Meningococcal Disease Part II: Diagnostic Studies, Differential Diagnosis, and Management
Meningococcal Disease Part II: Diagnostic Studies, Differential Diagnosis, and Management
Authors: Sharon G. Humiston, MD, MPH, Associate Professor of Emergency Medicine, Department of Emergency Medicine, University of Rochester, NY; and Anne F. Brayer, MD, Department of Emergency Medicine, University of Rochester, NY.
Peer Reviewers: Robert W. Schafermeyer, MD, FACEP, FAAP, FIFEM, Associate Chair, Department of Emergency Medicine, Carolinas Medical Center; Adjunct Professor of Emergency Medicine and Pediatrics, University of North Carolina School of Medicine, Charlotte; and Ann Dietrich, MD, FAAP, FACEP, Associate Clinical Professor, Ohio State University, Attending Physician, Columbus Children's Hospital, Associate Pediatric Medical Director, MedFlight, Columbus, OH.
This issue of Emergency Medicine Reports contains the second and final part of the two-part series on meningococcal disease. Part I focused on the epidemiology, etiology, pathophysiology, and clinical features. Part II will cover diagnostic studies, differential diagnosis, and management of the disease.
The Editor
Diagnostic Studies
In the case of fulminant meningococcal disease, laboratory tests are not available fast enough to be helpful, and may be within normal ranges early in a precipitous course.1 Provide rapid fluid support and antibiotics immediately and obtain blood cultures with the initial IV placement if possible, but do not delay antibiotics for the sake of good cultures.
Detection and Confirmation of N. meningitidis Infection. Culture of the organism from a normally sterile site is the gold standard for bacteriologic diagnosis, but because of appropriate early administration of antibiotics, it may have low sensitivity.2 When CSF is available, Gram stain is highly sensitive and specific,3 and continues to be a fast and accurate test. Antigen detection assays of CSF, but not serum or urine, are of some use, but have high false-negative rates.2 Polymerase chain reaction (PCR) analysis of blood specimens has shown promise, with sensitivity of 91% and specificity of 76%.4 Because the test is neither widely available nor timely, it is more useful as a surveillance measure than as a clinical tool.5 If the patient's condition and time permit, send a throat swab for culture (most laboratories require specification of the organism from this site) and Gram stain and culture of aspirates from the edges of purpuric lesions.6
Detection of Meningitis. Always defer lumbar puncture until the patient has been stabilized fully. Do not perform a lumbar puncture in the presence of any of the following contraindications: shock, elevated ICP, coagulopathy, or an unstable airway (especially in a young, obtunded child).7,8 Nadel9 suggests that lumbar puncture always is contraindicated early in the course of treatment. If CSF is obtained, send it for total and differential white blood cell (WBC) counts, total protein, and glucose determinations. WBC counts will be elevated in most patients with meningitis, although when disease is severe and rapidly progressive, CSF WBC counts will be low or even normal; this is a negative prognostic sign. In such patients, markedly low glucose and elevated protein levels are associated with the diagnosis of meningitis; these ancillary tests add little information when they are only mildly abnormal.10 Remember that a negative lumbar puncture is an ominous, not a reassuring, finding in patients with meningococcal sepsis. Conversely, patients with meningococcal meningitis do not have worse outcomes even if treatment is delayed for many hours.11,12
Immune and Metabolic Determinations. Blood work in patients with SMS or MM is useful less for diagnostic purposes than for establishing and following the degree of immune response and metabolic injury. A complete blood count (CBC) may be useful, but be cautious in interpreting the results. Because of the rapid progress of SMS in particular, the WBC count may be normal. A very low WBC suggests overwhelming sepsis, as may the presence of toxic granulations. Hematocrit also may be low, normal, or high, depending upon the stage of progression and the patient's volume status. The platelet count is useful because it may be the fastest means of learning about the extent to which the patient has disseminated vascular coagulation (DIC), although, again, it may be normal early in the course. Determine other coagulation parameters through the use of standard measures such as international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT). Follow products of fibrinolysis, fibrin dimers, or fibrins split products.
Send blood for standard metabolic panels to detect abnormalities in electrolytes and acid-base status. Arterial blood gas determination may be useful, particularly after fluid resuscitation as an indirect measure of lung water. Elevated serum lactate correlates well with other measures of rapidly advancing sepsis and may be available quickly.13 Serum lactate elevations are specific, but not sensitive, as predictors of mortality from sepsis in adults.14
Differential Diagnosis
Meningococcal disease may be confused with "viral syndrome," influenza, upper respiratory infections, and abdominal pain.2,15,16-18 Later in its course, particularly once the classical confluent purpuric lesions are present, keep SMS at the top of the differential. Consider other conditions after initial resuscitation, antibiotics, and stabilization.
In the patient with early MM or other localizing disease, include other invasive bacterial infections in the differential depending on the site involved, bearing in mind that meningococcal disease causes pneumonia up to 15% of the time in adults.19 In evaluating the patient with rash, consider viral causes such as enteroviruses (in children in summer), parvovirus,20 the human herpesvirus 6, and the Rickettsial diseases (particularly when headache is present).21
The major presenting signs and symptoms of SMS and MM are compared in Table 1.
Management
Initial Treatment and Stabilization. The first step in managing the meningococcal clinical syndromes is to recognize them and be prepared to treat early and aggressively.22,23 Initial treatment and stabilization are per ED routine. These are outlined in Table 2.
Management Priorities and Overview. Treating Shock. The cornerstone of management of a patient with suspected N. meningitidis disease is the early recognition and treatment of shock. Give large isotonic fluid boluses (10-20 mL/kg in children, 1 liter in adults) over the first five minutes.24 This rate usually will require either manual "push" with a large volume syringe on a three-way stopcock, or a high volume infusion pump. Total fluid administration on the order of 60-100 cc/kg in the first hour is associated with improved survival.24 Monitor vital signs frequently during fluid resuscitation, bearing in mind that blood pressure may be an inaccurate measure of hemodynamic stability in children.
Vasoactive Agents. Once a patient has received 60 mL/kg or more of fluid, consider starting an inotropic/vasoactive agent such as dopamine or dobutamine.12,25 Starting these drugs sooner is of questionable value; they work best with a "full tank." If the patient continues to have circulatory instability following fluid resuscitation, rapid sequence intubation and administration of inotropes, then norepinephrine, epinephrine, or other agents that more dramatically increase peripheral resistance, may be required. These, however, are associated with the risk of further end-organ compromise as the result of vasoconstriction.26 In the vast majority of cases of SMS, initial fluid boluses alone will be insufficient to produce more than transient stabilization. Recognize this from the beginning of the encounter and plan both to administer large fluid volumes and to manage the inevitable consequences.
Airway Management. Fortunately, most patients with meningococcal disease, even with SMS, present with spontaneous respirations. Since one of the most threatening consequences of fluid volumes in this range is respiratory compromise from pulmonary edema,24,27 prepare for early, elective intubation.25 Convincing oneself to electively intubate a reasonably alert patient in early sepsis can be difficult, but this may prevent having to deal with severe airway edema later.
Rapid Sequence Intubation. Rapid sequence intubation (RSI) in a patient with septic shock carries its own risks. All sedative/anesthetic drugs used in RSI produce peripheral vasodilation and are negative inotropes. Neuromuscular paralysis reduces resting muscle tone, and positive pressure ventilation increases intrathoracic pressureboth of these factors reduce venous return. Together, the pronounced drop in peripheral resistance, inotropy, and venous return frequently produce markedly decreased cardiac output. It is not unusual for the already dysfunctional cardiac conduction system and myocardium to collapse at this point.25 If that occurs, further efforts at resuscitation may well fail.
Therefore, it is prudent to optimize the patient's physiological parameters immediately before the procedure, and to use the controlled airway to maximum advantage afterward. To do this:
- choose appropriate RSI drugs;
- optimize preload with continued rapid fluid infusions to maintain perfusion;
- strongly consider vasoactive pressors/inotropes such as dopamine or dobutamine before RSI;
- have a senior and experienced person perform the actual intubation as rapidly and efficiently as possible;
- choose a cuffed endotracheal tube even in children,25 in anticipation of the need for high ventilatory pressures and the use of positive end-expiratory pressure (PEEP) (cuffed tubes in sizes smaller than 6.0 often are difficult to finda good practice is to order a small number in assorted small sizes and keep them readily accessible but marked for use when specifically indicated only); and
- have a PEEP valve or other device available so that moderate positive pressure can be maintained to mitigate the inevitable pulmonary edema, atelectasis, and increased airway resistance.
Addressing Altered Mental Status. Altered mental status may result from shock or from meningitis with associated elevations in ICP. Patients in shock will have normal to low blood pressure and elevated heart rate, while those with ICP elevations will have normal to high blood pressure and low heart rate for age. When in doubt, treat shock aggressively and do not restrict fluids to protect ICP.28 The patient who dies of shock with a normal ICP is not a therapeutic success.
In patients who do have raised ICP, cerebral perfusion is at risk of compromise. Because cerebral perfusion pressure (CPP) is equal to the difference between mean arterial pressure (MAP) and ICP, cerebral perfusion can be increased by both reduction in ICP and increase in MAP. Reduce ICP using usual methods. [Bring ICP down by assuring adequate ventilation to keep arterial pCO2 in the normal (not below normal) range.25 Keep the patient's head midline and the head of the bed elevated (reverse Trendelenberg). Fluid restriction to two-thirds maintenance may help, again remembering that adequate circulating volume is the first concern. Diuretics such as furosemide or mannitol may help to reduce cerebral edema. (They will not address decreased CSF absorption.) Use both fluid restriction and diuretics with caution so long as there is any doubt at all about circulatory stability.25,29] Subsequent care is addressed in Table 3.
| Table 3. Care Subsequent to Initial Management |
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Steroid Use. As with other aspects of these conditions, the role(s) of steroids differs between the management of meningococcal sepsis and meningitis.
Steroid Use in SMS. Children with septic shock have lower overall cortisol levels and higher ACTH levels than do those with meningitis only.30 Adrenal insufficiency is associated with more profound and refractory shock states.31 For these reasons, physiologic doses of hydrocortisone are recommended (1 mg/kg q 6h) in patients who respond poorly to vasopressors.25 High-dose corticosteroids or dexamethasone have not been shown to be effective for septic shock.32
Steroid Use in MM. High-dose or high-potency corticosteroids have not been adequately studied in meningococcal meningitis, but experience with pneumococcal and H. influenzae disease suggests their efficacy. In these conditions, dexamethasone given early in the course reduces opening pressure, lowers levels of inflammatory mediators in CSF, and reduces hearing loss and other neurological sequelae.33 Most authorities recommend dexamethasone administration when meningitis is suspected with N. meningitidis.25
Admission and Transfer Considerations. All patients with known or suspected meningococcal disease need to be admitted to a hospital with intensive care capabilities. (See Table 3 and 4.) When such admission requires transport, be certain that the patient is stabilized adequately before transport. Usually this means early and frequent telephone consultations with the receiving institution.25 Get started on the transport arrangements as soon as possible, even while the initial resuscitation is under way.
| Table 4. Disposition, Observation, and Transfer Strategies |
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Cutting Edge Therapies. The increase in understanding of meningococcal disease has been accompanied by only a small increase in survivorship. This may be due to persistent delays in starting treatment.23 In fact, in at least one well-designed drug trial,36 the mortality rate prior to randomization to the study drug was so high that the study's power to detect treatment effect was impaired because of the exclusion of potential subjects who died prior to treatment. The following section briefly outlines the rationale for and success to date of treatment of meningococcal sepsis.
Anti-endotoxin Agents. Antibodies or antibody fragments directed against meningococcal lipopolysaccharide toxin or its bound complexes should, in theory, prevent or mitigate the effects of endotoxin, but they had negative effects in a randomized controlled trial.37 Early trials using the recombinant form of human bacterial permeability-increasing protein (rBPI) showed reduced mortality and improved functional outcome.35,36,38 This rBPI is produced naturally in neutrophils and binds endotoxin while also producing bactericidal effects.
Anti-Cytokines. Antibodies directed against most of the humoral mediators of inflammation such as TNF and the interleukins have been studied intensively and have failed.22,39 Again, it seems likely that by the time severe disease is recognized, the inflammatory process is too far advanced for interventions to be effective.
Anti-Coagulopathy Agents. Interfering with the sepsis cascade further down the line by modifying the sequence leading to coagulopathy has shown some benefit, but not without significant risks of exacerbation of bleeding. Activated protein C, a necessary component of the antithrombotic pathway, has shown efficacy in adult randomized controlled trials.40 The risk of uncontrolled hemorrhage limits its applicability.
Vaccines. The newest generations of meningococcal conjugate vaccines are highly efficacious and safe41-44 and can be used in very young patients, though none are licensed for infants younger than 2 years of age. Unfortunately, no widely available vaccine provides protection against capsular type B, still one of the more prevalent types in some environments. Newer multivalent vaccines likely will change this.45 The first conjugate meningococcal vaccine offering protection against capsular types groups A, C, Y, and W-135 was made available in the United States in early 2005 and is recommended for routine administration for children 11-12 years old, teens entering high school, and first-year college students living in dormitories.46
Additional Aspects
Treatment of Contacts. Treat household contacts of patients with meningococcal disease to eradicate nasopharyngeal carriage of the organism.47 It is not necessary to treat ambulance or hospital personnel who did not have close contact with respiratory secretions of the patient (such as intubating or providing mouth-to-mouth respirations). Use azithromycin, ciprofloxacin, or rifampin given orally for contacts. Surviving patients also require treatment with one of these drugspenicillin alone, while effective against sepsis and meningitis, does not eradicate nasopharyngeal carriage. (See Table 5.)
| Table 5. Antibiotic Prophylaxis for Patients and Contacts |
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Predictors of Outcome. A number of scoring systems have been developed aimed at predicting mortality from meningococcal disease, with varying success. Algren48 found that signs of circulatory insufficiency, a peripheral WBC count of less than 10,000/mm3, or coagulopathy were associated with high probability of organ system failure. Mortality rates are higher in patients with multiple organ system failure. The Pediatric Risk of Mortality Score (PRISM) and the Glasgow meningococcal septicemia prognostic score (GMSPS) have higher sensitivity but lower specificity than Algren's criteria.49,50
Summary
Perhaps ironically, despite the vastly improved understanding of the pathogenesis and molecular basis of meningococcal disease, no intervention has proved more effective at reduction in morbidity and mortality than the original "wonder drug" penicillin and the aggressive management of shock.25 It seems likely that the new-generation conjugate vaccines will have a greater ultimate impact on disease burden than any number of after-the-fact anti-endotoxin, anti-immune, or anti-inflammatory therapies. Clinicians still need to be watchful for patients with meningococcal disease and to be as aggressive as possible in treating it, but can look forward to a great reduction in disease incidence in the United States within a generation, if immunization results are comparable with those of the other recent conjugate vaccines.
References
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In the case of fulminant meningococcal disease, laboratory tests are not available fast enough to be helpful, and may be within normal ranges early in a precipitous course. Provide rapid fluid support and antibiotics immediately and obtain blood cultures with the initial IV placement if possible, but do not delay antibiotics for the sake of good cultures.Subscribe Now for Access
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