications include ischemic conditions caused by the coagulation abnormality and neurologic complications of meningitis. The patient must be observed for any neurologic sequelae; the frequency of neurologic abnormalities seems to be related to the severity of the acute disease. Some neurologic sequelae can develop in the absence of meningitis. Inpatient care Hospitalization usually is required for all patients even if only adequately monitor their response to antibiotic and other therapies. Promptly begin antibiotic treatment. Respiratory precautions generally include placement of the patient in a private room with proper air handling and the use of a respiratory mask by any person entering the patient's room. Discontinue respiratory isolation precautions after 24 hours of antibiotics. Monitor blood pressure, urine output, and cardiac function, as well as platelets, fibrin, and fibrin degradation products. Transfer to a PICU is necessary in approximately 20% of pediatric cases of meningococcal infection. Guidelines Several clinical guideline summaries related to meningococcal disease are available, as follows:

• American Academy of Pediatrics Committee on Infectious Diseases - Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients [5]

• Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices - Prevention and control of meningococcal disease [91]

• European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline - Diagnosis and treatment of acute bacterial meningitis [92]

Emergency Management of Meningococcal Infection

Although many meningococcal infections rapidly improve when treated with antibiotics, meningococcal disease may quickly progress. The time from the appearance of the first symptoms to death may be only a few hours. Because the mortality rate of meningococcal disease maybe as high as 40%, all patients with fever and petechiae warrant rapid initial assessment and empiric and ongoing assessment. The following findings may help in the identification of severely ill patients whose condition may deteriorate and who are likely to need intensive care:

• Shock/hypotension

• Absence of meningitis

• Rapidly extending rash

• Low WBC count

• Coagulopathy

• Deteriorating level of consciousness

• Increased ICP is more common in isolated cases of meningococcal meningitis.

Managing shock After basic life support and antibiotics are administered, the next priority is treating shock/hypotension with initial volume replacement at a rate of 20mL/kg. A satisfactory response to volume replacement is a reduction in heart rate and improved peripheral perfusion. The patient's condition may stabilize with only volume replacement, but the patient requires close monitoring and reassessment to detect further signs of shock or pulmonary edema (due to capillary leak syndrome). Managing raised intracranial pressure Suspect increased ICP if the patient has a decreased level of consciousness; focal neurologic signs; unequal, dilated, or poorly reacting pupils; abnormal posturing or seizures; relative hypertension or bradycardia; or if the patient is agitated or combative. Because papilledema is a late sign of increased ICP, its absence early on does not justify the discontinuance of monitoring for its development. After initiating basic life support measures and administering antibiotics, the therapeutic goal is to maintain oxygen and nutrient delivery to the brain. For this reason, shock must be corrected in individuals with both shock and increased ICP to maintain cerebral perfusion pressure. After correcting shock/hypotension with volume replacement and inotropic support as necessary, cautiously manage the fluid balance to avoid further increasing the ICP. Performance of a lumbar puncture should always be avoided Treatment of patients with limited shock and no increased ICP Reassess patients with limited shock and no increased ICP, as well as patients who respond rapidly to minimal volume replacement, for signs of deterioration during the first 48 hours following admission. The use of corticosteroids in meningitis may be considered. Several studies revealed that adjunctive dexamethasone reduces sensorineural hearing loss (but not mortality or other neurologic sequelae) in children and infants with H influenzae type B meningitis. Few adverse effects occur with dexamethasone administration. No reports of delayed CSF sterilization or treatment failure are known. A meta-analysis of findings from randomized, controlled trials suggested that such treatment has a benefit in preventing sequelae in meningococcal meningitis and pneumococcal meningitis in childhood. Data are limited for meningococcal meningitis, and the pathophysiologic events are likely to be similar to those of other forms of bacterial meningitis. In some animal models, anti-inflammatory therapy was beneficial. No evidence of the benefits of steroid use in patients with septic shock is known, and steroid use is necessary only with meningitis. If hypoadrenalism is suspected because of resistance to large doses of inotropic drugs, administer adrenal replacement doses of hydrocortisone. Replacement corticosteroids should not be used routinely in pediatric sepsis; their use is controversial in adult sepsis. [93, 94]

Pharmacologic Therapy The most important measure in treating meningococcemia is early detection and rapid administration of antibiotics. Third-generation cephalosporins such as ceftriaxone or cefotaxime are preferred because of their effectiveness and ease of administration. Meningococci are resistant to vancomycin, polymyxin, or achievable serum levels of aminoglycoside antibiotics. Empiric therapy Empiric antibiotic therapy should provide coverage of likely meningeal pathogens when no rash is present, when the etiology of meningitis is uncertain, and when an immediate microbiologic diagnosis is unavailable. This therapy can be narrowed down to specific therapy when the specific pathogen and its antibiotic sensitivities are determined. A third-generation cephalosporin is the appropriate antibiotic until culture results are available. Although meningococcal infection is the most common bacterial cause of a petechial or purpuric rash and meningitis, other organisms (including H influenzae type B and Streptococcus pneumoniae) can cause shock and a nonblanching rash. H influenzae type B is an uncommon cause of meningitis in developed countries with comprehensive vaccination programs. Most cases of bacterial meningitis that occur outside of the United States are due to N meningitides, with the rest resulting from S pneumoniae. In the United States, S pneumoniae is predominant. Empiric antibiotic therapy for meningitis based on age is as follows:

• Neonates - Ampicillin and ceftriaxone/cefotaxime

• Infants aged 1-3 months - Ampicillin and ceftriaxone/cefotaxime

• Older infants, children, and adults - Cefotaxime or ceftriaxone

Chloramphenicol 100 mg/kg/day in 4 divided doses (up to 4 g/day maximum dose) can be given as an alternative. Because there may be increased mortality compared with other regimens, it is no longer recommended as a first-line treatment. [95] Dexamethasone is indicated in the treatment of known or suspected pneumococcal meningitis in adults and children with H influenzae type B meningitis. Although of no benefit in meningococcal meningitis, it can be given until the causative organism is identified. [95]

Surgical Treatment of Ischemic Complications Patients who survive the initial acute phase of fulminant meningococcemia are at increased risk for serious complications due to extensive tissue necrosis. [96] Early in the course of tissue injury, conservative therapy is recommended until a distinct line of demarcation is apparent between viable and nonviable tissue.Once the patient is stable, débridement of all necrotic tissue is essential and may necessitate extensive removal of skin, subcutaneous tissue, and muscle. Large defects may be covered using microvascular free flaps or skin grafts. The use of artificial skin can spare the patient immediate use of autograft sites, which frequently are limited. [97] Avoid early limb amputation, because significant tissue recovery may occur as the disease progresses. Poor tissue perfusion also may lead to dental complications that require extensive extraction of severely affected teeth. [98] Anecdotally, fasciotomy may preserve limb and digit function in severe meningococcal septicemia when impending peripheral gangrene and increased compartment pressures are present. Measure compartment pressures and assess peripheral pulses with Doppler ultrasonography when patients have impaired limb perfusion or severe edema.

Monitoring and Follow-Up Pericarditis can occur during the recuperative period. It may present with fever and shortness of breath upon minimal exertion. Late skeletal deformities are rare, but epiphyseal avascular necrosis and epiphyseal-metaphyseal defects have been described. These usually occur in the lower extremities and result in angular deformity and inequality of leg length. Observe patients for any late neurologic sequelae. Abnormal findings on electroencephalography or cerebral computed tomography (CT) scanning, as well as epileptogenic activity, sensorineural hearing loss, impaired vestibular function, and neuropsychological impairment, have been found in up to 30% of survivors 1 year after an episode of meningococcal disease. The frequency of serious neurologic sequelae in individuals who survive an episode is 3%. Follow-up care at least 6 weeks after meningococcal infection should include the following:

• Ongoing management of specific complications such as amputations, skin grafting, or renal failure

• Thorough physical and nerological examination

• Assessment of plasma complement levels - Eg, total hemolytic complement, C3, and C4, with or without properdin

• Serologic confirmation of the diagnosis if no diagnosis was made at the time of presentation

• Audiologic function testing

• Basic assessment of psychological status after intensive care, if relevant

• Possible vaccination of contacts if an outbreak of group A, C, Y, or W-135 disease occurs

Vaccine

High-risk individuals Specific categories of individuals at high risk for meningococcal disease include the following [99] :

• Laboratory workers

• Patients with HIV

• Military recruits

• Outbreaks with type B among college freshmen living in dormitories

• Travelers to endemic zones (sub-Saharan Africa)

• Deficiencies of terminal complement including vaccinated patients on eculizumab

• Men who have sex with men (MSM) can develop urethritis due to an anaerobic tolerant clade of N meningitidis that facilitates rectal/urethral transmission. In this population, Gram negative diplococci should not be assumed to represent N gonorrhea.

• Individuals with asplenia

The recommendations include the following:

• Recommendations for use of MenB-4C vaccine are unchanged.

• The two MenB vaccines are not interchangeable, and the same product must be given for all doses in a series.

• Either MenB vaccine may be given concomitantly with other vaccines appropriate for this age, but preferably at a different anatomic site. [102, 103, 104, 105, 106, 107, 108, 109]

Prevention of Secondary Cases Antimicrobial chemoprophylaxis of close contacts is the primary means of preventing secondary cases of sporadic meningococcal disease. Person-to-person transmission can be interrupted by administration of an antimicrobial that eradicates the asymptomatic nasopharyngeal carrier state. Sulfonamides, rifampin, minocycline, ciprofloxacin, and ceftriaxone are the drugs that have been shown to eradicate meningococci from the nasopharynx. Because the rate of disease in secondary contacts is highest immediately after the onset of the disease in the patient, chemoprophylaxis should be administered as soon as possible, preferably within 24 hours. If chemoprophylaxis is delayed by more than 14 days, it probably is of limited value, although it still is recommended until 4 weeks after the patient's presentation. Populations at Risk for Secondary Cases Meningococcal infection probably is introduced into families by asymptomatic adults and then spread through 1 or more household contacts to infect younger family members. Household contacts are defined as individuals who live in the same home with a person who has a meningococcal disease. An operational definition commonly used by public health authorities includes persons eating and sleeping under the same roof as the index case. The attack rate of meningococcal disease among household contacts has been estimated to be several hundred times greater than that in the general population. The secondary attack rate is inversely proportional to age and is estimated to be approximately 10% in household contacts aged 1-4 years. Among adults, the risk is 3-4%. It should be assumed that the risk of acquiring meningococcal disease is signifcantly increased in other closed populations, such as those of daycare facilities and nursery schools. Healthcare workers who are exposed to aerosol secretions from patients with meningococcal disease are 25 times more likely to contract the disease compared with the general population. The likelihood of acquiring infection is increased 100-1000 times in sexually intimate contacts of individuals with meningococcemia. Indications for Chemoprophylaxis The American Academy of Pediatrics recommends antimicrobial chemoprophylaxis for contacts of persons with invasive meningococcal disease, including household members, individuals at daycare centers and nursery schools, and persons directly exposed to the patient's oral secretions (eg, kissing, sharing of food or beverages) within the 7 days preceding the onset of the illness in the index case. Consider antimicrobial chemoprophylaxis in hospital personnel who have had direct exposure to the oral secretions of a patient with meningococcal disease from such activities as mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management. To further decrease the risk for infection in the clinical setting, staff caring for patients with known or suspected meningococcal infections should wear masks, in addition to taking standard precautions. Patients with meningococcal disease who are hospitalized should be placed on respiratory precautions for the first 24 hours of effective antimicrobial therapy. When this is done, the risk for hospital personnel with casual or indirect contact is believed to be negligible. Antimicrobial chemoprophylaxis is not recommended in hospital personnel who have only casual or indirect contact with a patient with meningococcal disease. For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index patient or for anyone seated directly next to an index patient on a prolonged flight (ie, one that lasts ≥8h). Antibiotic chemoprophylaxis appears to be most effective if administerd within 24 h of contact. Little, if anything, is gained if given beyond 7days. Prophylactic Antibiotics Rifampin Rifampin commonly is used for meningococcal prophylaxis of household contacts in the United States; a 2-day oral course is recommended. Children younger than 1 month: 5mg /kg q12h Children older than 1 month: 10 mg/kg q12h Adults: 600mg q1h Ciprofloxacin Children younger than 18 years: not recommended because it has caused cartilage damage in immature experimental animals. Adults: A single dose of ciprofloxacin (500 mg) is an effective alternative to rifampin for the eradication of meningococcal carriage in adults. Ceftriaxone A single IM injection of ceftriaxone eradicates meningococcal carriage. Ceftriaxone is preferred in children who refuse oral medication and may be used in pregnancy. Children younger than 15 years: 125 mg IM Adults: 250 mg IM Meningococcal disease can be prevented by vaccination with group-specific meningococcal capsular polysaccharides. [91] Purified polysaccharides of groups A, C, Y, and W-135 meningococci have been used to stimulate group-specific humoral bactericidal antibodies.

Consultations Consultations in meningococcal disease include the following:

• Surgery - In cases involving gangrene of the extremities

• Hematology - May be needed to manage coagulopathy

• Cardiology - in cases with evidence of heart failure or pericarditis

• Infectious Disease - Required for all cases

• Preventive medicine specialist - To evaluate the community risk associated with an index case and to initiate reporting to local and regional health authorities if indicated

• Orthopedist and/or vascular surgeon

Local department of health to be notified of suspected and/or proven cases of meningococcal infection to assist in the evaluation and treatment of close contacts.

Medication

Medication Summary The role of antibiotics in managing meninogococcemia is to treat an active infection, provide prophylaxis to protect those with significant exposure to cases of N meningitidis, and eliminate the carrier state in asymptomatic individuals. Drugs effective in treating active meningococcal infection include 3rd generation cephalosporins like ceftriaxone, penicillin G, and chloramphenicol (in penicillin-allergic). Meningococcal resistance to penicillins has occurred; the mechanism of resistance involves altered penicillin-binding proteins. Chloramphenicol is less effective and should be avoided if other options are there. Antimicrobial susceptibility testing should be obtained prior to penicillin and ampicillin use. Resistance to ceftriaxone is rare. The duration of antimicrobial treatment is dictated by the clinical response. It should be no less than 7 days Individuals with greater than 4 hours of close contact with an index patient during the week before the onset of illness are at an increased risk for infection. Individuals at risk include housemates, daycare contacts, cellmates, or individuals exposed to infected nasopharyngeal secretions (eg, through kissing, mouth-to-mouth resuscitation, intubation, and suctioning). Rifampin and ciprofloxacin commonly are used for chemoprophylaxis. Ciprofloxacin should be avoided in pregnant and lactating women. Ciprofloxacin-resistant strains have been reported, and susceptibility testing should be used to guide prophylaxis based on local prevalence. [110] Rifampin may eradicate carriage in up to 80-90% of individuals, but resistant strains have occurred. [111] Other agents that can be used include ceftriaxone and azithromycin. A single dose of intramuscular ceftriaxone may be used in children or adults. During epidemics, vaccination should be adjunctive to antibiotic chemoprophylaxis for susceptible contacts. The eradication of carriage is also indicated in the index case unless third-generation cephalosporins have been used. See the Treatment Section for more detail.

Antimicrobial agents Class Summary Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. People who come into household contact with patients who have meningococcal disease are at risk of acquiring this illness. Person-to-person transmission can be interrupted by chemoprophylaxis, which eradicates the asymptomatic nasopharyngeal carrier state. Rifampin, ciprofloxacin and ceftriaxone are the antimicrobials used to eradicate meningococci from the nasopharynx. Mortality in meningococcal infections may be reduced with early antibiotic therapy. Regarding community management, because mortality may be reduced with early antibiotic therapy, patients with a meningococcal rash should receive parenteral benzyl penicillin by means of an IV or IM route as soon as the diagnosis is suspected. IM antibiotic injections may be less effective in a patient with shock and poor tissue perfusion. Give cefotaxime, ceftriaxone, or chloramphenicol to patients who are allergic to penicillin. Empiric antibiotic therapy for meningitis based on age is as follows: - Neonates - Ampicillin and cefotaxime - Infants aged 1-3 months - Ampicillin and cefotaxime - Older infants, children, and adults - Cefotaxime or ceftriaxone Penicillin G

Penicillin G interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. It should not be used empirically, against N Meningitidis. Infections caused by organisms classified as relatively resistant to penicillin, based on a minimum inhibitory concentration (MIC) of 0.1-1 µg/mL of penicillin, seem to respond to this drug as well as fully susceptible organisms do. Chloramphenicol

Chloramphenicol can be used in patients with penicillin and cephalosporin allergies. It binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria. Chloramphenicol-resistant strains are found in Southeast Asia but are rare in the United States. Ceftriaxone

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms. Ceftriaxone arrests bacterial growth by binding to 1 or more penicillin-binding proteins. It has successfully been used to treat pediatric meningococcal meningitis. It is useful in special circumstances (ie, relatively penicillin-resistant organisms, hypersensitivity reactions to penicillin or chloramphenicol). Ceftriaxone is a first-line antibiotic for empiric therapy of meningitis or sepsis while culture and susceptibility data are pending. Cefotaxime or ceftriaxone are the preferred agents for the treatment of confirmed meningococcal disease. Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin with a gram-negative spectrum. It has lower efficacy against gram-positive organisms. Cefotaxime has been used successfully in pediatric meningococcal meningitis The drug is more expensive than penicillin, but most authorities believe that it is as efficacious as penicillin in the treatment of meningococcal disease. Cefotaxime arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth. It is used for penicillin-resistant strains. Cefotaxime is used as a first-line antibiotic for the empiric therapy of meningitis or sepsis while culture and susceptibility data are pending. Cefotaxime or ceftriaxone are the preferred agents for the treatment of confirmed meningococcal disease. Ampicillin

A broad-spectrum penicillin that interferes with bacterial cell-wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Rifampin (Rifadin)

Rifampin is a semisynthetic derivative of rifamycin B that inhibits bacterial and mycobacterial RNA synthesis by binding to the beta subunit of deoxyribonucleic acid (DNA)–dependent RNA polymerase, thus inhibiting binding to DNA and blocking RNA transcription. Rifampin is commonly used for meningococcal prophylaxis of household contacts in United States, where one third of prevalent strains are sulfadiazine resistant. Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is a fluoroquinolone. It inhibits bacterial DNA synthesis and, consequently, growth. A single dose of 500mg has been found to provide an effective alternative to rifampin for the eradication of meningococcal carriage in adults. Ciprofloxacin is commonly used for meningococcal prophylaxis. It is not recommended for persons younger than 18 years because it has caused cartilage damage in immature experimental animals. Resistance has been reported, and it should only be used if the strain is known to be susceptible.

Corticosteroids Class Summary These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Dexamethasone (Decadron)

Dexamethasone may reduce sensorineural hearing loss in children and infants with H influenzae type B meningitis. Administer this agent to all children with suspected bacterial meningitis (the pathophysiology is likely to be similar). Dexamethasone does not reduce CNS clearance of bacteria or cause treatment failure. It is of no proven benefit in meningococcal meningitis and may be stopped following microbiologic confirmation.

Vaccines, Inactivated, Bacterial Class Summary These agents may be used to prevent and control outbreaks of serogroup C meningococcal disease. Meningitis group A C Y and W-135 vaccine diphtheria conjugate vaccine (Menactra, Menveo) Diphtheria toxoid conjugate vaccine induces the production of bactericidal antibodies specific to capsular polysaccharides of serogroups A, C, Y, and W-135. Meningococcal C and Y/haemophilus influenza type B vaccine (MenHibrix) Contains antigenic capsular polysaccharides (ie, meningococcal serogroups A and C, Haemophilus influenzae type b) that convey active immunity by stimulating endogenous antibody production; antibodies have been associated with protection from invasive meningococcal disease. Meningococcal Polysaccharide Vaccine A/C/Y/W-135

This is a quadrivalent vaccine for meningitis prophylaxis. It is considered an adjunct to antibiotic chemoprophylaxis. Meningococcal group B vaccine (Bexsero, Trumenba) Protection against invasive meningococcal disease is conferred mainly by complement-mediated antibody-dependent killing of N meningitidis.

References

1. Martínez JV, Verbanaz SC, Jordán R, Enríquez N, Efrón ED. [Chronic meningococcemia]. Medicina (B Aires). 2008. 68 (4):298-300. [QxMD MEDLINE Link].

2. Lau C-Y, Tremont EC. Meningococcus and miscellaneous neisseriae. Cunha CB. Schiossberg's Clinical Infectious Disease. 3rd. Oxford University Press; 2020. 946-952.

3. Welch SB, Nadel S. Treatment of meningococcal infection. Arch Dis Child. 2003 Jul. 88(7):608-14. [QxMD MEDLINE Link]. [Full Text].

4. Wang X, Theodore MJ, Mair R, Trujillo-Lopez E, du Plessis M, Wolter N, et al. Clinical validation of multiplex real-time PCR assays for detection of bacterial meningitis pathogens. J Clin Microbiol. 2012 Mar. 50 (3):702-8. [QxMD MEDLINE Link].

5. [Guideline] Crum-Cianflone N. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Infect Dis Ther. 2016. 116(2):89-112. [QxMD MEDLINE Link].

6. [Guideline] Prevention and control of meningococcal disease. MMWR Recomm Rep. 2013 Mar 22. 62:1-22. [QxMD MEDLINE Link].

7. Perea-Milla E, Olalla J, Sánchez-Cantalejo E, Martos F, Matute-Cruz P, Carmona-López G, et al. Pre-hospital antibiotic treatment and mortality caused by invasive meningococcal disease, adjusting for indication bias. BMC Public Health. 2009 Apr 3. 9:95. [QxMD MEDLINE Link].

8. Dhanoa RK, Selvaraj R, Shoukrie SI, Zahra A, Malla J, Selvamani TY, et al. Eculizumab's Unintentional Mayhem: A Systematic Review. Cureus. 2022 Jun. 14 (6):e25640. [QxMD MEDLINE Link].

9. Ladhani SN, Lucidarme J, Parikh SR, Campbell H, Borrow R, Ramsay ME. Meningococcal disease and sexual transmission: urogenital and anorectal infections and invasive disease due to Neisseria meningitidis. Lancet. 2020 Jun 13. 395 (10240):1865-1877. [QxMD MEDLINE Link].

10. Folaranmi TA, Kretz CB, Kamiya H, MacNeil JR, Whaley MJ, Blain A, et al. Increased Risk for Meningococcal Disease Among Men Who Have Sex With Men in the United States, 2012-2015. Clin Infect Dis. 2017 Sep 1. 65 (5):756-763. [QxMD MEDLINE Link].

11. Kratz MM, Weiss D, Ridpath A, Zucker JR, Geevarughese A, Rakeman J, et al. Community-Based Outbreak of Neisseria meningitidis Serogroup C Infection in Men who Have Sex with Men, New York City, New York, USA, 2010-2013. Emerg Infect Dis. 2015 Aug. 21 (8):1379-86. [QxMD MEDLINE Link].

12. Horino T, Kato T, Sato F, Sakamoto M, Nakazawa Y, Yoshida M, et al. Meningococcemia without meningitis in Japan. Intern Med. 2008. 47(17):1543-7. [QxMD MEDLINE Link].

13. Pollard AJ, Nadel S, Ninis N, Faust SN, Levin M. Emergency management of meningococcal disease: eight years on. Arch Dis Child. 2007 Apr. 92(4):283-6. [QxMD MEDLINE Link]. [Full Text].

14. Zughaier SM. Neisseria meningitidis capsular polysaccharides induce inflammatory responses via TLR2 and TLR4-MD-2. J Leukoc Biol. 2011 Mar. 89(3):469-80. [QxMD MEDLINE Link]. [Full Text].

15. Coureuil M, Join-Lambert O, Lécuyer H, Bourdoulous S, Marullo S, Nassif X. Pathogenesis of meningococcemia. Cold Spring Harb Perspect Med. 2013 Jun 1. 3 (6):[QxMD MEDLINE Link].

16. Brandtzaeg P, van Deuren M. Classification and pathogenesis of meningococcal infections. Methods Mol Biol. 2012. 799:21-35. [QxMD MEDLINE Link].

17. Brozna JP. Shwartzman reaction. Semin Thromb Hemost. 1990 Oct. 16 (4):326-32. [QxMD MEDLINE Link].

18. Cimé-Aké E, Carranza-Enríquez F, Hurtado-Arias JJ, Muñoz-Castañeda WRA, Medina-Fonseca B, Barrera-Vargas A, et al. Primary meningococcal septic arthritis associated with joint calcium oxalate crystals: A case report and review of the literature. Mod Rheumatol Case Rep. 2022 Jun 24. 6 (2):296-300. [QxMD MEDLINE Link].

19. Livorsi DJ, Stenehjem E, Stephens DS. Virulence factors of gram-negative bacteria in sepsis with a focus on Neisseria meningitidis. Contrib Microbiol. 2011. 17:31-47. [QxMD MEDLINE Link].

20. Plant L, Sundqvist J, Zughaier S, Lovkvist L, Stephens DS, Jonsson AB. Lipooligosaccharide structure contributes to multiple steps in the virulence of Neisseria meningitidis. Infect Immun. 2006 Feb. 74(2):1360-7. [QxMD MEDLINE Link]. [Full Text].

21. Sanders MS, van Well GT, Ouburg S, Morré SA, van Furth AM. Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors. BMC Infect Dis. 2012 May 11. 12:112. [QxMD MEDLINE Link].

22. Pathan N, Faust SN, Levin M. Pathophysiology of meningococcal meningitis and septicaemia. Arch Dis Child. 2003 Jul. 88(7):601-7. [QxMD MEDLINE Link]. [Full Text].

23. Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001 Aug 9. 345(6):408-16. [QxMD MEDLINE Link].

24. Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet. 2004 Jan 17. 363(9404):203-9. [QxMD MEDLINE Link].

25. Pathan N, Williams EJ, Oragui EE, Stephens AC, Levin M. Changes in the interleukin-6/soluble interleukin-6 receptor axis in meningococcal septic shock. Crit Care Med. 2005 Aug. 33(8):1839-44. [QxMD MEDLINE Link].

26. Bergounioux J, Coureuil M, Belli E, Ly M, Cambillau M, Goudin N, et al. Experimental evidences of human coronary microvasculature and myocardial tissue bacterial colonization during meningococcemia. Infect Immun. 2016 Aug 1. [QxMD MEDLINE Link].

27. MacLennan J, Kafatos G, Neal K, Andrews N, Cameron JC, Roberts R, et al. Social behavior and meningococcal carriage in British teenagers. Emerg Infect Dis. 2006 Jun. 12(6):950-7. [QxMD MEDLINE Link]. [Full Text].

28. Andersen UØ, Bay JT, Jensen LH. [Recurrent meningococcal infection in a young woman witha mutation in the C8B gene]. Ugeskr Laeger. 2022 Jun 6. 184 (23):[QxMD MEDLINE Link].

29. Faber J, Henninger N, Finn A, Zenz W, Zepp F, Knuf M. A toll-like receptor 4 variant is associated with fatal outcome in children with invasive meningococcal disease. Acta Paediatr. 2009 Mar. 98(3):548-52. [QxMD MEDLINE Link].

30. Jansen AG, Sanders EA, VAN DER Ende A, VAN Loon AM, Hoes AW, Hak E. Invasive pneumococcal and meningococcal disease: association with influenza virus and respiratory syncytial virus activity?. Epidemiol Infect. 2008 Nov. 136(11):1448-54. [QxMD MEDLINE Link]. [Full Text].

31. Fijen CA, Kuijper EJ, te Bulte MT, Daha MR, Dankert J. Assessment of complement deficiency in patients with meningococcal disease in The Netherlands. Clin Infect Dis. 1999 Jan. 28 (1):98-105. [QxMD MEDLINE Link].

32. Ladhani SN, Campbell H, Lucidarme J, Gray S, Parikh S, Willerton L, et al. Invasive meningococcal disease in patients with complement deficiencies: a case series (2008-2017). BMC Infect Dis. 2019 Jun 14. 19 (1):522. [QxMD MEDLINE Link].

33. MacNeil JR, Blain AE, Wang X, Cohn AC. Current Epidemiology and Trends in Meningococcal Disease-United States, 1996-2015. Clin Infect Dis. 2018 Apr 3. 66 (8):1276-1281. [QxMD MEDLINE Link].

34. Bacterial meningitis. CDC. Available at http://www.cdc.gov/meningitis/bacterial.html. 2015; Accessed: May 2015.

35. [Guideline] Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013 Mar 22. 62 (RR-2):1-28. [QxMD MEDLINE Link].

36. Ortega-Sanchez IR, Meltzer MI, Shepard C, Zell E, Messonnier ML, Bilukha O, et al. Economics of an adolescent meningococcal conjugate vaccination catch-up campaign in the United States. Clin Infect Dis. 2008 Jan 1. 46(1):1-13. [QxMD MEDLINE Link].

37. Cathie K, Levin M, Faust SN. Drug use in acute meningococcal disease. Arch Dis Child Educ Pract Ed. 2008 Oct. 93(5):151-8. [QxMD MEDLINE Link].

38. Mbaeyi SA, Joseph SJ, Blain A, Wang X, Hariri S, MacNeil JR. Meningococcal Disease Among College-Aged Young Adults: 2014-2016. Pediatrics. 2019 Jan. 143 (1):[QxMD MEDLINE Link].

39. Centers for Disease Control and Prevention (CDC). Meningococcal Disease, Surveillance Data Tables. Centers for Disease Control and Prevention (CDC). Available at https://www.cdc.gov/meningococcal/surveillance/surveillance-data.html#figure01. Accessed: 2021 Sep 7.

40. José Francisco Santos N, Viviane Matos F, Caroline Alves F, Martha Silva MS, Leila Carvalho C. Carriage prevalence of Neisseria meningitidis in the Americas in the 21st century: a systematic review. Braz J Infect Dis. 2019 Jul 22. [QxMD MEDLINE Link].

41. Tappero JW, Reporter R, Wenger JD, Ward BA, Reeves MW, Missbach TS, et al. Meningococcal disease in Los Angeles County, California, and among men in the county jails. N Engl J Med. 1996 Sep 19. 335(12):833-40. [QxMD MEDLINE Link].

42. Brundage JF, Ryan MA, Feighner BH, Erdtmann FJ. Meningococcal disease among United States military service members in relation to routine uses of vaccines with different serogroup-specific components, 1964-1998. Clin Infect Dis. 2002 Dec 1. 35(11):1376-81. [QxMD MEDLINE Link].

43. Mandal S, Wu HM, MacNeil JR, Machesky K, Garcia J, Plikaytis BD, et al. Prolonged university outbreak of meningococcal disease associated with a serogroup B strain rarely seen in the United States. Clin Infect Dis. 2013 Aug. 57 (3):344-8. [QxMD MEDLINE Link].

44. Simon MS, Weiss D, Gulick RM. Invasive meningococcal disease in men who have sex with men. Ann Intern Med. 2013 Aug 20. 159 (4):300-1. [QxMD MEDLINE Link].

45. Bozio CH, Blain A, MacNeil J, Retchless A, Weil LM, Wang X, et al. Meningococcal Disease Surveillance in Men Who Have Sex with Men - United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2018 Sep 28. 67 (38):1060-1063. [QxMD MEDLINE Link].

46. Miller L, Arakaki L, Ramautar A, Bodach S, Braunstein SL, Kennedy J, et al. Elevated risk for invasive meningococcal disease among persons with HIV. Ann Intern Med. 2014 Jan 7. 160 (1):30-7. [QxMD MEDLINE Link].

47. Sejvar JJ, Johnson D, Popovic T, Miller JM, Downes F, Somsel P, et al. Assessing the risk of laboratory-acquired meningococcal disease. J Clin Microbiol. 2005 Sep. 43 (9):4811-4. [QxMD MEDLINE Link].

48. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter ML, Danila R, et al. The changing epidemiology of meningococcal disease in the United States, 1992-1996. J Infect Dis. 1999 Dec. 180 (6):1894-901. [QxMD MEDLINE Link].

49. Centers for Disease Control and Prevention (CDC). Notice to Healthcare Providers: Recognizing and Reporting Serogroup B Meningococcal Disease Associated with Outbreaks at Princeton University and the University of California at Santa Barbara. Available at http://emergency.cdc.gov/han/han00357.asp. November 27, 2013;

50. Wilder-Smith A. W135 meningococcal carriage in association with the Hajj pilgrimage 2001: the Singapore experience. Int J Antimicrob Agents. 2003 Feb. 21(2):112-5. [QxMD MEDLINE Link].

51. Wilder-Smith A, Barkham TM, Earnest A, Paton NI. Acquisition of W135 meningococcal carriage in Hajj pilgrims and transmission to household contacts: prospective study. BMJ. 2002 Aug 17. 325(7360):365-6. [QxMD MEDLINE Link]. [Full Text].

52. Wilder-Smith A, Chow A, Goh KT. Emergence and disappearance of W135 meningococcal disease. Epidemiol Infect. 2010 Jul. 138(7):976-8. [QxMD MEDLINE Link].

53. Hart CA, Cuevas LE. Meningococcal disease in Africa. Ann Trop Med Parasitol. 1997 Oct. 91 (7):777-85. [QxMD MEDLINE Link].

54. Vyse A, Wolter JM, Chen J, Ng T, Soriano-Gabarro M. Meningococcal disease in Asia: an under-recognized public health burden. Epidemiol Infect. 2011 Apr 15. 1-19. [QxMD MEDLINE Link]. [Full Text].

55. Invasive meningococcal disease in England: annual laboratory confirmed reports for epidemiological year 2017 to 2018. Public Health England. Available at https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/751821/hpr3818_IMD.pdf. October 26, 2018; Accessed: August 13, 2019.

56. Sharip A, Sorvillo F, Redelings MD, Mascola L, Wise M, Nguyen DM. Population-based analysis of meningococcal disease mortality in the United States: 1990-2002. Pediatr Infect Dis J. 2006 Mar. 25 (3):191-4. [QxMD MEDLINE Link].

57. Christensen H, May M, Bowen L, Hickman M, Trotter CL. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis. 2010 Dec. 10(12):853-61. [QxMD MEDLINE Link].

58. Filippakis D, Gkentzi D, Dimitriou G, Karatza A. Neonatal meningococcal disease: an update. J Matern Fetal Neonatal Med. 2020 Nov 24. 1-6. [QxMD MEDLINE Link].

59. Moura AS, Pablos-Mendez A, Layton M, Weiss D. Epidemiology of meningococcal disease, New York City, 1989-2000. Emerg Infect Dis. 2003 Mar. 9(3):355-61. [QxMD MEDLINE Link]. [Full Text].

60. Kaplan SL, Schutze GE, Leake JA, Barson WJ, Halasa NB, Byington CL, et al. Multicenter surveillance of invasive meningococcal infections in children. Pediatrics. 2006 Oct. 118(4):e979-84. [QxMD MEDLINE Link].

61. Darton T, Guiver M, Naylor S, Jack DL, Kaczmarski EB, Borrow R, et al. Severity of meningococcal disease associated with genomic bacterial load. Clin Infect Dis. 2009 Mar 1. 48(5):587-94. [QxMD MEDLINE Link].

62. Bouneb R, Mellouli M, Regaieg H, Majdoub S, Chouchène I, Boussarsar M. Meningococcemia complicated by myocarditis in a 16-year-old young man: a case report. Pan Afr Med J. 2018. 29:149. [QxMD MEDLINE Link].

63. Gawalkar AA, Tale S, Chhabria BA, Bhalla A. Myocarditis and purpura fulminans in meningococcaemia. QJM. 2017 Nov 1. 110 (11):755-756. [QxMD MEDLINE Link].

64. Zeidan A, Tariq S, Faltas B, Urban M, McGrody K. A case of primary meningococcal pericarditis caused by Neisseria meningitidis serotype Y with rapid evolution into cardiac tamponade. J Gen Intern Med. 2008 Sep. 23(9):1532-5. [QxMD MEDLINE Link]. [Full Text].

65. Vienne P, Ducos-Galand M, Guiyoule A, Pires R, Giorgini D, Taha MK, et al. The role of particular strains of Neisseria meningitidis in meningococcal arthritis, pericarditis, and pneumonia. Clin Infect Dis. 2003 Dec 15. 37(12):1639-42. [QxMD MEDLINE Link].

66. Wong JS, Balakrishnan V. Neisseria meningitidis endogenous endophthalmitis: case report and literature review. J Pediatr Ophthalmol Strabismus. 1999 May-Jun. 36(3):145-52. [QxMD MEDLINE Link].

67. Feldman C, Anderson R. Meningococcal pneumonia: a review. Pneumonia (Nathan). 2019. 11:3. [QxMD MEDLINE Link].

68. Garcia NS, Castelo JS, Ramos V, Rezende GS, Pereira FE. Frequency of myocarditis in cases of fatal meningococcal infection in children: observations on 31 cases studied at autopsy. Rev Soc Bras Med Trop. 1999 Sep-Oct. 32 (5):517-22. [QxMD MEDLINE Link].

69. Borg J, Christie D, Coen PG, Booy R, Viner RM. Outcomes of meningococcal disease in adolescence: prospective, matched-cohort study. Pediatrics. 2009 Mar. 123(3):e502-9. [QxMD MEDLINE Link].

70. Buysse CM, Raat H, Hazelzet JA, Hulst JM, Cransberg K, Hop WC, et al. Long-term health status in childhood survivors of meningococcal septic shock. Arch Pediatr Adolesc Med. 2008 Nov. 162(11):1036-41. [QxMD MEDLINE Link].

71. Buysse CM, Oranje AP, Zuidema E, Hazelzet JA, Hop WC, Diepstraten AF, et al. Long-term skin scarring and orthopaedic sequelae in survivors of meningococcal septic shock. Arch Dis Child. 2009 May. 94(5):381-6. [QxMD MEDLINE Link].

72. Huang L, Fievez S, Goguillot M, Marié L, Bénard S, Elkaïm A, et al. A database study of clinical and economic burden of invasive meningococcal disease in France. PLoS One. 2022. 17 (4):e0267786. [QxMD MEDLINE Link].

73. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007 Jun 30. 369(9580):2196-210. [QxMD MEDLINE Link].

74. Feldman HA. Meningococcal infections. Adv Intern Med. 1972. 18:117-40. [QxMD MEDLINE Link].

75. Thimmesch M, Bodart E, Gavage P, Misson JP, Frère J. [Two case reports of meningococcemia. Review of the literature on chronic meningococcemia]. Arch Pediatr. 2016 Jun. 23 (6):595-8. [QxMD MEDLINE Link].

76. Prista-Leão B, Almeida F, Carvalho AC, Silva S, Sarmento A. Chronic meningococcemia. IDCases. 2019. 15:e00502. [QxMD MEDLINE Link].

77. Feldman HA. Meningococcal infections. Adv Intern Med. 1972. 18:117-40. [QxMD MEDLINE Link].

78. Giri S, Shrestha B, Gajurel BP, Sapkota D, Gautam N, Shrestha A. Staphylococcal endocarditis with meningitis and basal ganglia infarcts mimicking meningococcemia. Clin Case Rep. 2022 Mar. 10 (3):e05548. [QxMD MEDLINE Link].

79. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993 Jan 7. 328 (1):21-8. [QxMD MEDLINE Link].

80. Parmentier L, Garzoni C, Antille C, Kaiser L, Ninet B, Borradori L. Value of a novel Neisseria meningitidis--specific polymerase chain reaction assay in skin biopsy specimens as a diagnostic tool in chronic meningococcemia. Arch Dermatol. 2008 Jun. 144(6):770-3. [QxMD MEDLINE Link].

81. Periappuram M, Taylor MR, Keane CT. Rapid detection of meningococci from petechiae in acute meningococcal infection. J Infect. 1995 Nov. 31(3):201-3. [QxMD MEDLINE Link].

82. Arend SM, Lavrijsen AP, Kuijken I, van der Plas RN, Kuijper EJ. Prospective controlled study of the diagnostic value of skin biopsy in patients with presumed meningococcal disease. Eur J Clin Microbiol Infect Dis. 2006 Oct. 25(10):643-9. [QxMD MEDLINE Link].

83. Dolan Thomas J, Hatcher CP, Satterfield DA, Theodore MJ, Bach MC, Linscott KB, et al. sodC-based real-time PCR for detection of Neisseria meningitidis. PLoS One. 2011 May 5. 6(5):e19361. [QxMD MEDLINE Link]. [Full Text].

84. Guarner J, Greer PW, Whitney A, Shieh WJ, Fischer M, White EH, et al. Pathogenesis and diagnosis of human meningococcal disease using immunohistochemical and PCR assays. Am J Clin Pathol. 2004 Nov. 122(5):754-64. [QxMD MEDLINE Link].

85. Fernandez-Rodriguez A, Alcala B, Alvarez-Lafuente R. Real-time polymerase chain reaction detection of Neisseria meningitidis in formalin-fixed tissues from sudden deaths. Diagn Microbiol Infect Dis. 2008 Apr. 60(4):339-46. [QxMD MEDLINE Link].

86. Bryant PA, Li HY, Zaia A, Griffith J, Hogg G, Curtis N, et al. Prospective study of a real-time PCR that is highly sensitive, specific, and clinically useful for diagnosis of meningococcal disease in children. J Clin Microbiol. 2004 Jul. 42(7):2919-25. [QxMD MEDLINE Link]. [Full Text].

87. de Filippis I, do Nascimento CR, Clementino MB, Sereno AB, Rebelo C, Souza NN, et al. Rapid detection of Neisseria meningitidis in cerebrospinal fluid by one-step polymerase chain reaction of the nspA gene. Diagn Microbiol Infect Dis. 2005 Feb. 51(2):85-90. [QxMD MEDLINE Link].

88. Lin HW, Yin JH, Lo JP, Wang YH, Lee SY, Lu JJ. Use of universal polymerase chain reaction assay and endonuclease digestion for rapid detection of Neisseria meningitides. J Microbiol Immunol Infect. 2004 Dec. 37(6):371-4. [QxMD MEDLINE Link].

89. Richardson DC, Louie L, Louie M, Simor AE. Evaluation of a rapid PCR assay for diagnosis of meningococcal meningitis. J Clin Microbiol. 2003 Aug. 41(8):3851-3. [QxMD MEDLINE Link]. [Full Text].

90. Health Protection Agency. Guidance for the public health management of meningococcal disease in the UK. [Full Text].

91. [Guideline] Updated recommendations for use of meningococcal conjugate vaccines --- Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2011 Jan 28. 60(3):72-6. [QxMD MEDLINE Link].

92. van de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek AT, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May. 22 Suppl 3:S37-62. [QxMD MEDLINE Link].

93. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10. 358(2):111-24. [QxMD MEDLINE Link].

94. Jaeschke R, Angus DC. Living with uncertainty in the intensive care unit: should patients with sepsis be treated with steroids?. JAMA. 2009 Jun 10. 301(22):2388-90. [QxMD MEDLINE Link].

95. Brouwer MC, McIntyre P, de Gans J, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2010 Sep 8. CD004405. [QxMD MEDLINE Link].

96. Herrera R, Hobar PC, Ginsburg CM. Surgical intervention for the complications of meningococcal-induced purpura fulminans. Pediatr Infect Dis J. 1994 Aug. 13(8):734-7. [QxMD MEDLINE Link].

97. Besner GE, Klamar JE. Integra Artificial Skin as a useful adjunct in the treatment of purpura fulminans. J Burn Care Rehabil. 1998 Jul-Aug. 19(4):324-9. [QxMD MEDLINE Link].

98. Faibis S, Widmer R, Sapir S, Peretz B, Shapira J. Meningococcal septicaemia and dental complications: a literature review and two case reports. Int J Paediatr Dent. 2005 May. 15(3):213-9. [QxMD MEDLINE Link].

99. Dretler AW, Rouphael NG, Stephens DS. Progress toward the global control of Neisseria meningitidis: 21st century vaccines, current guidelines, and challenges for future vaccine development. Hum Vaccin Immunother. 2018 May 4. 14 (5):1146-1160. [QxMD MEDLINE Link].

100. Brown T. ACIP Updates Meningococcal B Vaccine Recommendations. Medscape. Available at http://www.medscape.com/viewarticle/880617. May 25, 2017; Accessed: June 1, 2017.

101. [Guideline] Patton ME, Stephens D, Moore K, MacNeil JR. Updated Recommendations for Use of MenB-FHbp Serogroup B Meningococcal Vaccine - Advisory Committee on Immunization Practices, 2016. MMWR Morb Mortal Wkly Rep. 2017 May 19. 66 (19):509-513. [QxMD MEDLINE Link].

102. Aaberge IS, Oster P, Helland OS, Kristoffersen AC, Ypma E, Høiby EA, et al. Combined administration of meningococcal serogroup B outer membrane vesicle vaccine and conjugated serogroup C vaccine indicated for prevention of meningococcal disease is safe and immunogenic. Clin Diagn Lab Immunol. 2005 May. 12(5):599-605. [QxMD MEDLINE Link]. [Full Text].

103. Bethell D, Pollard AJ. Meningococcal vaccines. Expert Rev Vaccines. 2002 Jun. 1(1):75-84. [QxMD MEDLINE Link].

104. Pollard AJ. Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr Infect Dis J. 2004 Dec. 23(12 Suppl):S274-9. [QxMD MEDLINE Link].

105. Tucker ME. New meningococcal vaccine recommended for high-risk infants. Medscape Medical News. Jan 24, 2013. Available at http://www.medscape.com/viewarticle/778124. Accessed: Feb 5, 2013.

106. Infant Meningococcal Vaccination: Advisory Committee on Immunization Practices (ACIP) Recommendations and Rationale. MMWR Morb Mortal Wkly Rep. 2013 Jan 25. 62:52-4. [QxMD MEDLINE Link].

107. Brown T. ACIP OKs Meningitis Vaccine (Menveo) for High-Risk Infants. Medscape Medical News. Available at http://www.medscape.com/viewarticle/813066. Accessed: October 28, 2013.

108. Basta NE, Mahmoud AA, Wolfson J, Ploss A, Heller BL, Hanna S, et al. Immunogenicity of a Meningococcal B Vaccine during a University Outbreak. N Engl J Med. 2016 Jul 21. 375 (3):220-8. [QxMD MEDLINE Link].

109. Update: Guillain-Barre syndrome among recipients of Menactra meningococcal conjugate vaccine--United States, June 2005-September 2006. MMWR Morb Mortal Wkly Rep. 2006 Oct 20. 55(41):1120-4. [QxMD MEDLINE Link].

110. McNamara LA, Potts C, Blain AE, Retchless AC, Reese N, Swint S, et al. Detection of Ciprofloxacin-Resistant, β-Lactamase-Producing Neisseria meningitidis Serogroup Y Isolates - United States, 2019-2020. MMWR Morb Mortal Wkly Rep. 2020 Jun 19. 69 (24):735-739. [QxMD MEDLINE Link].

111. Fraser A, Gafter-Gvili A, Paul M, Leibovici L. Prophylactic use of antibiotics for prevention of meningococcal infections: systematic review and meta-analysis of randomised trials. Eur J Clin Microbiol Infect Dis. 2005 Mar. 24(3):172-81. [QxMD MEDLINE Link].

112. Atkinson B, Gandhi A, Balmer P. History of Meningococcal Outbreaks in the United States: Implications for Vaccination and Disease Prevention. Pharmacotherapy. 2016 Aug. 36 (8):880-92. [QxMD MEDLINE Link].

113. Marshall GS, Dempsey AF, Srivastava A, Isturiz RE. US College Students Are at Increased Risk for Serogroup B Meningococcal Disease. J Pediatric Infect Dis Soc. 2019 May 11. [QxMD MEDLINE Link].

114. Soeters HM, Whaley M, Alexander-Scott N, Kanadanian KV, MacNeil JR, Martin SW, et al. Meningococcal Carriage Evaluation in Response to a Serogroup B Meningococcal Disease Outbreak and Mass Vaccination Campaign at a College-Rhode Island, 2015-2016. Clin Infect Dis. 2017 Apr 15. 64 (8):1115-1122. [QxMD MEDLINE Link].

115. Ladhani SN, Giuliani MM, Biolchi A, Pizza M, Beebeejaun K, Lucidarme J, et al. Effectiveness of Meningococcal B Vaccine against Endemic Hypervirulent Neisseria meningitidis W Strain, England. Emerg Infect Dis. 2016 Feb. 22 (2):309-11. [QxMD MEDLINE Link].

116. Tuncer AM, Gur I, Ertem U, et al. Once daily ceftriaxone for meningococcemia and meningococcal meningitis. Pediatr Infect Dis J. 1988 Oct. 7(10):711-3. [QxMD MEDLINE Link].

117. Hart CA, Cuevas LE. Meningococcal disease in Africa. Ann Trop Med Parasitol. 1997 Oct. 91(7):777-85. [QxMD MEDLINE Link].

118. U.S. Food and Drug Administration. First vaccine approved by FDA to prevent serogroup B Meningococcal disease. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm420998.htm. October 29, 2014;

119. [Guideline] American Academy of Pediatrics Committee on Infectious Diseases. Updated recommendations on the use of meningococcal vaccines. Pediatrics. 2014 Aug. 134 (2):400-3. [QxMD MEDLINE Link].

120. Harrison LH, Shutt KA, Arnold KE, Stern EJ, Pondo T, Kiehlbauch JA, et al. Meningococcal carriage among Georgia and Maryland high school students. J Infect Dis. 2015 Jun 1. 211 (11):1761-8. [QxMD MEDLINE Link].

121. Yue M, Xu J, Yu J, Shao Z. Carriage prevalence of Neisseria meningitidis in China, 2005-2022: a systematic review and meta-analysis. BMC Infect Dis. 2022 Jul 7. 22 (1):594. [QxMD MEDLINE Link].