Eastern Journal of Medicine 17 (2012) 40-45

Case Report : a case report and discussion of clinical presentation and management

PK Sethia, R Thukrala, NK Sethib,*, J Torgovnickc, E Arsurad, A Wasterlainb

aDepartment of Neurology, Sir Ganga Ram Hospital, New Delhi (India) bDepartment of Neurology, NYP-Weill Cornell Medical Center, New York (USA) cDepartment of Neurology, Saint Vincent’s Hospital and Medical Centers, New York (USA) dDepartment of Medicine, Saint Vincent’s Hospital and Medical Centers, New York (USA)

Abstract. Meningococcal disease caused by the gram negative diplococcus Neisseria meningitidis is a relatively common infectious disease in developing countries of Asia and Africa. Infection usually starts with a non-specific prodrome of fever, vomiting, malaise and lethargy followed by signs of septicemia and shock (tachycardia, tachypnea, cyanosis, oliguria, hypotension) and/or (stiff neck, headache, photophobia and impaired sensorium). Characteristic meningococcal rash may not appear early in the disease course, potentially delaying the diagnosis and institution of appropriate antibiotic therapy in the patient and isolation and chemoprophylaxis in close contacts. We present here a patient who presented with meningococcal shock associated with characteristic skin lesions of meningococcemia and discuss the clinical presentation and management. The importance of early identification of the characteristic skin lesions of meningococcemia and timely institution of appropriate antibiotic therapy is emphasized. Key words: Meningitis, meningococcal meningitis, meningococcal septicemia, meningococcal shock syndrome

nuchal rigidity and the patient exhibited a clear 1. Case report sensorium. Laboratory investigations revealed a 3 A 28-year-old immunocompetent male total leukocyte count of 21000/mm and a platelet presented to the emergency room with complaint 3 count of 12000/mm which decreased to of high grade fever for two days and rash over the 3 extremities for the past one day. The rash was 7000/mm . Lumbar puncture was deferred, taking widespread covering all four limbs, purpuric and the low platelet count and the initial absence of associated with ecchymoses (Fig 1 and 2). The meningeal signs into consideration. Biopsy of patient did not complain of headache or skin lesions revealed gram negative diplococci photophobia. There was no clinical evidence of consistent with N meningitidis. The patient was initially treated with vancomycin (1 gram intravenously every 12 *Correspondence: Nitin K. Sethi, MD hourly) and ceftriaxone (1 gram intravenously Department of Neurology every 12 hourly). Once N meningitidis had been New York-Presbyterian Hospital definitively identified vancomycin was stopped Weill Cornell Medical Center and ceftriaxone was continued. The patient 525 East, 68th Street became hemodynamically unstable (systolic New York, NY 10021 (U.S.A.) blood pressure of 80 mm Hg and heart rate of E-mail: [email protected] Tel: 212-746-2346 140/min) so hydrocortisone 100 mg thrice daily Fax: 212-746-8845 was administered which was subsequently tapered Received: 16.09.2010 off with complete resolution of septicemia and Accepted: 07.02.2011 skin lesions.

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Fig. 1. and 2. Widespread purpuric and ecchymotic rash covering all four limbs. meningococcal disease. For example, 2. Discussion plasminogen activator inhibitor-1 (PAI-1) polymorphisms may predict the severity of MD. 2. 1. Pathophysiology and risk factors Four conditions must be satisfied in order for Meningococcal disease (MD) caused by the invasive disease to occur: (i) exposure to gram negative diplococcus N meningitidis is pathogenic bacteria, (ii) colonization of naso- associated with high morbidity and mortality. It pharyngeal mucosa, (iii) passage of the bacteria primarily affects children and young adults in through the mucosa, and (iv) infection of the developing countries of Asia and Africa (1,2). bacteria in the bloodstream (9). Characteristics of Infection is acquired through close contact with the bacterium, the environment of the patient, airborne droplets of infected nasopharyngeal history of infection, and the strength of the secretions. MD has two main clinical patient's immune system contribute to whether presentations: meningitis and septicemia which invasive MD will develop. may occur together in about 40% of cases. While meningococcal meningitis has high morbidity and 2. 2. Diagnosis mortality, meningococcal septicemia is far more Meningococcus can be detected by Gram stain likely to kill with case fatality rates reaching as of a skin biopsy specimen, blood culture or high as 50% if the patient is already in shock by cerebrospinal fluid culture (6). Prior antibiotic the time he or she reaches medical care. use can make it difficult to recover bacteria from Individual susceptibility to MD varies. Household blood, producing a false negative result; by contacts of infected individuals are 300-1000 contrast, skin biopsy tests are unaffected by times more likely to acquire MD than those in the previous antibiotic therapy. Other diagnostic general population. Patients who are methods that are not impacted by prior antibiotic immunocompromised (HIV positive patients, use are meningococcal antigen detection and alcoholics, elderly, asplenic state, people with polymerase chain reaction (PCR) amplification of complement deficiency) are more vulnerable to meningococcal DNA. While skin biopsy, antigen fulminant MD (3-5). The complement system detection and PCR amplification provide a more provides a particularly important defense against reliable diagnosis, blood cultures are most meningococcus. Complement deficiency commonly used because they are relatively easy increases the risk of acquiring MD approximately to obtain even in countries with limited resources. 10,000-fold; conversely, MD accounts for 75% to 2. 3. Symptoms and signs 85% of infections in complement deficient MD begins with a nonspecific prodrome of patients. MD is most commonly associated with fever, lethargy, drowsiness, nausea and vomiting. deficiency of the terminal components of the In the pediatric age group this prodrome may complement pathway (C5-C9). Interestingly, for consist of irritability and poor feeding (7). Hence reasons still unclear, despite the increased risk of early on in the disease course it is difficult to acquiring MD, probability of death is 5 to 10 distinguish it from other common bacterial and times lower in complement-deficient patients. viral febrile illnesses. Rash is the most common Genetic polymorphism of molecules such as reason that patients with MD seek medical help. mannose binding lectin increases susceptibility to The purpuric ecchymotic rash is characteristic

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Eastern Journal of Medicine 17 (2012) 40-45

Case Report though it may not be noticeable until 12-24 hours protein C and/or cytokine serum concentrations, after disease onset. In its earliest stages the rash the absence of leukocytosis, and the presence of may be blanching and maculopapular later thrombocytopenia and disseminated intravascular developing into a non-blanching red or brown coagulation (DIC). petechial rash. Initially it may present with 2. 5. Complications isolated pin-prick spots and hence may be missed Coagulopathy is a complication of unless a diligent whole skin examination in good meningitis and other infectious diseases, and is lighting is carried out. In dark skinned people it mostly multi-factorial. The coagulopathy may be visible in paler areas such as soles of feet, associated with meningococcal septicemia is palms of hand, conjunctivae, skin of abdomen characterized by marked inflammatory cell and palate. The meningococcal rash may spread activation, disseminated intravascular rapidly; lesions may coalesce to form large coagulation, and vascular compromise. In ecchymotic lesions which may then get comparison to other forms of , the secondarily infected (8). The rash may continue coagulopathy and microvascular thromboses that to evolve and become more prominent even develop in this type of sepsis are severe with though the patient may start showing clinical thrombosis of the large vessels and infarction of improvement while being treated with antibiotics. the digits and limbs. As most patients with meningococcal disease Meningococcal endotoxin produces a severe develop a rash it is one of the clearest and most proinflammatory response and cytokines important signs to recognize. The rash may be stimulate the release of tissue factors, leading to very scanty or even absent in meningitis. A non- the formation of thrombin and fibrin clots. blanching petechial rash in a febrile patient Imbalance between coagulation and fibrinolytic should raise the suspicion for MD as other signs systems leads to microvascular thrombosis, which may be subtle even in a patient with advanced in turn may lead to hypoperfusion, shock, disease. If early antibiotic therapy is not disseminated intravascular coagulation (DIC) and instituted, circulatory and vasomotor collapse multi-organ failure. Waterhouse-Friderichsen ensues with signs of hypoperfusion (collapsed Syndrome (WFS), is a condition characterized by peripheral veins cause cold hands and feet), abrupt onset of fever, purpuric rash, weakness hypotension, tachycardia, tachypnea, arthralgias and myalgias leading to hemorrhagic necrosis of and oliguria. During the early stages of shock, the adrenal gland. WFS is most commonly tachycardia may be the sole sign. By the time associated with meningococcal septicemia, but hypotension develops, hemodynamic reserve is may also occur with sepsis caused by other precariously low. Decreased level of bacterial infections. Children and patients with a consciousness is a late clinical sign. Concomitant prior history of splenectomy are particularly meningitis presents clinically with headache, susceptible to WFS. depressed sensorium, stiff neck and photophobia (neck stiffness and photophobia may be absent in 2. 6. Management young children). Infants with meningococcal Early aggressive fluid resuscitation and meningitis are irritable with a high pitched cry, appropriate antibiotic therapy form the mottled skin and bulging fontanelle. cornerstones of management of meningococcal shock syndrome. 2. 4. Indicators of septic shock As per the British Infection Society guidelines 2. 7. Fluid resuscitation signs which may warn health care providers of Fluid resuscitation should be initiated at the impending shock, respiratory failure or signs of first sign of shock (i.e. at the stage of increased intracranial pressure include rapidly tachycardia) with the aim of reestablishing progressive rash, poor peripheral perfusion physiological parameters (heart rate, blood (capillary refill time >4 seconds, oliguria and pressure, urine output and capillary refill time). systolic BP <90), respiratory rate <8 or >30, Ideal resuscitation fluid is normal saline. pulse rate <40 or >140, acidosis (pH <7.3), WBC Controversy exists on the use of colloids 3 (albumin). The aim should be to correct the fluid count <4000/mm , GCS <12, focal neurological deficit rapidly. Vasoactive agents such as examination, persistent seizures and dopamine and dobutamine are used if there is papilloedema. Poor prognostic indicators for evidence of myocardial depression despite patients with meningococcal septicemia include adequate fluid loading. Epinephrine or extreme youth and old age, rapid onset of disease, norepinephrine is started if the patient has the absence of meningitis, extensive skin lesions, ongoing hypotension or evidence of progressive shock, hypotension, metabolic acidosis, elevated organ dysfunction despite sufficient fluid and

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P.K. Sethi et al / Meningococcal disease dopamine or dobutamine, depending on whether are to use third generation cephalosporins the hemodynamic pattern is most consistent with (Ceftriaxone or Cefotaxime), a class of beta- poor myocardial contractility (epinephrine) or lactam antibiotics that are particularly potent distributive shock (norepinephrine). Arginine against gram-negative bacteria and able to vasopressin (0.001 units/kg/min), low-dose penetrate the CNS. Drug doses for septicemia and hydrocortisone (1 mg/kg 8 hourly), and calcium meningitis vary (1 g intravenously twice daily of infusions (0.2 ml/kg/day) can be considered in Ceftriaxone for septicemia while anti-meningitic cases of refractory hypotension. A further dose is 2 g intravenously twice daily). Penicillin subgroup of these critically ill patients develop is the drug of choice if third generation progressive hypotension with or without organ cephalosporins are unavailable, and dysfunction associated with dilated, poorly chloramphenicol may be used in patients with a functioning ventricles on echocardiography, history of to both cephalosporins and increasing serum lactate, or decreasing central penicillin. venous oxygen saturation and may require 2. 9. Role of steroids in meningococcal meningitis extracorporeal membrane oxygenation (ECMO). Steroids are sometimes used in conjunction Patients frequently require venoarterial ECMO with antibiotics for the treatment of MD, as using the highest flows (150 to 300 mL/kg/min) steroids facilitate the transport of antibiotic achievable to maintain adequate peripheral molecules across the blood-brain barrier. The perfusion. ECMO flow rates need to be adjusted European Dexamethasone in Adulthood Bacterial to achieve maximal systemic perfusion at age- Meningitis Study found dexamethasone to be appropriate perfusion pressures. The associated most beneficial in patients with pneumococcal maldistribution of tissue perfusion requires meningitis with a reduction in the risks of both increased flows to adequately perfuse tissue and unfavorable outcome and death. It did not have a avoid hypoxic ischaemia. Studies have shown beneficial effect on neurologic sequel, including that persistent shock has an adverse effect on hearing loss. The small number of patients with survival in a time-dependent manner (10). meningococcal meningitis prevented detection of Delayed treatment leads to increased mortality a beneficial effect though the authors and on the other hand there is 94% rate of recommended dexamathasone treatment for all survival if shock is reversed within 75 minutes of patients with acute bacterial meningitis. Hence presentation. Shock and DIC are interrelated, and paucity of data precludes a recommendation that reinforce each other. As such, anti-shock therapy dexamethasone be administered routinely in is an effective treatment for DIC, and usually adults with meningococcal meningitis. The reverses clotting abnormalities. Treatment with duration and timing of dexamethasone therapy is fresh frozen plasma may be warranted if clotting important. Though data suggests that two-day and parameters are severely deranged and there is four-day regimens are equally effective, the evidence of . Heparin may be used as an authors recommended 10 mg every six hours for alternative treatment, but has not yet shown a net four days initiated before or with the first dose of reduction in mortality from DIC; at present there antibiotics. Importantly, this treatment did not is no evidence for routine use of activated protein increase the risk of gastrointestinal bleeding. C in severe meningococcal sepsis. 2. 10. Role of steroids in septic shock 2. 8. Antibiotic therapy The use of steroids in septic shock has been Mortality from MD is reduced by early investigated in the past. While the use of high appropriate antibiotic therapy. In the past, dose steroids (30 mg/kg of methylprednisolone or meningococcal infections were usually treated equivalent) for a short period has not been proven with penicillin, ampicillin, or a combination of to improve outcomes, use of low dose steroids penicillin and chloramphenicol. Isolates of N (200-300mg of hydrocortisone, 2-5 mg/kg/day in meningitidis with increased levels of resistance to children) as replacement therapy has shown penicillin have been reported in the last few years promising results with reduction in the duration from different countries. Resistance is due in part of inotropic requirement and 28-day to development of altered forms of the penicillin- mortality. Meningococcal septic shock presents binding protein (PBP 2), and in some isolates to with an early massive inflammatory response. the production of beta lactamase. Minimum While absolute adrenal failure due to adrenal inhibitory concentrations (MICs) for penicillin- hemorrhage is rare, partial adrenal insufficiency intermediate isolates (0.12 to 1 μg/ml) are 2 to 20 is quite common, thus current recommendations fold higher than those for the susceptible ones are to use hydrocortisone in patients with septic (≤0.06 μg/ml). Hence, current recommendations shock requiring catecholamines for blood

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Eastern Journal of Medicine 17 (2012) 40-45

Case Report pressure support and with laboratory evidence of through collaboration between the Meningitis adrenal insufficiency (12-14). Vaccine Project (WHO) and the Serum Institute 2. 11. Treatment of hyperglycemia of India. Clinical trials are ongoing and shall Hyperglycemia may increase mortality in these determine whether the vaccine provides long- critically ill patients with recent studies showing lasting protection in infants (17). that the intensity and duration of hyperglycemia 3. 2. Chemoprophylaxis is associated with outcomes. The use of insulin to The Centers for Disease Control (CDC) treat hyperglycemia improved outcomes in recommends chemoprophylaxis for intimate and children, but data has been less conclusive in the household contacts of a patient with MD with adult population. At present the use of insulin to rifampicin, ciprofloxacin, ofloxacin, or treat hyperglycemia and normalize blood glucose ceftriaxone (for pregnant women). The purpose of levels should be made on a case by case basis chemoprophylaxis is to eliminate carriage in the until more definitive information is obtained from contact group; it does not prevent illness in those future studies (11). already infected, so contacts should continue to be alert to the symptoms of MD and seek medical 3. Prevention attention at the earliest sign of infection. Sulfonamides should only be used if there is 3. 1. Vaccination known susceptibility. Vaccination is the most effective preventative measure against MD. Serogroups B, C, and Y are 4. Conclusion the major causes of meningococcal disease in the United States, each being responsible for MD is an important infectious cause of morbidity approximately one third of cases. In the United and mortality in the developing world. The States a tetravalent polysaccharide-protein disease has two main clinical presentations: TM meningitis and septicemia which may occur conjugate vaccine ((MCV4) Menactra , manufactured by Sanofi Pasteur, Inc, Swiftwater, together in about 40% of cases. MD can spread Pennsylvania) effective against serogroups A, C, rapidly and a high index of suspicion is needed to W-135 and Y is currently available, and licensed diagnose it in its initial stage as the characteristic for use among persons aged 11-55 years (15). purpuric skin lesions may not be apparent until CDC’s Advisory Committee on Immunization 12-24 hours after disease onset. Early and Practices (ACIP) recommends routine vaccination aggressive fluid resuscitation and timely of young adolescents with MCV4 at the appropriate antibiotic therapy improves the preadolescent health-care visit (at age 11-12 outcome in meningococcal shock syndrome. years). Outbreaks of serogroup B meningococci Chemoprophylaxis with either rifampicin, (NMB) have been reported worldwide and it is ciprofloxacin or for pregnant contacts, now the predominant disease causing isolate in ceftriaxone is recommended for intimate and industrialized countries. Because group B household contacts of a patient with MD. polysaccharide mimics the neural cell adhesion molecule, a vaccine against group B would risk inducing autoimmunity; moreover, the antibody response to the group B capsular polysaccharide References is limited, and thus cannot be used to develop an effective vaccine and it remains unclear whether 1. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and recent advances in vaccine development shall Neisseria meningitidis. Lancet 2007; 369: 2196- lead to a universal NMB vaccine in the 2210. foreseeable future (16). Few studies are ongoing 2. Nair D, Dawar R, Deb M, et al. Outbreak of in some European countries and New Zealand meningococcal disease in and around New Delhi, with the serogroup B vaccine. In 1999 the India, 2005-2006: a report from a tertiary care hospital. Epidemiol Infect 2009; 137: 570-576. meningococcal group C polysaccharide-protein 3. Stein-Zamir C, Abramson N, Zentner G, et al. conjugate vaccine (MenC) was introduced in the Invasive meningococcal disease in children in United Kingdom into schedules for routine infant Jerusalem. Epidemiol Infect 2008; 136: 782-789. immunization. MenC provides significant herd 4. Saha R, Gadre D, Mathur M. Meningococcaemia: immunity and the introduction of this vaccine led experience at a tertiary care hospital in East Delhi. to a significant decrease in group C carriage and Indian J Med Microbiol 2006; 24: 299-300. 5. Shah A, Lettieri CJ. Fulminant meningococcal disease. Group A disease is responsible for large sepsis in a woman with previously unknown epidemics in Africa. MenAfriVac is an affordable hyposplenism. Medscape J Med 2008; 10: 36. conjugate vaccine against group A developed

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