- Email: [email protected]
Meningococcal disease
African Journal of Emergency Medicine (2011) 1, 174–178
African Federation for Emergency Medicine
African Journal of Emergency Medicine www.afjem.com www.sciencedirect.com
Meningococcal disease La Me´ningococcie Alex Koyfman
a,*,#
, James Kimo Takayesu
b
a Department of Emergency Medicine, Brigham and Women’s Hospital and Massachusetts General Hospital, Boston, MA, United States b Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 5 Emerson Place, Boston, MA 02114, United States
Available online 28 July 2011
KEYWORDS Meningococcus; Meningococcemia; Meningitis; Sepsis; DIC; Chemoprophylaxis
Abstract The first cases of meningococcal meningitis were described in Geneva in 1805 and in New England in 1806, the causative agent finally being identified by Anton Weichselbaum in 1887. The first meningococcal epidemics occurred in sub-Saharan Africa in the early 1900s and periodic outbreaks continue to occur worldwide today. Neisseria meningitidis colonizes the naso-oropharyngeal mucosa in approximately 10–20% of healthy individuals. When it invades the bloodstream, meningococcus has the potential to cause devastating disease. It can affect people of any age, but primarily infects children and adolescents. Meningococcemia classically follows an upper respiratory illness consisting of myalgias, fever, headache, and nausea. It can present as an indolent infection with rapid recovery or progress within a few hours into a fulminant illness affecting multiple organ systems. As such, meningococcemia is one of the important causes of sepsis. Prior to antibiotic therapy, the disease carried a 70% mortality rate. Despite advances in early diagnosis and treatment, 10–15% of affected patients die from the disease and another 10–20% are left with severe morbidities (neurologic disability, hearing loss, loss of a limb). Meningococcal disease remains a significant global health threat. ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: +1 917 658 2802. E-mail address: [email protected] (A. Koyfman). # Address: 75 Francis Street, Neville House Boston, MA 02115, United States 2211-419X ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of African Federation for Emergency Medicine. doi:10.1016/j.afjem.2011.07.007
Production and hosting by Elsevier
Meningococcal disease
KEYWORDS Meningococcus; Meningococcemia; Meningitis; Sepsis; DIC; Chemoprophylaxis
175
Resume´ Les premiers cas de me´ningite a` me´ningocoques ont e´te´ de´crits a` Gene`ve en 1805 et en Nouvelle Angleterre en 1806, l’agent causal de la maladie e´tant finalement identifie´ par Anton Weichselbaum en 1887. Les premie`res e´pide´mies de me´ningococcie se sont pre´sente´es en Afrique subsaharienne au de´but du 20e` sie`cle et des e´pide´mies re´gulie`res se produisent toujours de nos jours dans le monde. Neisseria meningitidis colonise la muqueuse rhino-oropharynge´e chez 10 a` 20% environ des personnes en bonne sante´. Lorsqu’elle envahit le syste`me sanguin, Neisseria meningitidis peut provoquer une maladie de´vastatrice. Elle peut affecter des personnes de tout aˆge, mais infecte principalement les enfants et les adolescents. La me´ningococce´mie suit ge´ne´ralement une maladie des voies respiratoires supe´rieures consistant en myalgie, fie`vre, maux de teˆte et nause´es. Elle peut se pre´senter sous forme d’infection a` la malignite´ re´duite avec gue´rison rapide ou progresser en quelques heures en une maladie foudroyante affectant de multiples organes. C’est pourquoi la me´ningococce´mie est l’une des causes importantes de la septice´mie. Avant l’arrive´e des traitements antibiotique, la maladie e´tait associe´e a` un taux de mortalite´ de 70%. En de´pit des progre`s re´alise´s en matie`re de diagnostic et de traitement, 10 a` 15% des patients affecte´s de´ce`dent de la maladie et 10 a` 20% supple´mentaires souffrent de morbidite´s graves (handicap neurologique, perte d’audition, perte d’un membre). La me´ningococcie est toujours une menace sanitaire mondiale importante. ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Brief epidemiology, microbiology, and diagnosis. Pathophysiology and clinical presentation . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . African Relevance . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction The first cases of meningococcal meningitis were described in Geneva in 1805 and in New England in 1806, the causative agent finally being identified by Anton Weichselbaum in 1887.1,2 The first meningococcal epidemics occurred in sub-Saharan Africa in the early 1900s and periodic outbreaks continue to occur worldwide today. Neisseria meningitidis colonizes the naso-oropharyngeal mucosa in approximately 10–20% of healthy individuals. When it invades the bloodstream, meningococcus has the potential to cause devastating disease.3,4 It can affect people of any age, but primarily infects children and adolescents. Meningococcemia classically follows an upper respiratory illness consisting of myalgias, fever, headache, and nausea. It can present as an indolent infection with rapid recovery or progress within a few hours into a fulminant illness affecting multiple organ systems. As such, meningococcemia is one of the important causes of sepsis.3 Prior to antibiotic therapy, the disease carried a 70% mortality rate.5 Despite advances in early diagnosis and treatment, 10–15% of affected patients die from the disease and another 10–20% are left with severe morbidities (neurologic disability, hearing loss, loss of a
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175 175 176 176 177 177 177
limb).6,7 Meningococcal disease remains a significant global health threat. Brief epidemiology, microbiology, and diagnosis The incidence and timing of meningococcal outbreaks vary throughout the world. The major influences on this variability include the virulence characteristics of different strains, local vaccination and carriage rates, as well as individual susceptibility to infection. The incidence of endemic disease is <1–25 cases per 100,000 population per year worldwide. Higher rates are seen in sub-Saharan Africa from Ethiopia in the east to Senegal in the west, also known as the ‘‘meningitis belt’’, during December–June.8 Neisseria meningitidis is an encapsulated gram-negative diplococcus that can cause a wide spectrum of disease from a benign infection to septic shock. It is classified into serogroups based on the immunologic reactivity of its capsular polysaccharide. The five most clinically important serogroups are A, B, C, Y, and W-135.3 Serogroups A, B, and C predominate worldwide with group A being responsible for most African outbreaks.9,10 The virulence of meningococcus
176 is related to the release of its endotoxin lipopolysaccharide. This endotoxin is structurally different from that of other gram-negative bacteria. The level of endotoxin correlates with disease severity and can be up to 100-fold that of other gram-negative infections. Humans are the only known natural reservoir. Transmission is by direct contact with or inhalation of large droplet nuclei through respiratory secretions and saliva. Meningitis from hematogenous spread occurs in about 50% of patients. N. meningitidis can be isolated in up to 75% of patients, but meningococcemia develops in only 5–20%.3 Several options are available to ascertain the diagnosis including Gram stain, culture, antigen detection using latex agglutination, and PCR. Blood, CSF, or skin specimens may be tested depending on the specific presentation of the disease. In the setting of acute infection, the peripheral white blood cell count is typically elevated, sometimes as high as 65,000/mm3 with a polymorphonuclear predominance and thrombocytopenia may be present. White blood cell counts less than 500/mm3 and platelet counts less than 100,000/mm3 are both associated with poor prognosis. CSF pressure is usually elevated with an increased protein and decreased glucose level indicative of active bacterial replication and metabolism. Gram stain of the CSF may demonstrate gram-negative diplococci, but can be free of inflammatory cells early in the disease course.11 CSF can clear within 2 h of antibiotic administration.12 Immunoassays may be required cases in which antibiotics have been administered prior to cultures; PCR testing has demonstrated sensitivities and specificities at or above 90% for testing of CSF, serum, and whole blood.13 Pathophysiology and clinical presentation Any patient presenting with fever, headache, nausea, vomiting, myalgias, and a maculopapular or petechial rash should prompt the consideration of meningococcal infection.14 Petechial rash is the hallmark of invasive meningococcal disease and may be subtle at first, but progress rapidly.15,16 Patients with invasive meningococcal disease can present in one of four ways: meningitis only, shock and meningitis, acute mild meningococcemia (bacteremic with no shock), and fulminant meningococcemia (bacteremic with shock, no meningitis). Early on, the patient will present with tachycardia, normal systolic blood pressure with widened pulse pressure, bounding peripheral pulses, and warm extremities. As the disease progresses and hypotension ensues, extremities become cool, and peripheral pulses are diminished. Death in cases of meningococcemia is secondary to circulatory collapse resulting from vasodilation, capillary leak, intravascular volume depletion, and myocardial dysfunction. Tissue hypoxia and acidosis resulting from an inability to both utilize and receive nutrients further impairs myocardial function.17 Myocarditis, pericarditis, and/or direct bacterial invasion of the heart further contributes to hemodynamic failure. Major complications include pulmonary edema, acute respiratory distress syndrome, disseminated intravascular coagulation (DIC), adrenal hemorrhage (Waterhouse-Friderichsen syndrome), and purpura fulminans. Respiratory complications are secondary to capillary leak. DIC is initiated by activation of inflammatory mediators and can lead to end-organ damage. The progression of skin disease can lead to severe ecchymoses and limb ischemia as a result of hypoxia, hypoper-
A. Koyfman, J.K. Takayesu fusion, DIC, and direct cutaneous bacterial invasion.17,18 Long-term neurologic sequelae include deafness, mental retardation, seizures, and concentration problems in 10–20% of survivors.19 Management Meningococcal disease is a true medical emergency. It requires prompt recognition, early antibiotic therapy, and intensive patient management. The antibiotic of choice is high-dose intravenous ceftriaxone because of its good CSF penetration. Other options include penicillin G, ampicillin, cefotaxime, and chloramphenicol.3,14,18,20 Ideally, blood cultures should be drawn before antibiotic administration but antibiotic administration should never be delayed if cultures are not immediately obtainable. Lumbar puncture should be performed in hemodynamically stable patients without DIC not requiring immediate resuscitation. As with blood cultures, antibiotic therapy should not be delayed while waiting to perform lumbar puncture. Prior to bacterial speciation and susceptibility results, vancomycin should be added to cover drug-resistant S. pneumoniae. It is essential to adhere to local antibiotic resistance patterns to guide treatment as there will be variability from region to region. There is limited data to suggest that empiric steroid treatment prior to the initiation of antibiotic therapy may not be of benefit in meningitis caused by meningococcus compared to pneumoncoccus.21 Meningococcal infection is transmitted by respiratory droplets, therefore transmission prevention is achieved with airborne precautions. A surgical mask and gown should be worn by all persons entering the patient’s room, especially those within 3 feet (1 m) of the patient or having contact with patient secretions. These precautions should remain in place until 24 h after the patient exhibits no signs of ongoing infection including persistent fever; new skin lesions; or worsening leukocytosis, headache, confusion or neck stiffness.11 Further management of patients with meningococcal disease should be directed at restoring adequate oxygen and substrate delivery to the tissues. Intravascular volume should be repleted with isotonic crystalloid. Vasopressors may be necessary to counteract vasodilatory effects of the lipopolysaccharide endotoxin. Epinephrine and dopamine are good options because they improve contractility and vasoconstrict dilated vessels. Intravascular monitoring with central venous catheters for tracking volume status and intra-arterial blood pressure monitoring are useful to guide ongoing resuscitation. The role of steroids for adrenal replacement in septic shock remains unclear. If hypotension persists after adequate volume resuscitation and initiation of inotropic support, hydrocortisone should be considered. Unlike in Haemophilus influenza type B meningitis, few data exist to support the role of steroids in the prevention of hearing loss in patients with meningococcal meningitis.18,22 Data is also limited for the use of protein C concentrate and, to date, this therapy has no proven benefit on survival.23,24 Airway management may be required for patients with significantly compromised mental status requiring supplemental respiratory support or airway protection. Correction of coagulopathy with FFP is essential to prevent further complications from DIC such as intracranial hemorrhage, gastrointestinal bleeding, and hemorrhage into skin lesions.
Meningococcal disease DIC is a dynamic condition requiring clinical diagnosis based on the presence of multiple features including thrombocytopenia, prolongation of PT and aPTT, fibrin degradation with associated hypofibrinogenemia, and intravascular thrombosis. The International Society of Thrombosis and Haemostasis (ISTH) recommends a scoring system based on these features to diagnose DIC given the variations in presentation among patients.25 Treatment of DIC is based on treating the underlying condition rather than the manifestations of DIC itself. Due to the ongoing intravascular destruction of platelets and coagulation factors, platelet and plasma transfusions are reserved for patients with active bleeding or undergoing invasive procedures. Prophylactic transfusion is not recommended.11,25 Patients with thrombosis leading to purpura fulminans or vascular infarction may require anticoagulation with unfractionated heparin (10 units/kg/hr); aPTT monitoring is not useful due to the coincident coagulation disorder.25 Other specific therapies such renal replacement therapy (RRT) to correct volume status, electrolyte imbalances, and acid-base disturbances may be necessary. Some patients may require amputation of extremities as a result of limb ischemia resulting from DIC and septic shock. Antibiotic prophylaxis is recommended for individuals with close contact to the patient. This is defined as any prolonged (>8 h) contact in close proximity (<3 feet) to the patient and/or direct exposure to oral secretions one week prior to the onset of the patient’s symptoms until 24 h after initiation of appropriate antibiotic treatment. Chemoprophylaxis is recommended for health care workers whose mouth or nose is directly exposed to infectious respiratory droplets or secretions within a distance of 3 feet from an infected person, whether suspected or confirmed. This would include those providing care to a patient requiring direct contact (e.g., airway management without wearing a protective mask).11 Eye exposure alone is not an indication for chemoprophylaxis.26 Rifampin is the mainstay prophylactic agent; although ciprofloxacin, azithromycin, and ceftriaxone can also be used.3,27,28 Chemoprophylaxis is limited by issues of resistance (e.g., emerging ciprofloxacin-resistant strains), access to drugs, and the large number of people affected during epidemics, making prevention by vaccination the best control strategy. Those who most benefit from the vaccine include college students, military recruits, people with complement or other immune deficiencies, post-splenectomy patients, microbiologists routinely exposed to N. meningitidis isolates, and people who travel to or reside in countries where the bacterium is endemic.6,29 Routine immunization of health care workers is not recommended given the variety of serotypes possible and the narrow spectra of available immunizations. Conflict of interest None. African Relevance Very common disease in Africa Lots of time dedicated to this topic by WHO Area ripe for advances since morbidity/mortality still high
177 References 1. Vieusseux M. Mimoire sur la maladie qui a regni a Genjve au printemps de 1805. J Med Chir Pharmacol 1805;11:163. 2. Weichselbaum A. Ueber die Aetiologie der akuten Meningitis cerebrospinalis. Fortschr Med 1887;5:573–83. 3. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes J. Medical progress: Meningococcal disease. New Engl J Med 2001;344:1378–88. 4. Janda WM, Knapp JS. Neisseria and Moraxella catarrhalis. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH, editors. Manual of Clinical Microbiology, vol. 1. Berlin: Springer; 2003. p. 585–608. 5. Flexner S. The results of serum treatment in thirteen hundred cases of epidemic meningitis. J Exp Med 1913;17:553–76. 6. Healy CM, Baker CJ. The future of meningococcal vaccines. Pediatr Infect Dis J 2005;24:175–6. 7. Goldacre MJ, Roberts SE, Yeates D. Case fatality rates for meningococcal disease in an English population, 1963–8: database study. BMJ 2003;327:596–7. 8. World Health Organization 2010. World Health Organization, Meningococcal meningitis (Fact Sheet) (2010). http:// www.who.int/mediacentre/factsheets/fs141/en/print.html. 9. Caugant DA. Population genetics and molecular epidemiology of Neisseria meningitidis. APMIS 1998;106:505–25. 10. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter R, Danila R, et al.. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis 1999;180:1894–901. 11. Apicella MA. Neisseria Meningitidis. In: Mandell GL et al., editors. Principles and practice of infectious disease. 7 ed. Philadelphia: Churchill Livingstone; 2009. 12. Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics 2001;108(5):1169–74. 13. Corless CE, Guiver M, Borrow R, et al.. Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae in suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol 2001;39(4):1553–8. 14. Kirsch EA, Barton RP, Kitchen L, Giroir BP. Pathophysiology, treatment and outcome of meningococcemia: a review and recent experience. Pediatr Infect Dis J 1996;15:967–79. 15. Wells LC, Smith JC, Weston VC, et al.. The child with a nonblanching rash: how likely is meningococcal disease? Arch Dis Child 2001;85:218–22. 16. Nielsen HE, Andersen EA, Andersen J, et al.. Diagnostic assessment of haemorrhagic rash and fever. Arch Dis Child 2001;85:160–5. 17. Pathan N, Faust SN, Levin M. Pathophysiology of meningococcal meningitis and septicaemia. Arch Dis Child 2003;88:601–7. 18. Welch SB, Nadel S. Treatment of meningococcal infection. Arch Dis Child 2003;88:608–14. 19. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129:1307–26. 20. Wang VJ, Malley R, Fleisher GR, Inkelis SH, Kuppermann N. Antibiotic treatment of children with unsuspected meningococcal disease. Arch Pediatr Adolesc Med 2000;154:556–60. 21. De Gans J et al.. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347(20):1549–56, Nov 14. 22. McIntyre PB, Berkey C, King SM, Schaad UB, Kilpi T, Kanra GY, et al.. Dexamethasone as adjunctive therapy in bacterial meningitis: a meta-analysis of randomized clinical trials since 1988. JAMA 1997;278:9925–31. 23. Rintala E et al.. Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med. 2000;28(7):2373–8.
178 24. Pettenazzo A, Malusa T. Use of protein C concentrate in critical conditions: clinical experience in pediatric patients with sepsis. Minerva Anestesiol 2004;70(5):357–63. 25. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br J Haematol 2009;145:24–33. 26. Stuart JM, Gilmore AB, Ross A, et al.. Preventing secondary meningococcal disease in health care workers: recommendations of a working group of the PHLS Meningococcus Forum. Commun Dis Public Health 2001;4:102–5.
A. Koyfman, J.K. Takayesu 27. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Prevention and Control of Meningococcal Disease. MMWR 2000;49:1–10. 28. Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mortal Wkly Rep 1997;46:13–21. 29. Veeken H, Ritmeijer K, Hausman B. Priority during a meningitis epidemic: vaccination or treatment? Bull WHO 1998;76:135–41.
African Federation for Emergency Medicine
African Journal of Emergency Medicine www.afjem.com www.sciencedirect.com
Meningococcal disease La Me´ningococcie Alex Koyfman
a,*,#
, James Kimo Takayesu
b
a Department of Emergency Medicine, Brigham and Women’s Hospital and Massachusetts General Hospital, Boston, MA, United States b Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, 5 Emerson Place, Boston, MA 02114, United States
Available online 28 July 2011
KEYWORDS Meningococcus; Meningococcemia; Meningitis; Sepsis; DIC; Chemoprophylaxis
Abstract The first cases of meningococcal meningitis were described in Geneva in 1805 and in New England in 1806, the causative agent finally being identified by Anton Weichselbaum in 1887. The first meningococcal epidemics occurred in sub-Saharan Africa in the early 1900s and periodic outbreaks continue to occur worldwide today. Neisseria meningitidis colonizes the naso-oropharyngeal mucosa in approximately 10–20% of healthy individuals. When it invades the bloodstream, meningococcus has the potential to cause devastating disease. It can affect people of any age, but primarily infects children and adolescents. Meningococcemia classically follows an upper respiratory illness consisting of myalgias, fever, headache, and nausea. It can present as an indolent infection with rapid recovery or progress within a few hours into a fulminant illness affecting multiple organ systems. As such, meningococcemia is one of the important causes of sepsis. Prior to antibiotic therapy, the disease carried a 70% mortality rate. Despite advances in early diagnosis and treatment, 10–15% of affected patients die from the disease and another 10–20% are left with severe morbidities (neurologic disability, hearing loss, loss of a limb). Meningococcal disease remains a significant global health threat. ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: +1 917 658 2802. E-mail address: [email protected] (A. Koyfman). # Address: 75 Francis Street, Neville House Boston, MA 02115, United States 2211-419X ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of African Federation for Emergency Medicine. doi:10.1016/j.afjem.2011.07.007
Production and hosting by Elsevier
Meningococcal disease
KEYWORDS Meningococcus; Meningococcemia; Meningitis; Sepsis; DIC; Chemoprophylaxis
175
Resume´ Les premiers cas de me´ningite a` me´ningocoques ont e´te´ de´crits a` Gene`ve en 1805 et en Nouvelle Angleterre en 1806, l’agent causal de la maladie e´tant finalement identifie´ par Anton Weichselbaum en 1887. Les premie`res e´pide´mies de me´ningococcie se sont pre´sente´es en Afrique subsaharienne au de´but du 20e` sie`cle et des e´pide´mies re´gulie`res se produisent toujours de nos jours dans le monde. Neisseria meningitidis colonise la muqueuse rhino-oropharynge´e chez 10 a` 20% environ des personnes en bonne sante´. Lorsqu’elle envahit le syste`me sanguin, Neisseria meningitidis peut provoquer une maladie de´vastatrice. Elle peut affecter des personnes de tout aˆge, mais infecte principalement les enfants et les adolescents. La me´ningococce´mie suit ge´ne´ralement une maladie des voies respiratoires supe´rieures consistant en myalgie, fie`vre, maux de teˆte et nause´es. Elle peut se pre´senter sous forme d’infection a` la malignite´ re´duite avec gue´rison rapide ou progresser en quelques heures en une maladie foudroyante affectant de multiples organes. C’est pourquoi la me´ningococce´mie est l’une des causes importantes de la septice´mie. Avant l’arrive´e des traitements antibiotique, la maladie e´tait associe´e a` un taux de mortalite´ de 70%. En de´pit des progre`s re´alise´s en matie`re de diagnostic et de traitement, 10 a` 15% des patients affecte´s de´ce`dent de la maladie et 10 a` 20% supple´mentaires souffrent de morbidite´s graves (handicap neurologique, perte d’audition, perte d’un membre). La me´ningococcie est toujours une menace sanitaire mondiale importante. ª 2011 African Federation for Emergency Medicine. Production and hosting by Elsevier B.V. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Brief epidemiology, microbiology, and diagnosis. Pathophysiology and clinical presentation . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . African Relevance . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction The first cases of meningococcal meningitis were described in Geneva in 1805 and in New England in 1806, the causative agent finally being identified by Anton Weichselbaum in 1887.1,2 The first meningococcal epidemics occurred in sub-Saharan Africa in the early 1900s and periodic outbreaks continue to occur worldwide today. Neisseria meningitidis colonizes the naso-oropharyngeal mucosa in approximately 10–20% of healthy individuals. When it invades the bloodstream, meningococcus has the potential to cause devastating disease.3,4 It can affect people of any age, but primarily infects children and adolescents. Meningococcemia classically follows an upper respiratory illness consisting of myalgias, fever, headache, and nausea. It can present as an indolent infection with rapid recovery or progress within a few hours into a fulminant illness affecting multiple organ systems. As such, meningococcemia is one of the important causes of sepsis.3 Prior to antibiotic therapy, the disease carried a 70% mortality rate.5 Despite advances in early diagnosis and treatment, 10–15% of affected patients die from the disease and another 10–20% are left with severe morbidities (neurologic disability, hearing loss, loss of a
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limb).6,7 Meningococcal disease remains a significant global health threat. Brief epidemiology, microbiology, and diagnosis The incidence and timing of meningococcal outbreaks vary throughout the world. The major influences on this variability include the virulence characteristics of different strains, local vaccination and carriage rates, as well as individual susceptibility to infection. The incidence of endemic disease is <1–25 cases per 100,000 population per year worldwide. Higher rates are seen in sub-Saharan Africa from Ethiopia in the east to Senegal in the west, also known as the ‘‘meningitis belt’’, during December–June.8 Neisseria meningitidis is an encapsulated gram-negative diplococcus that can cause a wide spectrum of disease from a benign infection to septic shock. It is classified into serogroups based on the immunologic reactivity of its capsular polysaccharide. The five most clinically important serogroups are A, B, C, Y, and W-135.3 Serogroups A, B, and C predominate worldwide with group A being responsible for most African outbreaks.9,10 The virulence of meningococcus
176 is related to the release of its endotoxin lipopolysaccharide. This endotoxin is structurally different from that of other gram-negative bacteria. The level of endotoxin correlates with disease severity and can be up to 100-fold that of other gram-negative infections. Humans are the only known natural reservoir. Transmission is by direct contact with or inhalation of large droplet nuclei through respiratory secretions and saliva. Meningitis from hematogenous spread occurs in about 50% of patients. N. meningitidis can be isolated in up to 75% of patients, but meningococcemia develops in only 5–20%.3 Several options are available to ascertain the diagnosis including Gram stain, culture, antigen detection using latex agglutination, and PCR. Blood, CSF, or skin specimens may be tested depending on the specific presentation of the disease. In the setting of acute infection, the peripheral white blood cell count is typically elevated, sometimes as high as 65,000/mm3 with a polymorphonuclear predominance and thrombocytopenia may be present. White blood cell counts less than 500/mm3 and platelet counts less than 100,000/mm3 are both associated with poor prognosis. CSF pressure is usually elevated with an increased protein and decreased glucose level indicative of active bacterial replication and metabolism. Gram stain of the CSF may demonstrate gram-negative diplococci, but can be free of inflammatory cells early in the disease course.11 CSF can clear within 2 h of antibiotic administration.12 Immunoassays may be required cases in which antibiotics have been administered prior to cultures; PCR testing has demonstrated sensitivities and specificities at or above 90% for testing of CSF, serum, and whole blood.13 Pathophysiology and clinical presentation Any patient presenting with fever, headache, nausea, vomiting, myalgias, and a maculopapular or petechial rash should prompt the consideration of meningococcal infection.14 Petechial rash is the hallmark of invasive meningococcal disease and may be subtle at first, but progress rapidly.15,16 Patients with invasive meningococcal disease can present in one of four ways: meningitis only, shock and meningitis, acute mild meningococcemia (bacteremic with no shock), and fulminant meningococcemia (bacteremic with shock, no meningitis). Early on, the patient will present with tachycardia, normal systolic blood pressure with widened pulse pressure, bounding peripheral pulses, and warm extremities. As the disease progresses and hypotension ensues, extremities become cool, and peripheral pulses are diminished. Death in cases of meningococcemia is secondary to circulatory collapse resulting from vasodilation, capillary leak, intravascular volume depletion, and myocardial dysfunction. Tissue hypoxia and acidosis resulting from an inability to both utilize and receive nutrients further impairs myocardial function.17 Myocarditis, pericarditis, and/or direct bacterial invasion of the heart further contributes to hemodynamic failure. Major complications include pulmonary edema, acute respiratory distress syndrome, disseminated intravascular coagulation (DIC), adrenal hemorrhage (Waterhouse-Friderichsen syndrome), and purpura fulminans. Respiratory complications are secondary to capillary leak. DIC is initiated by activation of inflammatory mediators and can lead to end-organ damage. The progression of skin disease can lead to severe ecchymoses and limb ischemia as a result of hypoxia, hypoper-
A. Koyfman, J.K. Takayesu fusion, DIC, and direct cutaneous bacterial invasion.17,18 Long-term neurologic sequelae include deafness, mental retardation, seizures, and concentration problems in 10–20% of survivors.19 Management Meningococcal disease is a true medical emergency. It requires prompt recognition, early antibiotic therapy, and intensive patient management. The antibiotic of choice is high-dose intravenous ceftriaxone because of its good CSF penetration. Other options include penicillin G, ampicillin, cefotaxime, and chloramphenicol.3,14,18,20 Ideally, blood cultures should be drawn before antibiotic administration but antibiotic administration should never be delayed if cultures are not immediately obtainable. Lumbar puncture should be performed in hemodynamically stable patients without DIC not requiring immediate resuscitation. As with blood cultures, antibiotic therapy should not be delayed while waiting to perform lumbar puncture. Prior to bacterial speciation and susceptibility results, vancomycin should be added to cover drug-resistant S. pneumoniae. It is essential to adhere to local antibiotic resistance patterns to guide treatment as there will be variability from region to region. There is limited data to suggest that empiric steroid treatment prior to the initiation of antibiotic therapy may not be of benefit in meningitis caused by meningococcus compared to pneumoncoccus.21 Meningococcal infection is transmitted by respiratory droplets, therefore transmission prevention is achieved with airborne precautions. A surgical mask and gown should be worn by all persons entering the patient’s room, especially those within 3 feet (1 m) of the patient or having contact with patient secretions. These precautions should remain in place until 24 h after the patient exhibits no signs of ongoing infection including persistent fever; new skin lesions; or worsening leukocytosis, headache, confusion or neck stiffness.11 Further management of patients with meningococcal disease should be directed at restoring adequate oxygen and substrate delivery to the tissues. Intravascular volume should be repleted with isotonic crystalloid. Vasopressors may be necessary to counteract vasodilatory effects of the lipopolysaccharide endotoxin. Epinephrine and dopamine are good options because they improve contractility and vasoconstrict dilated vessels. Intravascular monitoring with central venous catheters for tracking volume status and intra-arterial blood pressure monitoring are useful to guide ongoing resuscitation. The role of steroids for adrenal replacement in septic shock remains unclear. If hypotension persists after adequate volume resuscitation and initiation of inotropic support, hydrocortisone should be considered. Unlike in Haemophilus influenza type B meningitis, few data exist to support the role of steroids in the prevention of hearing loss in patients with meningococcal meningitis.18,22 Data is also limited for the use of protein C concentrate and, to date, this therapy has no proven benefit on survival.23,24 Airway management may be required for patients with significantly compromised mental status requiring supplemental respiratory support or airway protection. Correction of coagulopathy with FFP is essential to prevent further complications from DIC such as intracranial hemorrhage, gastrointestinal bleeding, and hemorrhage into skin lesions.
Meningococcal disease DIC is a dynamic condition requiring clinical diagnosis based on the presence of multiple features including thrombocytopenia, prolongation of PT and aPTT, fibrin degradation with associated hypofibrinogenemia, and intravascular thrombosis. The International Society of Thrombosis and Haemostasis (ISTH) recommends a scoring system based on these features to diagnose DIC given the variations in presentation among patients.25 Treatment of DIC is based on treating the underlying condition rather than the manifestations of DIC itself. Due to the ongoing intravascular destruction of platelets and coagulation factors, platelet and plasma transfusions are reserved for patients with active bleeding or undergoing invasive procedures. Prophylactic transfusion is not recommended.11,25 Patients with thrombosis leading to purpura fulminans or vascular infarction may require anticoagulation with unfractionated heparin (10 units/kg/hr); aPTT monitoring is not useful due to the coincident coagulation disorder.25 Other specific therapies such renal replacement therapy (RRT) to correct volume status, electrolyte imbalances, and acid-base disturbances may be necessary. Some patients may require amputation of extremities as a result of limb ischemia resulting from DIC and septic shock. Antibiotic prophylaxis is recommended for individuals with close contact to the patient. This is defined as any prolonged (>8 h) contact in close proximity (<3 feet) to the patient and/or direct exposure to oral secretions one week prior to the onset of the patient’s symptoms until 24 h after initiation of appropriate antibiotic treatment. Chemoprophylaxis is recommended for health care workers whose mouth or nose is directly exposed to infectious respiratory droplets or secretions within a distance of 3 feet from an infected person, whether suspected or confirmed. This would include those providing care to a patient requiring direct contact (e.g., airway management without wearing a protective mask).11 Eye exposure alone is not an indication for chemoprophylaxis.26 Rifampin is the mainstay prophylactic agent; although ciprofloxacin, azithromycin, and ceftriaxone can also be used.3,27,28 Chemoprophylaxis is limited by issues of resistance (e.g., emerging ciprofloxacin-resistant strains), access to drugs, and the large number of people affected during epidemics, making prevention by vaccination the best control strategy. Those who most benefit from the vaccine include college students, military recruits, people with complement or other immune deficiencies, post-splenectomy patients, microbiologists routinely exposed to N. meningitidis isolates, and people who travel to or reside in countries where the bacterium is endemic.6,29 Routine immunization of health care workers is not recommended given the variety of serotypes possible and the narrow spectra of available immunizations. Conflict of interest None. African Relevance Very common disease in Africa Lots of time dedicated to this topic by WHO Area ripe for advances since morbidity/mortality still high
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