Meningococcal Septicemia Case Report Biology Essay

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Meningococcal septicemia caused by the gram negative diplococcus Neisseria meningitides 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 (rash, tachycardia, tachypnea, cyanosis, oliguria, hypotension) and/or meningitis (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. The patient did not complain of headache or photophobia. There was no clinical evidence of nuchal rigidity with the patient exhibiting a clear sensorium. Lumbar puncture was not carried out. The patient was treated with broad-spectrum antibiotics including. Intravenous steroids were administered which were subsequently tapered off with complete resolution of septicemia and skin lesions. Our case adds to the existing literature and emphasizes the importance of early identification of the characteristic skin lesions of meningococcemia is emphasized and institution of timely appropriate antibiotic therapy.

Case Report

A 28-year-old right handed male presented to the emergency room with complaints of high grade fever for two days and rash over the extremities for the past one day. The rash was widespread covering all four limbs, purpuric and associated with ecchymoses (Fig 1 and 2). The patient did not complain of headache or photophobia. There was no clinical evidence of nuchal rigidity and the patient exhibited a clear sensorium. Laboratory investigations revealed a total leukocyte count of 21000/mm3 and a platelet count of 12000/mm3 which decreased to 7000/mm3. Lumbar puncture was not carried out, taking the low platelet count and the absence of meningeal signs into consideration. Biopsy of skin lesions revealed gram negative diplococci consistent with Neisseria meningitides. The patient was treated with broad-spectrum antibiotics including vancomycin and ceftriaxone. Hydrocortisone 100 mg thrice daily was administered which was subsequently tapered off with complete resolution of septicemia and skin lesions.

Discussion   

Meningococcal disease (MD) caused by gram negative diplococcus Neisseria meningitides is associated with high morbidity and mortality. It primarily affects children and young adults in developing countries of Asia and Africa 1, 2. Disease presentation may vary from a mild self limited febrile illness to a fulminant sepsis syndrome with circulatory and vasomotor collapse. Infection is acquired through close contact with airborne droplets of infected nasopharyngeal secretions. MD has two main clinical presentations: meningitis and septicemia which may occur together in about 40% of cases. While meningococcal meningitis has high morbidity and mortality, meningococcal septicemia is far more likely to kill with case fatality rates reaching as high as 50% if the patient is already in shock by the time he or she reaches medical care. Infection is more fulminant in susceptible population groups such as those immunocompromised due to HIV infection, alcoholics and in post splenectomy patients 3, 4.

Individual susceptibility to MD varies. Household contacts of infected individuals are 300-1000 times more likely to acquire MD than those in the general population. Patients who are immunocompromised (HIV positive patients, alcoholics, elderly, post-splenectomy patients, people with complement deficiency) are more vulnerable to fulminant MD 5. The complement system provides a particularly important defense against meningococcus. Complement deficiency increases the risk of acquiring MD approximately 10,000-fold; conversely, MD accounts for 75% to 85% of infections in complement deficient patients. MD is most commonly associated with deficiency of the terminal components of the complement pathway (C5-C9). Interestingly, for reasons still unclear, despite the increased risk of acquiring MD, probability of death is 5 to 10 times lower in complement-deficient patients. Genetic polymorphism of molecules such as mannose binding lectin increases susceptibility to meningococcal disease. For example, plasminogen activator inhibitor-1 (PAI-1) polymorphisms may predict the severity of MD.

Meningococcus can be detected by Gram stain of a skin biopsy specimen or blood culture 6. Prior antibiotic use can make it difficult to recover bacteria from blood, producing a false negative result; by contrast, skin biopsy tests are unaffected by previous antibiotic therapy. Other diagnostic methods that are not impacted by prior antibiotic use are meningococcal antigen detection and polymerase chain reaction (PCR) amplification of meningococcal DNA. While skin biopsy, antigen detection and PCR amplification provide a more reliable diagnosis, blood cultures are most commonly used because they are relatively easy to obtain even in countries with meager resources.

MD begins with a nonspecific prodrome of fever, lethargy, drowsiness, nausea and vomiting. In the pediatric age group this prodrome may consist of irritability and poor feeding 7. Hence early on in the disease course it is difficult to distinguish it from other common bacterial and viral febrile illnesses. Rash is the most common reason that patients with MD seek medical help. The purpuric ecchymotic rash is characteristic though it may not be noticeable till about 12-24 hours after disease onset. In its earliest stages the rash may be blanching and maculopapular later developing into a non-blanching red or brownish petechial rash. Initially it may present with isolated pin-prick spots and hence may be missed unless a diligent whole skin examination in good lighting is carried out. In dark skinned people it may be visible in paler areas such as soles of feet, palms of hand, conjunctivae, skin of abdomen and palate. Meningococcal rash may spread rapidly; lesions may coalesce to form large ecchymotic lesions which may then get secondarily infected 8. The rash may continue to evolve and become more prominent even though the patient may start showing clinical improvement while being treated with antibiotics. As most patients with meningococcal disease develop a rash it is one of the clearest and most important signs to recognize. The rash may be very scanty or even absent in meningitis. A non-blanching petechial rash in a febrile patient should raise the suspicion for MD as other signs may be subtle even in a patient with advanced disease.

Four conditions must be satisfied in order for invasive disease to occur: (i) exposure to pathogenic bacteria, (ii) colonization of naso-pharyngeal mucosa, (iii) passage of the bacteria through the mucosa, and (iv) infection of the bacteria in the bloodstream 9. Characteristics of the bacterium, the environment of the patient, history of infection, and the strength of the patient's immune system contribute to whether invasive MD will develop. If early antibiotic therapy is not instituted, circulatory and vasomotor collapse ensues with signs of hypoperfusion (collapsed peripheral veins cause cold hands and feet), hypotension, tachycardia, tachypnea, arthralgias and oliguria. During the early stages of shock, tachycardia may be the sole sign. By the time hypotension develops, hemodynamic reserve is precariously low. Decreased level of consciousness is a late clinical sign. Concomitant meningitis presents clinically with headache, depressed sensorium, stiff neck and photophobia (neck stiffness and photophobia may be absent in young children). Babies with meningococcal meningitis are irritable with a high pitched cry, mottled skin and bulging fontanelle. The British Infection Society lists signs which may warn health care providers of impending shock, respiratory failure or signs of increased intracranial pressure requiring urgent intervention. These include rapidly progressive rash, poor peripheral perfusion (capillary refill time >4 seconds, oliguria and systolic BP <90), respiratory rate <8 or >30, pulse rate <40 or >140, acidosis (pH <7.3), WBC count <4000/mm3, GCS <12, focal neurological examination, persistent seizures and papilloedema.

Early aggressive fluid resuscitation and appropriate antibiotic therapy form the cornerstones of management of meningococcal shock syndrome. Fluid resuscitation should be initiated at the first sign of shock (i.e. at the stage of tachycardia) with the aim of reestablishing physiological parameters (heart rate, blood pressure, urine output and capillary refill time). Ideal resuscitation fluid is either normal saline or colloids (albumin). One should calculate the fluid deficit and aim to correct it rapidly. Patient presenting in extremis require volume loading with colloid infusions before a vasoactive such as dopamine agent is used. Dobutamine is used if there is evidence of myocardial depression despite adequate fluid loading. Epinephrine or norepinephrine is started if the patient has ongoing hypotension or evidence of progressive organ dysfunction despite sufficient fluid and dopamine or dobutamine, depending on whether the hemodynamic pattern is most consistent with poor myocardial contractility (epinephrine) or distributive shock (norepinephrine). Arginine vasopressin (0.001 units/kg/min), low-dose hydrocortisone (1 mg/kg 8 hourly), and calcium infusions (0.2 ml/kg/day) are all considered in cases of refractory hypotension. A further subgroup of these critically ill patients develop progressive hypotension with or without organ dysfunction associated with dilated, poorly functioning ventricles on echocardiography, increasing serum lactate, or decreasing central venous oxygen saturation requiring extracorporeal membrane oxygenation (ECMO). Patients frequently require venoarterial ECMO using the highest flows (150 to 300 mL/kg/min) achievable to maintain adequate peripheral perfusion. ECMO flow rates need to be adjusted to achieve maximal systemic perfusion at age-appropriate perfusion pressures. The associated maldistribution of tissue perfusion requires increased flows to adequately perfuse tissue and avoid hypoxic ischaemia. This is achieved via transthoracic cannulation using larger cannulae than with percutaneous cannulation of the jugular or femoral veins. Studies have shown that persistent shock has an adverse effect on survival in a time-dependent manner 10. Delayed treatment leads to increased mortality with 94% rate of survival if shock is reversed within 75 minutes of presentation.

Hyperglycemia may increase mortality in these critically ill patients with recent studies showing that the intensity and duration of hyperglycemia are associated with outcomes. The use of insulin to treat hyperglycemia improved outcomes in children, but data has been less conclusive in the adult population. At present the use of insulin to treat hyperglycemia and normalize blood glucose levels should be made on a case by case basis until more definitive information is obtained from future studies 11.

Mortality from MD is reduced by early antibiotic therapy. In the past, meningococcal infections were usually treated with penicillin, ampicillin, or a combination of penicillin and chloramphenicol. Isolates of Neisseria meningitides with increased levels of resistance to penicillin have been reported in the last few years from different countries. Resistance is due in part to development of altered forms of the penicillin-binding protein (PBP 2), and in some isolates to the production of beta lactamase. Minimum inhibitory concentrations (MICs) for penicillin-intermediate isolates (0.12 to 1 μg/ml) are 2 to 20 fold higher than those for the susceptible ones (≤0.06 μg/ml). Hence, current recommendations are to use third generation cephalosporins (Ceftriaxone or Cefotaxime), a class of beta-lactam antibiotics that are particularly potent against gram-negative bacteria and able to penetrate the CNS. The National Committee for Clinical Laboratory Standards (NCCLS) breakpoints recommended  for penicillin, cefotaxime, ceftriaxone, and ciprofloxacin are as follows: for penicillin, susceptible, ≤0.06 μg/ml; intermediate, 0.12 to 1 μg/ml; and resistant, ≥2 μg/ml; for cefotaxime, susceptible, ≤0.5 μg/ml; for ceftriaxone susceptible, ≤0.25 μg/ml; for ciprofloxacin, susceptible, ≤0.06 μg/ml, intermediate, 0.12 to 0.5 μg/ml; and resistant, ≥1 μg/ml. Septicemia and meningitic doses vary (1 g intravenously twice daily of Ceftriaxone for septicemia while meningitic dose is 2 g intravenously twice daily). Penicillin is the drug of choice if third generation cephalosporins are unavailable, and chloramphenicol may be used in patients with a history of anaphylaxis to both cephalosporins and penicillin. Steroids are sometimes used in conjunction with antibiotics for the treatment of meningococcal disease, as steroids facilitate the transport of antibiotic molecules across the blood-brain barrier. The European Dexamethasone in Adulthood Bacterial Meningitis Study found dexamethasone to be most beneficial in patients with pneumococcal meningitis with a reduction in the risks of both unfavorable outcome and death. However, paucity of data precludes a recommendation that dexamethasone be administered routinely in adults with meningococcal meningitis. It did not have a beneficial effect on neurologic sequel, including hearing loss. The small number of patients with meningococcal meningitis prevented detection of a beneficial effect though the authors recommended dexamathasone treatment for all patients with acute bacterial meningitis. The duration and timing of dexamethasone therapy is important. Though data suggests that two-day and four-day regimens are equally effective, the authors recommended 10 mg every six hours for four days initiated before or with the first dose of antibiotics. Importantly, this treatment did not increase the risk of gastrointestinal bleeding. The use of steroids in septic shock has been investigated in the past. While the use of high dose steroids (30 mg/kg of methylprednisolone or equivalent) for a short period has not been proven to improve outcomes, use of low dose steroids (200-300mg of hydrocortisone, 2-5 mg/kg/day in children) as replacement therapy has shown promising results with reduction in the duration of inotropic requirement and 28-day mortality. Meningococcal septic shock presents with an early massive inflammatory response. While absolute adrenal failure due to adrenal hemorrhage is rare, partial adrenal insufficiency is quite common, thus current recommendations are to use hydrocortisone in patients with septic shock requiring catecholamines for blood pressure support and with laboratory evidence of adrenal insufficiency 12, 13, 14.

In 1966, Stiehm and Damrosch identified a number of indicators of poor prognosis for patients with meningococcal septicemia. These indicators include extreme youth and old age, rapid onset of disease, the absence of meningitis, extensive skin lesions, shock, hypotension or metabolic acidosis, elevated protein C and/or cytokine serum concentrations, the absence of leukocytosis, and the presence of thrombocytopenia and disseminated intravascular coagulation (DIC).

Coagulopathy is a complication of meningitis and other infectious diseases, and is mostly multi-factorial. The coagulopathy associated with meningococcal septicemia is characterized by marked inflammatory cell activation, disseminated intravascular coagulation, and vascular compromise. In comparison to other forms of septic shock, the coagulopathy and microvascular thromboses that develop in this type of sepsis are severe with thrombosis of the large vessels and infarction of the digits and limbs.

Meningococcal endotoxin produces a severe proinflammatory response and cytokines stimulate the release of tissue factors, leading to the formation of thrombin and fibrin clots. Imbalance between coagulation and fibrinolytic systems leads to microvascular thrombosis, which in turn may lead to hypoperfusion, shock, disseminated intravascular coagulation (DIC) and multi-organ failure. Shock and DIC are interrelated, and reinforce each other. As such, anti-shock therapy is an effective treatment for DIC, and usually reverses clotting abnormalities. Treatment with fresh frozen plasma may be warranted if clotting parameters are severely deranged and there is evidence of bleeding. Heparin may be used as an alternative treatment, but has not yet shown a net reduction in mortality from DIC­­; at present there is no evidence for routine use of activated protein C in severe meningococcal sepsis.

Waterhouse-Friderichsen Syndrome (WFS), also known as purpura fulminans, is a condition characterized by abrupt onset of fever, purpuric rash, weakness and myalgias leading to hemorrhagic necrosis of the adrenal gland. WFS is most commonly associated with meningococcal septicemia, but may also occur with sepsis caused by other bacterial infections. Children and patients with a prior history of splenectomy are particularly susceptible to WFS.

Vaccination is the most effective preventative measure against MD. Vaccines should be given intravenously, and not intranasally, to prevent inducing immunogenetic variability among the natural nasopharyngeal reservoirs of meningococcal bacteria. A quadrivalent unconjugated polysaccharide vaccine against serogroups A, C, W-135 and Y is currently available, and confers protection to people over age two, including those who are complement deficient. Although these unconjugated vaccines have been very effective in reducing outbreaks in military centers and susceptible African populations, they do not induce immunological memory and confer no immunity in children under age two. These problems may be resolved by newer compounds in which the vaccine is conjugated to a protein15.

Currently, there is no vaccine against group B meningococci, despite the comparatively high prevalence of this serogroup in Western countries. Because group B 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 is limited, and thus cannot be used to develop an effective vaccine16.

The Centers for Disease Control (CDC) recommends chemoprophylaxis for intimate and household contacts of a patient with MD with rifampicin, ciprofloxacin, ofloxacin, or ceftriaxone (for pregnant women). The purpose of chemoprophylaxis is to eliminate carriage in the contact group; it does not prevent illness in those already infected, so contacts should continue to be alert to the symptoms of MD and seek medical attention at the earliest sign of infection. Sulfonamides should only be used if there is known susceptibility.

Conclusion

MD is an important infectious cause of morbidity and mortality in the developing world. The disease has two main clinical presentations: meningitis and septicemia which may occur together in about 40% of cases. MD can spread rapidly and a high index of suspicion is needed to diagnose it in its initial stage as the characteristic purpuric skin lesions may not be apparent till about 12-24 hours after disease onset. Early and aggressive fluid resuscitation and timely appropriate antibiotic therapy may improve the outcome in meningococcal shock syndrome. Chemoprophylaxis with either rifampicin, ciprofloxacin or for pregnant contacts, ceftriaxone is recommended for intimate and household contacts of a patient with MD.

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