Meningiococcemia (Menningococcemia (Menningiococcemia, Meningococcal bacteremia, Meningococcal septicemia)

Are You Confident of the Diagnosis?

Meningococcemia most commonly presents as an acute, rapidly evolving clinical syndrome. To avoid delaying or missing the diagnosis a vigilant clinician must be aware of the wide spectrum of clinical presentations. Treatment needs to be initiated as soon as the diagnosis is considered and then the classic history and examination findings and laboratory confirmation of the diagnosis should be sought.

What you should be alert for in the history

An acute illness is most often the hallmark of meningococcal disease, although chronic infection can occur and will be described below. The initial symptoms of acute disease are often nonspecific and include fever, malaise, and myalgias but rapid deterioration leading to septic shock, multiorgan failure and death within hours of symptom onset can occur. Since the presenting features may be so nonspecific, epidemiological and other risk factors as well as clinical examination clues should be kept in mind. The most striking feature and useful diagnostic clue of meningococcemia is the presence of a rash, occurring in 50 to 90% of patients with acute disease and more than 90% of patients with chronic meningococcemia.

Characteristic findings on physical examination

However, a very careful examination of a fully undressed patient is required to adequately assess for the presence of the rash of meningococcal disease, including inspection of the palms, soles and conjunctiva. Petechial lesions, 1-2 mm across, found most commonly on the lower half of the body, should be carefully sought. In the early stages of infection the petechial rash may be absent or subtle and only clearly visible in pressure areas (such as along constrictions caused by clothing). The petechiae and larger ecchymotic lesions that may develop from coalescence of petechial lesions reflect subcutaneous hemorrhage and the presence of thrombocytopenia. A transient maculopapular rash which can be easily mistaken for a viral exanthem is also occasionally present early in the disease process (Figure 1).

Figure 1.

Purpuric macules in a patient with meningococcemia. The patient eventually died from the disease.

In addition, patients with meningococcemia may present with the classic symptoms and signs of bacterial meningitis, including headache, photophobia, neck stiffness and a positive Kernig’s (pain on extending the knee > 135 degrees) and Brudzinski’s signs (flexion of knee and hip when examiner places one hand on the patient’s chest and flexes the patient’s neck with the other hand). Altered sensorium on presentation, or deterioration after presentation, is suggestive of meningoencephalitis.

An interesting feature of invasive meningococcal disease is that patients presenting with meningococcemia without meningitis have a worse prognosis than those presenting also with meningitis and meningococcemia. A timely diagnosis is often easier to make in a patient presenting with classic signs and symptoms of meningitis.

Expected results of diagnostic studies

Since the sensitivity of routinely available laboratory tests for meningococcemia is low, the diagnosis cannot be ruled out by negative cultures in a patient with a compatible presentation and no other confirmed diagnosis. Blood cultures, even if taken before antibiotics are administered will only have a sensitivity of approximately 50-70%.

Interestingly, cerebrospinal fluid (CSF) smear revealing gram-negative intracellular diplococci and cultures are positive in up to 70% of patients and may even be positive in patients not presenting with classic signs of meningeal involvement. Lumbar puncture and CSF analysis should therefore be performed if invasive meningococcal disease is a likely diagnosis unless a contraindication to lumbar puncture is present.

CSF analysis findings compatible with bacterial meningitis include a high protein, low glucose, and polymorphonuclear predominance. Patients who have received antibiotics may demonstrate a pleocytosis rather than a neutrophil predominance, and gram stain of the CSF may still show bacteria. Biopsy and/or needle aspiration of petechial skin lesions can also be a useful tool, since gram-negative diplococci can sometimes still be seen on the Grams stain of skin lesions 2-3 days after initiation of antibiotics.

Polymerase chain reaction performed on CSF, whole blood, or formalin-fixed tissue is a very useful tool in the timely diagnosis and typing of invasive meningococcal disease. The commercial availability has been limited thus far in the United States, but sending whole blood (ethylenediaminetetraacetic acid [EDTA] sample) for real-time meningococcal polymerase chain reaction (PCR) is part of routine clinical practice in Europe.

Diagnosis confirmation

The differential diagnosis of meningococcemia should include bacteremia and/or meningitis caused by other bacteria with a predilection for causing community acquired sepsis, such as Streptococcus pneumoniae and Staphylococcus aureus (including methicillin-resistant S aureus [MRSA]). Initial treatment should consider this differential but also other infectious diseases that can mimic the petechial/ purpuric skin lesions of meningococcal disease, including Rocky Mountain Spotted Fever (risk factor tick exposure), Dengue and other hemorrhagic fevers (with compatible travel history), Spirillum minus (rat bite fever), and Capnocytophaga canimorsus infection (dog exposure).

Blood cultures are the most useful test to help differentiate between most of these infections. Serology is needed to confirm Rocky Mountain Spotted fever or Dengue fever. If Rocky Mountain spotted fever is considered a possible diagnosis, the addition of doxycycline while confirmatory studies are pending should be considered.

Who is at Risk for Developing this Disease?

Infants younger than 1 year are most at risk for developing invasive meningococal disease, followed by young adults age 15 to 18. Young adults such as freshman college students and military recruits living in dormitories are at an increased risk compared to individuals of the same age not living in close accommodations.

Close contacts of individuals with recent invasive disease (meningitis or meningococcemia) are at risk of also developing invasive disease and should be considered promptly for prophylaxis (see treatment section below). Household contacts of individuals with invasive disease have an infection rate of more than 300 times the rate of the general population.

Individuals with immunodeficiencies including hypogammaglobulinemia, splenic deficiency (anatomic or functional), or complement or properdin deficiencies are more likely to develop invasive and/or recurrent meningococcal disease.

There are two circumstances when meningococcal disease should be considered as a potential cause of disease in travelers. Firstly, outbreaks of invasive disease have been associated with the Hajj pilgrimage to Saudi Arabia, with disease occurring in travelers and household contacts of travelers. Residents and travelers to sub-Saharan Africa during epidemic dry seasons are also at risk.

Routine vaccination of adolescents with the meningococcal conjugate vaccine (MCV4), preferably at 11 or 12 years of age, with a booster dose at 16 years of age is recommended by the American College of Immunization Practices (ACIP). Persons who receive their first dose of meningococcal conjugate vaccine at or after age 16 years of age do not need a booster.

A two-dose primary series of MCV4 is recommended for persons aged 2 to 54 with terminal complement deficiency, and persons with functional or anatomic asplenia. A booster dose should be provided every 5 years for these individuals.

The following persons at higher risk of disease should also be vaccinated:

  • college freshmen living in a dormitory

  • military recruits

  • microbiologists routinely exposed to Neisseria meningitidis

  • travelers (including children) to countries in which meningococcal disease is endemic

Other adolescents, college students, and persons infected with human immunodeficiency virus who wish to decrease their risk for meningococcal disease may also elect to receive vaccine.

What is the Cause of the Disease?

Neisseria meningitidis is a gram-negative diplococci which can asymptomatically colonize and persist in the oro or nasopharynx of healthy individuals for weeks to months. Transmission to other individuals then occurs via direct contact with respiratory secretions or airborne droplets.

In a very small proportion of colonized individuals the meningococcus disseminates from the oro or nasopharynx and causes invasive disease, most commonly meningococcemia and/or meningitis. The factors contributing to an asymptomatic colonized individual developing invasive disease are not fully understood but bacterial, host and environmental factors are all thought to play a role.

C5-C9 mediated serum bactericidal activity is a vital host defense mechanism against developing invasive disease and 15% of patients who develop invasive disease have a deficiency in C5-C9 terminal complement. Individuals with hypogammaglobulinemia, functional or anatomic asplenia or properdin deficiency are also at risk for invasive and recurrent disease.

The role environmental factors and living in close contact have in transmission of bacteria is better understood than the role of seasonal variation and temperature/humidity variations in promoting the development of invasive disease. However, a marked rise in epidemic invasive disease occurs in sub-Saharan Africa during the dry season and promptly ceases as soon as the rainy season commences.

Systemic Implications and Complications

The most common complications of meningococcemia are related to the effects of devastating sepsis or the sequelae of associated meningoencephalitis. The onset of sepsis is often sudden and can occur within a few hours of initial symptoms leading to hypotension, multiorgan dysfunction and peripheral necrosis and gangrene.

Patients with extensive peripheral or skin necrosis may require amputation of limbs or skin grafting to aid wound healing in the recovery phase. Secondary bacterial infection of the necrotic skin, soft tissues or underlying bone may occur and should be considered in a patient developing new fever or sepsis markers.

Complications of the meningoencephalitis which may accompany meningococcal bacteremia include cranial nerve (including eighth nerve) dysfunction, focal neurological deficits, and developmental problems in children.

Adrenal hemorrhage and acute Addisonian crisis (the Waterhouse Friderichsen syndrome) can occur even in the recovery phase of the disease and renal failure may persist into the recovery phase or long-term.

Treatment Options

Treatment of Invasive Meningococcal Disease (meningococcemia or meningococcal meningities

Resistance of meningococcal isolates to penicillin is rare but isolates with decreased susceptibility to penicillin have been reported in the United States, Europe, and Africa. On presentation the clinical manifestations of meningococcemia or meningitis cannot be confidently differentiated from bacteremia or meningitis, due to other common pathogens such as S pneumonia and S aureus (including MRSA).

Therefore, initial treatment should include a third-generation cephalosporin with reliable central nervous system (CNS) penetration (such as ceftriaxone or cefotaxime) and vancomycin. Dosages of antibiotics are listed in Table I. If culture and susceptibility results confirm a meningococcus susceptible to penicillin (MIC < 0.12μg/ml), treatment can be switched to penicillin G. However, cephalosporins are often continued for dosing convenience if out-patient antibiotic therapy is being considered.

Table I.
  Suspected invasive meningococcal disease Confirmed invasive meningococcal disease Duration
Adults             Ceftriaxone 2g every 12 hours intravenously+           Vancomycin 25-30mg/kg intravenously (loading) #                                    then           15-20mg/kg every 8-12hours inttravenously. (Trough 15-20ug/ml) Option 1 (if MIC < 0.12ug/ml):  Penicillin G 4MU every 4 hours intravenouslyOption 2:  Ceftriaxone 2 g every 12 hours intravenously   10-14 days
Children           Ceftriaxone 50mg/kg/dose (up to 2g) every 12h intavenously+        Vancomycin 10-15mg/kg/dose every 6 hours intravenously * Option 1 (if MIC < 0.12ug/ml):  Penicillin G 50,000U/kg every 4 hours intravenously (up to 4MU every 4 hours)Option 2:  Ceftriaxone 50mg/kg/dose every 12 hours intravenously (up to 2g every 12 hours) 10-14 days
Severely Penicillin Allergic Adults/Children Chloramphenicol 25mg/kg every 6 hours intravenously (up to 1g every 6 hours intravenously) Chloramphenicol 1g every 6 hours intravenously 10-14 days

*Vancomycin added to cover other bacterial etiologies of severe sepsis and/or meningitis eg, S pneumoniae and MRSA.  Consider broadening therapy further if special circumstances e.g. neutropenia or history of resistant pathogen in patient.

Management of Contacts of a Patient with Invasive Meningococcal Disease

Close contacts of patients with invasive meningococcal disease should receive prophylaxis within 24 hours of diagnosis and should be advised to promptly seek medical attention if they develop fever.

Chemoprophylaxis (Table II) is recommended for individuals who are household contacts of the index case or in the last 7 days prior to onset of symptoms in the index case were:

  • Frequent visitors to sleep and eat in the index case’s household.

  • Child care or nursery school contacts.

  • Exposed to index patients secretion (a) through social contact of kissing or sharing utensils or toothbrushes or (b) in a healthcare setting by performing mouth- to-mouth resuscitation, endotracheal intubation, or suctioning (without patient or healthcare provider a mask).

Table II.
  Prophylactic Regimens Notes
Adults Ciprofloxacin 500mg orally (single dose)1                            ORCeftriaxone 250 mg intramuscularly (single dose)                            ORRifampin 600mg every  12 hours X 4 doses orally2                             ORSpiramycin 500mg every 6 hours x 5 days orally                  1Ciprofloxacin-resistant meningococcus has been reported from North Dakota and Minnesota.  2If local resistant cases reported, use other optionsCheck carefully for drug interactions
Children Ceftriaxone 125mg intramuscularly (single dose) if < 15 years of age                           ORRifampin 10mg/kg every 12 hours X 4 doses orally if > 1 month old 2                          ORRifampin  5mg/kg every 12 hours X 4 doses orally if < 1 month old 2                          ORSpiramycin 10mg/kg every 6 hours x 5 days orally 2Check carefully for druginteractions

Optimal Therapeutic Approach for this Disease

Blood cultures should be performed as soon as the diagnosis of meningococcemia is considered and antibiotics administered immediately after drawing blood cultures. Remember that the outcome of the patient depends on how quickly you administer antibiotics.

Initial antibiotic selection should cover bacterial causes that may mimic meningococcemia, eg, Pneumococcus and S aureus (including MRSA) sepsis. If tick exposure is possible and the rash is compatible with that of Rocky Mountain spotted fever, doxycycline100mg twice daily or intravenously if the patient is unable to tolerate oral medications should also be given. Antibiotics should be rationalized once cultures and sensitivities are available, if necessary with assistance from infectious diseases specialist consultation.

The patient should be managed in a hospital unit with the availability to perform close cardiac, respiratory and neurological monitoring and should be placed in “droplet” isolation. Droplet isolation requires that all persons coming within 3-6 feet of the patient should wear a surgical tie-on mask. Any patient who finds it necessary to leave the isolation room temporarily for any reason should wear a tie-on mask . Droplet isolation precautions should be continued for 24 hours after the patient starts appropriate antibiotic therapy.

A lumbar puncture and CSF analysis for Gram stain, bacterial culture, cell count, protein and glucose should be performed in any patient without an irreversible contraindication to lumbar puncture who has symptoms (ie, headache, photophobia, confusion), or signs (eg, decreased mental status, neck stiffness, positive Kernig’s or Brudzinski’s signs) of meningeal inflammation.

A computed tomography (CT) scan of the head looking for evidence of raised intracranial pressure or a space-occupying lesion, such as an abscess should be performed before a lumbar puncture if the patient has decreased mental status, focal neurological signs, or is immunosupressed. Antibiotic administration should not be delayed while investigations are underway.

In an uncomplicated case treated promptly with antibiotics, fever and signs of sepsis may subside 48-72 hours after commencing antibiotics. However, development of complications including shock and multiorgan failure within 24-48 hours of onset of symptoms is not uncommon and supportive care, including admission to an Intensive Care Unit for aggressive fluid replacement, inotropic, ventilatory support, and renal replacement therapy are needed in the most severe cases.

The hospital infection control department should be notified and local health department staff informed that a patient with suspected (or confirmed) invasive meningococcal disease has been admitted. Decisions regarding prophylaxis of household, or in special circumstances such as daycare attendees other community contacts, are often best made in conjuction with the local health department, which, will also coordinate vaccination efforts if an outbreak with appropriate serogroups is underway in the community.

Blood and/or CSF culture results should be reviewed daily. Rationalization of antibiotics should be based on susceptibility results and if a penicillin susceptible meningococcus is confirmed (MIC < 0.12μg/ml), antibiotics can be simplified to penicillin alone (see treatment options section)

Monitoring of skin lesions for development of necrosis and of peripheries for development of vascular compromise and gangrene is an important part of patient care. Vascular and plastic surgery consultation may be necessary to aid in management of patients with severe complications of skin and soft tissue necrosis or peripheral limb gangrene.

After initial clinical stabilization, a new onset of hypotension and shock may reflect either a hospital-acquired infection (including bacterial superinfection and cellulitis of necrotic skin lesions, central line or urinary catheter infection or healthcare/ventilator associated pneumonia) or adrenal failure due to adrenal hemorrhage. A high index of suspicion for adrenal failure should be maintained and refractory or new hypotension in a patient being treated for meningococcemia should be investigated with a cortisol level and prompt steroid replacement therapy.

Patients should complete 10-14 days days of antibiotic therapy. In uncomplicated infections, patients may complete antibiotics as an outpatient through a peripherally inserted central catheter (PICC) or other central line. Laboratory monitoring of renal function and complete blood counts should be performed at least weekly during outpatient antibiotic therapy.

During the recovery phase, consideration should be given to investigating patients with severe or recurrent disease for an underlying immunodeficiency unless a predisposing condition such as anatomic or functional asplenia is readily apparent. Complement levels and properidin levels, should be performed along with discussion of any special circumstances with immunology or infectious diseases consultation.

Patient Management

Tell the patient that a bacterial infection is suspected, that they will receive antibiotics and be closely monitored, and that more information from cultures should be available over the next 24 hours. Explain to the patient that while tests are pending, precautions (droplet isolation), will be taken in case they have an infection that could be transmitted to close contacts, and that as their treating clinician you will work with infection control and public health authorities to determine if their community contacts (including family) should be treated with prophylactic antibiotics.

Explain to the patient (and/or family as appropriate) that their rash may worsen over the next few days and that the condition of the skin and underlying tissues will be closely monitored as well as their blood pressure, urine output and kidney function.

Unusual Clinical Scenarios to Consider in Patient Management

Remember that although most presentations of meningococcemia are acute, an indolent, or occasionally relapsing/remitting presentation known as chronic meningococcemia may occur. Presentation is accompanied with low-grade fever, rash and arthritis and closely resembles the symptoms and physical findings of chronic gonococcemia. Diagnosis is confirmed by blood cultures or bacterial cultures of the skin lesions and treatment regimens for acute meningococcemia should be followed. Interestingly, a few case reports of patients whose meningococcal bacteremia has cleared without antibiotic therapy are available in the literature.

Clinicians treating a patient with meningococcemia should be aware of the possibility of a patient developing an adrenal crisis secondary to adrenal hemorrhage. Known as the Waterhouse-Friderickson syndrome, the clinical deterioation of hypotension and/or recurrent fever may occur in a patient who had started to recover from the meningococcemia and may be mistaken for recurrent sepsis or superinfection.

Complications of meningococcal bacteremia from seeding of sterile sites, including septic arthritis, endocarditis and pericarditis, occasionally occur as part of the acute presentation or following initial recovery.

What is the Evidence?

Pickering, LK. Meningococcal Infections. Red Book: 2009 Report on the Committee on Infectious Diseases. 2009. pp. 455-63. (The definitive guidelines for management of close contacts of patients with invasive meningococcal disease, including the definition of a close contact and indications for antibiotic prophylaxis and consideration of meningococcal vaccination.)

Harrison, LH. ” Epidemiological Profile of meningococcal disesae in the United States”. Clin Infecti Dis. vol. 50. 2010. pp. S37-S44. (A review of the epidemiology of invasive meningococcal disease in the US and the vaccines available to cover the most prevalent strains in the US, describing the lack of vaccine for endemic disease caused by serogroup B strains.)

Apicella, MA, Mandel, GL, Bennett, JE, Dolin, R. “Neisseria meningitidis”. Principles and practice of Infectious diseases. 2006. pp. 2499-2513. (This chapter includes a thorough review of the microbiology, epidemiology and complications of meningococcal disease, including treatment options and outcomes.)

Visintin, C, Mugglestone, MA, Fields, E, Jacklin, P, Murphy, MS, Pollard, AJ. ” Management of bacterial meningitis and meningococcal septicemia in children and young people: summary of NICE guidance”. BMJ . vol. 341. 2010. pp. 92-8. (A succinct review of the presenting features of invasive meningoccal disease and shock as well as recommendations for management including management in the pre-hospital setting and intravenous fluid replacement.)

Sperenza, G, Javaheri, S. “Flu-like illness and a rash”. Lancet. vol. 372. 2008. pp. 688(An interesting description of a case of chronic meningococcal bacteremia.)

Brouwer, AC, Read, RC, van de Beek, D. ” Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis”. The Lancet Infectious Diseases. vol. 10(4). 2010. pp. 262-74. (A meta-analysis of published case-control studies on the influence of host genetics on severity and outcome in meningococcal disease, concluding that gene variation influences morbidity and mortality, specifically discussing an effect of polymorphisms in SERPINE 1, IL1RN and IL1B.)

(Up-to-date advice and information about the risk of meningococcal disease in travelers (specifically to sub-Saharan Africa) and indications for prohylaxis.)

Bilukha, OO, Rosenstein, N. ” Prevention and control of meningococcal disease, Recommendations of the Advisory Committee on Immunization Practices”. MMWR. vol. 54 (RR07). 2005. pp. 1-21. (Provides guidance on populations who should be considered for meningococcal vaccination.)