Critical Care Medicine

Meningococcemia/purpura fulminans

Meningococcemia

Synonyms

Meningococcus, meningococcal sepsis, meningococcal meningitis, Neisseria meningitidis

Related conditions

Purpura fulminans

1. Description of the problem

What every clinician needs to know

Meningococcal infections caused by the bacteria Neisseria meningitidis represent some of the most common and severe invasive bacterial infections in adults and children. N. meningitidis is now the leading cause of bacterial meningitis in children and young adults, and the second most common cause of bacterial meningitis across all age groups. The time from onset of symptoms to the development of shock and multiorgan system failure can be rapid - less than 24 hours - so a high index of suspicion and rapid interventions if suspected are important.

Infections may range from asymptomatic carriage to severe shock-like syndromes with or without meningitis. This illness may be classically considered in the differential of acute shock syndromes - presenting with fever and shock, or fever, shock, and rash (typically petechial), but it is important to consider that the classic presentation of fever with petechial rash is a late finding, and death or severe morbidity may occur in those presenting for therapy at that stage of illness.

If suspected, aggressive fluid resuscitation for shock syndromes and early antibiotic administration may be critical to improving patient outcome.

Consensus guidelines have been published on the management of severe meningococcal infections in children and young adults and may be found at http://guidance.nice.org.uk/CG102.

Clinical features

The classic clinical presentation associated with meningococcal sepsis (fever and petechiae, or fever and purpuric rash) are late findings that portend a worse outcome if present. Clinical features and laboratory tests may both be unreliable in ruling out an early meningococcal infection.

Based on a recent large retrospective review, symptoms may be classified as early, classic or late. Most children in this study had only non-specific symptoms in the first 4-6 hours but were close to death by 24 hours. Limb pain or refusal to walk are occasional complaints in young children with meningococcemia.

Nonspecific very early symptoms (first 4-6 hours):

Fever

Headache

Myalgia

Influenza-like symptoms

Early symptoms (median time to onset = 7-12 hours):

Leg pains

Thirst

Diarrhea

Abnormal skin color

Breathing difficulty

Cold hands and feet

Classic symptoms (median time to onset = 13-22 hours):

Hemorrhagic rash

Neck pain or stiffness

Photophobia

Bulging fontanelle

Late symptoms (median time to onset = 16-22 hours):

Confusion or delirium

Seizure

Unconsciousness

N. meningitidis may have several forms of presentation aside from fulminant meningococcal sepsis presenting with fever and petechial rash. Other forms include: occult bacteremia (typically in the setting of an upper respiratory infection), meningitis, pneumonia, septic arthritis, pericarditis, endopthalmitis and chronic meningococcemia.

The rash of meningococcemia may initially start as a blanching, nonpalpable macular rash. Rash is not invariably present, and its absence should not rule out a possible diagnosis of meningococcemia. It is important to completely disrobe the patient when looking for rash and to evaluate mucous membranes, so that hidden lesions are not missed. Over a short period of hours, the rash typically becomes petechial and then may progress to widespread purpura, potentially leading to loss of digits or extremities.

The petechial rash is most commonly found on the trunk and lower extremities, but can be hidden in places such as the conjunctiva. The lesions may be found underneath areas of skin pressure, such as the elastic band from underwear. Although a history of fever and a petechial rash should prompt early consideration of meningococcus as a cause, less than 15% of all children presenting with this combination are found to actually have N. meningitidis infection.

In young children, fever and vomiting may be the only symptoms, and children may not present until seizures or altered mental status occur. The symptoms of meningitis are nonspecific, and up to 20% of children may have seizures with meningococcal meningitis.

The term purpura fulminans refers to a severe, often fatal illness characterized by symmetric, progressive purpura, usually of the extremities, and typically occurring in children. The main association is with acute infection from Neisseria meningitidis, although the constellation of findings may also occur from other causes.

The term Waterhouse-Friderichsen syndrome refers to the clinical findings of diffuse purpuric lesions and disseminated intravascular coagulation, coupled with adrenal hemorrhage, adrenal insufficiency and shock. The most classic presentation of this illness is secondary to meningococcal infection, although other agents also may be causative.

Key management points

Early suspicion of meningococcus as a cause of illness is critical to appropriate management and therapy. The signs and symptoms of infection may be non-specific in the early course. The classic presentation of fever with petechiae or purpura is a late finding.

  1. Examination of mucous membranes and the entire body surface area for rash is important to see potentially hidden lesions that may help confirm the diagnosis (completely disrobe patient).

  2. For those with meningococcal sepsis/bacteremia/shock, aggressive fluid resuscitation is critical to improve outcome.

  3. For those with suspected meningococcal meningitis, management of raised intracranial pressure is critical to improve outcome.

  4. Antibiotics should be administered as soon as possible once a potential diagnosis of a meningococcal infection has been considered.

  5. Close contacts should receive prophylaxis as soon as possible as secondary cases may have a rapid onset.

Consensus guidelines have been published on the management of severe meningococcal infections in children and young adults and may be found at http://guidance.nice.org.uk/CG102.

2. Emergency Management

Emergency management steps

1. The initial priorities in management of meningococcal infections are the management of acute shock and if present, raised intracranial pressure. Aggressive fluid resuscitation is important for those presenting with shock. For those with raised intracranial pressure, neurointensive management should be considered.

Consensus guideline recommendations (NICE Clinical Guideline 102) for fluid management of children and young adults <16 years of age with meningococcal septic shock include:

  • If shock is present give immediate fluid bolus of 20 ml/kg sodium chloride 0.9% over 5-10 minutes.

  • If shock persists, immediately give a second bolus of 20 ml/kg of intravenous or intraosseous sodium chloride 0.9% or human albumin 4.5% solution over 5-10 minutes.

  • If shock still persists after the first 40 ml/kg, immediately give a third bolus of 20 ml/kg of intravenous or intraosseous sodium chloride 0.9% or human albumin 4.5% solution over 5-10 minutes, and:

    • Urgently intubate and mechanically ventilate.

    • Start treatment with vasoactive drugs.

    • Consider further fluid boluses at 20 ml/kg of intravenous or intraosseous sodium chloride 0.9% or human albumin 4.5% solution over 5-10 minutes based on clinical signs and appropriate laboratory investigations including urea and electrolytes.

2. Antibiotics should be administered as soon as possible when the diagnosis is considered. Some studies indicate that early antibiotic administration (even orally in the outpatient pre-hospital setting) may reduce morbidity and mortality. If possible, blood cultures or cultures of skin lesion scrapings should be obtained before administration of antibiotics, as therapy dramatically reduces the likelihood of organism recovery.

3. Consider adjunctive dexamethasone therapy with first dose of antibiotics if meningococcal meningitis is suspected (adult patients only).

4. Lumbar puncture should be considered as part of the diagnostic work up, but may be contraindicated in certain situations, including:

  • Raised intracranial pressure.

  • Relative bradycardia and hypertension.

  • Focal neurological signs.

  • Abnormal posture or posturing.

  • Unequal, dilated or poorly responsive pupils.

  • Papilloedema.

  • Abnormal ‘doll’s eye’ movements.

  • Shock.

  • Extensive or spreading purpura.

  • Uncontrolled seizures.

  • Coagulation abnormalities, thrombocytopenia.

  • Local superficial infection at the lumbar puncture site.

  • Respiratory insufficiency.

5. Metabolic derangements are common and need to be considered in patients presenting with severe meningococcal infections. These include:

  • Hypoglycemia, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia.

  • Anemia.

  • Thrombocytopenia.

  • Coagulopathy.

  • Metabolic acidosis.

  • SIADH may occur in the setting of meningitis.

  • Myocardial dysfunction can occur directly from meningococcal myocarditis or indirectly from acidosis and electrolyte abnormalities.

6. Droplet precautions are indicated for health professionals caring for patients with suspected meningococcal infections until adequate antimicrobial therapy has been administered.

7. Suspected or proven disease should be reported to the local health department. Prophylaxis should be administered to at risk close contacts given the rapidity with which secondary cases can occur.

8. Early consultation with intensive care and infectious diseases specialists may be indicated.

Algorithms are available for the acute management of adult and pediatric patients with meningococcal infections at http://www.meningitis.org/.

Management pathways for pediatric patients with meningococcal infections can be found at http://www.meningitis.org/health-professionals/hospital-protocols-paediatrics.

Management pathways for adult patients with meningococcal infections can be found at http://www.meningitis.org/health-professionals/hospital-protocols-adults.

3. Diagnosis

Establishing a specific diagnosis

Characteristic clinical findings plus isolation of the causative agent, Neisseria meningitidis, in normally sterile samples are the gold standards for diagnosis of meningococcal infections.

In patients presenting with suspected meningococcal infections, cultures should be obtained from clinical sites of likely infection. These include blood culture in almost all cases, CSF cultures in those with suspected meningitis and cultures of other sites such as joint fluid, pericardial fluid, etc. if clinically indicated. For those with petechial or purpuric rash, viable organisms may be found in aspirates or scrapings of lesions, and Gram stain and culture from lesions may yield the diagnosis.

Receipt of prior antibiotics significantly reduces the recovery of meningococcal organisms from culture specimens and may render Gram stains negative for visible organisms.

Prior antibiotics may reduce the recovery of bacteria from blood cultures by more than 90%. Blood culture bottles containing sodium polyanethol sulfonate (commonly found in adult, but not pediatric blood culture bottles) may inhibit growth of the organism and lead to a falsely negative result. N. meningitidis is relatively fastidious, and culture recovery may be impaired by refrigeration or delay in transport to the microbiology lab.

Cultures from sites that are not normally sterile, such as the throat or nasopharynx, are not acceptable specimens for diagnosis, as up to 10-15% of individuals may have asymptomatic carriage of N. meningitidis bacteria.

Latex agglutination for antigen detection on CSF from patients who have received prior antibiotics is occasionally used as an adjunctive measure for diagnosis. However, this test has poor sensitivity and specificity, and CSF latex agglutination tests in general have been shown to have little impact on overall patient management and outcome.

Polymerase chain reaction (PCR) testing has been extensively used for the diagnosis of meningococcal infections in the United Kingdom, but is not routinely available in most centers in the United States. More than 50% of cases in the U.K. are confirmed by PCR testing, and this modality may increase sensitivity over blood cultures by 30-40%. PCR based testing can also be performed successfully in some patients who have previously received antibiotics.

Routine laboratory values are generally neither sensitive nor specific for the diagnosis of meningococcal infections, but rather should be obtained to evaluate for hematopoietic and metabolic derangements. Evaluation of white blood counts may show leukocytosis or leukopenia (which may have poor prognostic significance). Anemia may occasionally be seen. Thrombocytopenia is common.

Electrolyte abnormalities are common and may occur in association with metabolic acidosis. Hyponatremia may occur as a result of SIADH secondary to meningitis.

Generalized coagulopathy may be present, often in the setting of disseminated intravascular coagulopathy (DIC). For this reason tests of coagulatory function and factors may be indicated.

A compatible clinical history coupled with culture confirmation of Neisseria meningitidis organisms provides a definitive diagnosis of meningococcal infection, however definitive diagnosis is often not possible and culture confirmation may take hours or days. Therefore, the initial diagnosis should be made on clinical grounds, as therapy should be instituted immediately and not delayed pending definitive confirmation.

Gram stain results from clinical specimens such as CSF or skin scraping may provide valuable immediate information. It is important to consider that some blood culture bottles may have inhibitors which prevent the growth of N. meningitidis in a culture system.

This has particular relevance when standard "adult" blood culture bottles are used, which are more likely to be inhibitory. Knowing which blood culture bottles were used for culture samples, and whether they contain the inhibitor sodium polyanethol sulfonate may be helpful if the culture results are negative in a clinically compatible case.

Prior studies have indicated that more than 50% of blood cultures are positive when meningococcal disease is present. Positivity of CSF Gram stains and cultures has ranged from 46% to 94% in various reports for those with meningitis. Skin lesion Gram stains and cultures have been reported to have sensitivities ranging from 50-70% when both tests are used in combination.

A surveillance case definition has been described for invasive meningococcal disease, which may be helpful in determining the need for public health reporting and prophylaxis of contacts (Red Book, 2009 Report of the Committee on Infectious Diseases):

Confirmed case of meningococcal infection:

A clinically compatible case and isolation of N. meningitidis from a usually sterile site, for example:

  • Blood.

  • CSF.

  • Synovial fluid.

  • Pleural fluid.

  • Pericardial fluid.

  • Isolation from skin scrapings of petechial or purpuric lesions.

Probable case of meningococcal infection:

  • A clinically compatible case with either a positive result of antigen test or immunohistochemistry of formalin-fixed tissue or a positive polymerase chain reaction test of blood or CSF without a positive sterile site culture

Suspect case of meningococcal infection:

  • A clinically compatible case and Gram-negative diplococci in any sterile fluid

  • Clinical purpura fulminans without a positive blood culture

The differential diagnosis of meningococcal infections includes:

  • Infectious causes:

    • Sepsis and/or meningitis from Streptococcus pneumoniae.

      • may also present with purpura fulminans type picture.

    • Rocky Mountain spotted fever.

    • Group A Streptococcal sepsis and/or toxic shock syndrome.

    • Staphylococcus aureus sepsis and/or toxic shock syndrome.

      • Fulminant staphylococcal bacteremia has been reported to present with a purpura fulminans picture similar to meningococcemia.

    • Haemophilus influenzae type B meningitis.

    • Disseminated gonococcal infection.

    • Enteroviral infections.

      • common cause of well appearing child with fever and petechial rash.

      • most common cause of meningitis in children

    • Epstein-Barr virus infection.

      • may be associated with petechial rash from autoimmune thrombocytopenia.

    • Parvovirus infection.

      • especially papular-purpuric gloves and socks syndrome in adolescents/young adults.

    • Gram-negative rod sepsis.

      • consider sources from urinary tract and/or intraabdominal.

    • Disseminated strongyloidiasis (immune compromised host).

  • Non-infectious causes:

    • Henoch-Schoenlein purpura.

    • Inherited coagulation disorders such as protein S or C deficiency.

    • Thrombotic thrombocytopenic purpura (TTP).

    • Idiopathic thrombocytopenic purpura (ITP).

    • Connective tissue disorders.

    • Trauma (especially children).

    • Side effects from drug anticoagulation.

Culture confirmation from normally sterile sites provides definitive evidence of meningococcal infection.

Other tests which may be used to provide evidence of meningococcal infection include:

  • Gram stain from sterile sites showing Gram-negative diplococci.

  • Latex agglutination test from CSF positive for N. meningitidis antigens.

  • PCR from normally sterile samples positive for N. meningitidis.

4. Specific Treatment

Antimicrobial agents

The treatment of meningococcal infections is most often initially empiric. Antimicrobial therapy should be given directed against meningococci as well as other common treatable causes with similar presentations. Although most meningococci are susceptible to penicillin, and this remains the drug of choice in many parts of the world, resistance has been documented, and penicillin may not provide adequate therapy empirically against other potential agents. In the United States, penicillin resistance among N. meningitidis remains below 5%.

For patients presenting with fever, shock, and/or petechial/purpuric rash considerations for empiric therapy should include:

  • Ceftriaxone or cefotaxime.

  • Vancomycin.

    • To provide coverage for drug resistant S. pneumoniae and S. aureus,including MRSA.

    • Consider in areas with high incidence of community acquired MRSA.

  • Doxycycline.

    • Provides coverage for Rocky Mountain spotted fever (endemic areas only).

For patients presenting with meningitis as a distinct syndrome, the age of the patient must be taken into account when providing empiric therapy:

  • Birth to 2 months:

    • Ampicillin.

    • Cefotaxime.

    • +/- Gentamicin if Gram-negative rod meningitis suspected.

    • +/- Acyclovir if Herpes Simplex Virus encephalitis is suspected.

  • 2 months to 55 years:

    • Ceftriaxone or cefotaxime.

    • Vancomycin.

  • > 55 years:

    • Ceftriaxone or cefotaxime.

    • Vancomycin.

    • Ampicillin.

Once a definitive diagnosis of meningococcal infection has been obtained, antimicrobial therapy can be tailored specifically to cover N. meningitidis:

  • Penicillin G remains the drug of choice for treatment of meningococcal infections in most parts of the world.

    • Alternative drugs should be used in areas with high endemic rates of resistance (e.g. Spain).

  • Ceftriaxone or cefotaxime are acceptable alternatives.

    • Ceftriaxone offers the advantages of once daily dosing, eradication of nasopharyngeal carriage with a single dose, and some data indicate it may have greater efficacy for treating meningococcal infections than comparator drugs.

    • Ceftriaxone should not be administered concurrently with calcium containing solutions. In that event, cefotaxime should be used instead.

  • Chloramphenicol may be used for patients with a history of severe anaphylactic reactions to penicillins or cephalosporins.

The treatment duration for meningococcal infections is typically 5-7 total days of therapy.

Adjunctive agents:

  • Steroids in conjunction with antibiotics for therapy of acute meningitis:

    • Dexamethasone therapy in conjunction with antibiotics just prior to, or with the first dose of initial antibiotics, has been shown in adults to provide benefit in meningitis from all causes, and may also provide benefit in meningococcal meningitis.

      • Recommended regimen: dexamethasone 0.15 mg/kg q6h for 4 days started with or just before the first dose of antibiotics.

        • There is no benefit to dexamethasone therapy if started after the initial dose of antibiotics.

        • In children, use of steroids as adjunctive therapy for meningitis is recommended routinely only for Haemophilus influenzae type B meningitis. The use of adjunctive steroids in this manner is considered controversial for pneumococcal and meningococcal infections in children due to conflicting and limited data.

  • Steroids for adrenal replacement:

    • Physiologic low dose replacement steroid therapy may be beneficial in the subset of patients presenting with shock and adrenal insufficiency.

      • This may particularly apply to patients presenting with meningococcemia and the Waterhouse-Friderichsen syndrome characterized by adrenal hemorrhage causing adrenal insufficiency and shock.

    • Patients most likely to benefit include those with absolute or relative adrenal insufficiency who are already requiring vasopressor support of blood pressure.

    • This practice varies by center and is considered controversial based on conflicting reports in the literature. If used, the possible side effects of superinfections, hyperglycemia and bleeding need to be carefully monitored for and managed if present.

Agents specifically indicated for N. meningitidis infections:

Penicillin G:

  • 250,000 Units/kg/day in divided doses IV every 4-6 hours. Maximum dosage 12 million Units/day.

Ceftriaxone:

  • 75-100 mg/kd/day in divided doses IV every 12-24 hours. Maximum dosage 4 grams/day.

Cefotaxime:

  • 200 mg/kg/day in divided doses IV every 6 hours. Maximum dosage 8 grams/day.

Chloramphenicol:

  • 75-100 mg/kg/day in divided doses IV/PO every 6 hours. Maximum dosage 2 grams/day.

Agents which may be indicated empirically for patients with suspected septic shock or meningitis:

Ampicillin:

  • Children older than 7 days: 200-400 mg/kg/day in divided doses IV every 6 hours. Maximum dosage 12 grams/day.

  • Adults: 150-200 mg/kg/day in divided doses IV every 6 hours. Maximum dosage 12 grams/day.

Vancomycin:

  • Adults: 45-60 mg/kg/day in divided doses IV every 8-12 hours.

  • Children: 60 mg/kg/day in divided doses IV every 6-8 hours.

Doxycycline:

  • Adults: 100 mg/dose IV/PO every 12 hours.

  • Children: 4.4 mg/kg/day in divided doses IV/PO every 12 hours. Maximum dosage 200 mg/day.

Refractory cases

For refractory cases of meningococcal sepsis, several additional therapy options may be considered:

  • Steroids for adrenal replacement:

    • Physiologic low dose replacement steroid therapy may be beneficial in the subset of patients presenting with shock and adrenal insufficiency.

      • This may particularly apply to patients presenting with meningococcemia and the Waterhouse-Friderichsen syndrome characterized by adrenal hemorrhage causing adrenal insufficiency and shock.

    • Patients most likely to benefit include those with absolute or relative adrenal insufficiency who already require vasopressor support of blood pressure.

    • This practice varies by center and is considered controversial based on conflicting reports in the literature. If used, the possible side effects of superinfections, hyperglycemia, and bleeding need to be carefully monitored for and managed if present.

  • Activated protein C (drotrecogin alfa, Xigris®) may be considered for adult patients only:

    • Administration of activated protein C has been demonstrated in a large, randomized, double-blind, placebo-controlled trial of adult patients to significantly reduce mortality in adult patients with severe sepsis.

      • The incidence of severe bleeding was increased in those patients receiving activated protein C.

        • Activated protein C should not be administered to any patients with baseline bleeding risk factors, including meningococcal shock patients with evidence of bleeding.

    • Activated protein C administration is contraindicated in pediatric patients due to lack of efficacy in published trials and increased risk of bleeding events noted in children receiving therapy. In particular CNS hemorrhage was noted more commonly in those children receiving drotrecogin alfa.

  • Plasmapheresis, hemofiltration, extra corporeal membrane oxygenation (ECMO):

    • For patients with severe or refractory septic shock, alternative therapies including plasmapheresis, hemofiltration and ECMO may be considered. Published data is mainly limited to single center experiences and no randomized, controlled trials have been performed.

5. Disease monitoring, follow-up and disposition

Monitoring and follow-up

Meningococcal infections have a high fatality rate, with an overall mortality rate of 10%.

For uncomplicated, non-severe disease, rapid improvement is generally expected. The organism is typically exquisitely sensitive to antibiotic therapy, often with a single dose of effective antibiotic therapy rendering body tissues sterile. Patients with uncomplicated meningitis tend to improve quickly, with return to normal function in a matter of days.

Those with fulminant meningococcemia tend to fare worse, often with long term morbidity. Unlike patients with only meningitis, a rapidly progressive course with death occurring within a matter of hours sometimes occurs. Severe ischemic skin or soft tissue damage may lead to loss of extremities or digits.

Specific complications which must be considered include:

  • SIADH in the setting of meningitis.

  • Acute interstitial myocarditis leading to depressed myocardial function, as a direct result of disseminated meningococcemia.

  • Adrenal hemorrhage leading to adrenal insufficiency and compounding shock (Waterhouse-Friderichsen syndrome).

  • Hearing loss from meningitis.

  • Skin, soft tissue and musculoskeletal morbidity as a result of ischemic necrosis.

  • Post-infectious inflammatory syndromes:

    • Secondary to immune complex deposition.

    • May lead to arthritis, vasculitis, iritis, pericarditis.

    • Typically occurs several days after the onset of infection.

    • Generally self resolves, therapy with NSAIDs may provide benefit.

Incorrect diagnosis

When adequate therapy is being provided for meningococcemia and the patient continues to worsen, alternative etiologies that are not currently being treated should be considered. In addition, although rare in the United States, drug resistance to penicillin and alteration in therapy to include ceftriaxone or cefotaxime should be considered, if therapy was initiated with penicillin.

However, it is difficult to use clinical deterioration while on therapy as a single marker of lack of response due to a possible incorrect diagnosis, as many patients with meningococcal sepsis have hypotension and multiorgan system dysfunction at the time of presentation, and mortality rates remain high even with appropriate therapy.

New clinical findings that support a different syndrome or disease, or identification of an organism other than Neisseria meningitidisfrom a diagnostic specimen, should prompt consideration of a different diagnosis. In areas with endemic Rocky Mountain spotted fever, consideration should also be given to that diagnosis at the time of presentation, and empiric therapy with doxycycline may be indicated.

Patients with meningitis will need followup hearing screens and close neurodevelopmental screens. The rates of sequelae are lower for meningococcal meningitis than for other pyogenic causes of meningitis (3-7%).

Patients with significant skin, soft tissue or extremity ischemia may need followup with orthopedic or plastic surgeons. It is generally recommended to allow ischemic limbs sufficient time to self demarcate viable from non-viable tissue prior to performing amputations to provide for maximum potential extremity recovery.

Patients with significant end organ dysfunction (myocarditis, acute renal insufficiency) typically have complete recovery, but some may need followup with subspecialists if persistent deficits remain.

Pathophysiology

Neisseria meningitidis are Gram-negative organisms that typically appear as diplococci morphologically. The diplococci may appear as "coffee bean" shapes with dimpling where they meet.

Pathogenic strains are surrounded by a polysaccharide capsule that increases virulence by preventing phagocytosis. This is a particularly important virulence factor for those with functional or anatomic asplenia, complement deficiency, and young children under 2 who produce relatively poor polysaccharide antibody responses.

Nasopharyngeal colonization with pathogenic strains typically precedes acute infection. Humans represent the only reservoir for Neisseria meningitidis. Acute infection occurs when nasopharyngeal colonization precedes bacteremia and seeding in secondary sites such as the meninges.

A systemic inflammatory response syndrome (SIRS) may occur when meningococci invade the bloodstream secondary to release of lipopolysaccharide (LPS) endotoxin, which is a potent promoter of the inflammatory cascade. Measures levels of LPS may directly correlate with severity of infection and risk for mortality in meningococcal disease.

This cascade may ultimately lead to the development of septic shock. In addition, disseminated intravascular coagulopathy is common with severe meningococcal infection, leading to ischemia and infarction in skin, soft tissue, and internal organs. The diffuse petechial or purpuric rash seen in association with meningococcemia represents widespread embolization of organisms, and frequently viable bacteria may be seen on Gram stain or culture taken directly from skin lesions.

The morbidity and mortality from meningitis is typically secondary to the inflammatory response occuring in the subarachnoid space leading to increased intracranial pressure, CNS vasculitis, and ischemia.

Epidemiology

Meningococcal infections occur in two major patterns: epidemic outbreaks or endemic disease. For epidemic outbreaks, the period of onset to secondary cases is typically short, with a median of 2 days and range of 1-31 days. For endemic sporadic cases among households, the median onset to secondary cases was 7 weeks in one study, with a range of 1-39 weeks.

Given the short onset of secondary cases in outbreak settings, immediate prophylaxis of at risk exposees is critical. The attack rate for household contacts is 500-800 times that for the general population.

Five major serogroups of N. meningitidis account for the vast majority of all invasive infections worldwide, and include types A, B, C, Y, and W-135. Routine vaccination with a polysaccharide-protein conjugate vaccine directed against serogroups A, C, Y, and W-135 is recommended for all adolescents and those at high risk in the United States.

The current vaccine will not eliminate meningococcal disease, as serogroup B accounts for a significant percentage of reported cases, and a licensed vaccine is as yet unavailable.

In the United States, the annual incidence of meningococcal infection is 1/100,000, with the exception of Oregon, which has witnessed an annual incidence that is 4 times higher than the rest of the nation since the early 1990s.

Other nations have significantly higher rates, in particular the United Kingdom (where rates to some serogroups have fallen since the introduction of routine vaccination), and sub-Saharan Africa in the "meningitis belt" that runs from east to west across the continent below the desert, where large outbreaks are commonly seen during the dry season. In addition, outbreaks have been reported among Muslim groups attending the Hajj pilgrimage.

Age is the most important risk factor for the acquisition of meningococcal infection, with infants less than 1 year having the highest rates of disease, and children under 5 accounting for 35-40% of cases.

Other risk factors that may be important for the acquisition of meningococcal infection or more severe disease include: complement deficiency, antibody deficiency, manose-binding lectin deficiency, functional/anatomic asplenia, household smoking, preceding viral respiratory illness, poverty, overcrowding or change of living conditions to a new closely associated community (e.g. college freshmen, new military recruits).

Prognosis

With early and aggressive management, most patients with meningococcal infection recover rapidly and do not suffer permanent sequelae. However, the overall mortality rate for meningococcal infections remains high at approximately 10%.

The most significant complication leading to long term morbidity from meningococcemia is the potential for loss of extremities and digits associated with purpura fulminans. This complication may occur in up to 4% of survivors and often involves more than one extremity.

Meningitis from N. meningitidis tends to produce somewhat lower rates of long-term neurologic sequelae in survivors than other common bacterial causes, such as pneumococcus and H. influenzae.

Several recent studies have looked at long term outcomes in patients with meningococcal infections. A 33 year review of complications from meningococcal infection in Denmark showed an overall case fatality rate of 7.6%, with the highest fatality rates in those over 50 (17.9%), and rates ranging from 3.5%-9.4% in those less than 50 years.

Case fatality rates were highest for those presenting to the hospital on the day of or following the day of onset (9.7%) versus those presenting after 2-4 days of illness (range 0.8% to 2.7%) suggesting those with more fulminant disease are likely to present earlier in a profound shock-like state. Other long-term complications included hearing loss in 1.9%, epilepsy in 1.4%, and cerebral palsy or limb plegia in 0.3%.

Another long-term followup study of those surviving meningococcal septic shock reported outcomes of major physical sequelae in 24%, mild neurological impairments in 33%, problem behavior in 14% and total IQ under 85 in 16%. Adolescent patients with fulminant meningococcemia often have more severe infections than other age groups with higher rates of morbidity.

One review of complications in college students in Pennsylvania reported an overall mortality rate of 11%, with 20% having permanent physical sequelae mainly due to tissue ischemia and necrosis. Another case control study of outcomes in adolescents with meningococcal disease in the U.K. reported that 57% of survivors had major physical sequelae. Survivors also had greater depressive symptoms, greater fatigue, less social support, greater reduction in quality of life and lower educational attainment compared to controls.

Special considerations for nursing and allied health professionals.

Immediate prophylaxis is indicated for exposed contacts when meningococcal infection is proven or strongly suspected.

Recommendations for prophylaxis (Red Book, 2009 Report of the Committee on Infectious Diseases):

High risk: chemoprophylaxis recommended (close contacts)

  • Household contact, especially children younger than 2 years of age.

  • Child care or pre-school contact at any time during 7 days before onset of illness.

  • Direct exposure to index patient's secretions through kissing or through sharing toothbrushes or eating utensils, markers of close social contact, at any time during 7 days before onset of illness.

  • Mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation at any time 7 days before onset of illness.

  • Frequently slept in same dwelling as index patient during 7 days before onset of illness.

  • Passengers seated directly next to the index case during airline flights lasting more than 8 hours

Low risk: chemoprophylaxis not recommended

  • Casual contact: no history of direct exposure to index patient's oral secretions (e.g. school or work).

  • Indirect contact: only contact is with high-risk contact, no direct contact with the index patient.

  • Health care professionals without direct exposure to patient's oral secretions.

In outbreak or cluster

  • Chemoprophylaxis for people other than people at high risk should be administered orally only after consultation with local public health authorities.

Chemoprophylactic drug regimens for Infants, children and adults:

  • Rifampin

    • < 1 mo of age: 5 mg/kg PO q12h x 2 days.

    • >= 1 mo of age: 10 mg/kg (max 600 mg) PO q12h x 2 days.

  • Ceftriaxone

    • < 15 y of age: 125 mg IM single dose.

    • >= 15 y of age: 250 mg IM single dose.

  • Ciprofloxacin

    • >= 1 mo of age: 20 mg/kg (max 500 mg) PO single dose.

    • Not routinely recommended for children under 18, use should be justified by risk/benefit analysis.

  • Azithromycin

    • 10 mg/kg (max 500 mg) PO single dose.

    • Not routinely recommended.

What's the evidence?

Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. "Meningococcal Infections". Red Book: 2009 Report of the Committee on Infectious Diseases. American Academy of Pediatrics. 2009. pp. 455-63.

(Standard reference for pediatric infectious disease management with up to date consensus treatment recommendations including prophylaxis guidelines.)

Visintin, C, Mugglestone, MA, Fields, EJ, Jacklin, P, Murphy, MS. "Management of bacterial meningitis and meningococcal septicaemia in children and young people: summary of NICE guidance". BMJ. vol. 340. 2010 Jun 28. pp. c3209.

(Summary of important consensus guidelines on the management of meningococcal infections in children in the U.K.)

Long, SS, Pickering, LK, Prober, CG. "Neisseria meningitidis". Principals and Practice of Pediatric Infectious Diseases. Churchill Livingston, Elsevier Inc. 2008. pp. 734-43.

(Excellent general reference on all aspects of meningococcal infections.)

Stephens, DS, Greenwood, B, Brandtzaeg, P. "Epidemic meningitis, meningococcaemia, and Neisseria meningitidis". Lancet. vol. 369. 2007 Jun 30. pp. 2196-210.

(Excellent general review on meningococcal infections.)

Thompson, MJ, Ninis, N, Perera, R, Mayon-White, R, Phillips, C. "Clinical recognition of meningococcal disease in children and adolescents". Lancet. vol. 367. 2006 Feb 4. pp. 397-403.

(Significant article describing clinical features and timeline of symptoms in meningococcal infections.)

Brierley, J, Carcillo, JA, Choong, K. "Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine". Crit Care Med. vol. 37. 2009 Feb. pp. 666-88.

(Consensus guidelines on management of septic shock in children.)

MacLaren, G, Butt, W, Best, D, Donath, S. "Central extracorporeal membrane oxygenation for refractory pediatric septic shock". Pediatr Crit Care Med. vol. 12. 2011 Mar. pp. 133-6.

(Study describing the utility of central ECMO for children with septic shock syndromes.)

Fortenberry, JD. "Pediatric critical care management of septic shock prior to acute kidney injury and renal replacement therapy". Semin Nephrol. vol. 28. 2008 Sep. pp. 447-56.

(Review on management measures for pediatric septic shock, including adjunctive measures such as ECMO.)

De Kleijn, ED, Joosten, KF, Van Rijn, B, Westerterp, M, De Groot, R. "Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease". Pediatr Infect Dis J. vol. 21. 2002 Apr. pp. 330-6.

(Report describing the high incidence and impact on mortality of adrenal insufficiency in children presenting with meningococcal disease.)

Hebbar, KB, Stockwell, JA, Leong, T, Fortenberry, JD. "Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock". Crit Care Med. vol. 39. 2011 May. pp. 1145-50.

(Study showing the importance of evaluating for and managing adrenal insufficiency in children presenting with shock, and impact of steroid replacement on reducing vasopressor use.)

Sprung, CL, Annane, D, Keh, D, Moreno, R, Singer, M. "CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock". N Engl J Med. vol. 358. 2008 Jan 10. pp. 111-24.

(Randomized, placebo control trial showing lack of survival benefit or shock reversal in patients treated with low dose steroid replacement.)

Annane, D, Bellissant, E, Bollaert, PE, Briegel, J, Confalonieri, M. "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review". JAMA. vol. 301. 2009 Jun 10. pp. 2362-75.

(Large meta-analysis describing a beneficial effect of low dose steroid replacement therapy on short-term mortality.)

Kalil, AC, Sun, J. "Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies". Intensive Care Med. vol. 37. 2011 Mar. pp. 420-9.

(Analysis of meta-analyses of low dose steroids for septic shock which reports no survival benefit, but a high probability of developing steroid-induced side effects with low dose steroid regimens.)

Bernard, GR, Vincent, JL, Laterre, PF, LaRosa, SP, Dhainaut, JF. "Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis". N Engl J Med. vol. 344. 2001 Mar 8. pp. 699-709.

(Seminal study showing significant reduction in mortality with use of activated protein C for sepsis in adult patients.)

Nadel, S, Goldstein, B, Williams, MD, Dalton, H, Peters, M. "REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial". Lancet. vol. 369. 2007 Mar 10. pp. 836-43.

(Important study showing lack of mortality benefit and higher risk of serious bleeding events with use of activated protein C in children.)

Zangwill, KM, Schuchat, A, Riedo, FX, Pinner, RW, Koo, DT. "School-based clusters of meningococcal disease in the United States. Descriptive epidemiology and a case-control analysis". JAMA. vol. 277. 1997 Feb 5. pp. 389-95.

(Epidemiologic study describing the timing of secondary cases among school children during an outbreak.)

Cooke, RP, Riordan, T, Jones, DM, Painter, MJ. "Secondary cases of meningococcal infection among close family and household contacts in England and Wales, 1984-7". BMJ. vol. 298. 1989 Mar 4. pp. 555-8.

(Study describing the timing and epidemiology of secondary cases among household contacts in the U.K.)

Borg, J, Christie, D, Coen, PG, Booy, R, Viner, RM. "Outcomes of meningococcal disease in adolescence: prospective, matched-cohort study". Pediatrics. vol. 123. 2009 Mar. pp. e502-9.

(Study describing long term outcomes among adolescents.)

Howitz, M, Lambertsen, L, Simonsen, JB, Christensen, JJ, Mølbak, K. "Morbidity, mortality and spatial distribution of meningococcal disease, 1974-2007". Epidemiol Infect. vol. 137. 2009 Nov. pp. 1631-40.

(Large, long-term study of outcomes in meningococcal infections.)

Buysse, CM, Vermunt, LC, Raat, H, Hazelzet, JA, Hop, WC. "Surviving meningococcal septic shock in childhood: long-term overall outcome and the effect on health-related quality of life". Crit Care. vol. 14. 2010. pp. R124.

(Study evaluating long-term quality of life and complications after meningococcal infections in children.)

Erickson, LJ, De Wals, P, McMahon, J, Heim, S. "Complications of meningococcal disease in college students". Clin Infect Dis. vol. 33. 2001 Sep 1. pp. 737-9.

(Long-term outcomes of meningococcal infections in college students.)
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