Purpura Fulminans

■ Synonyms: Symmetrical peripheral gangrene

■ Etiology: Diffuse intravascular coagulation

■ Associations: Inherited protein C or S deficiency, postinfectious, bacteremic sepsis

■ Clinical: Widespread purpura with necrosis, skin and other organ systems

■ Evaluation: PT/PTT, protein C and S, antithrombin III, CBC with differential, platelets, fibrinogen, fibrin degradation products

■ Treatment: Reversal of underlying process

■ Prognosis: High incidence of long-term deformity related to necrosis and amputations, high mortality in that associated with sepsis.

Meningococcemia is an invasive bacterial infection by the gram-negative diplococcus, Neisseria meningitidis, which is often rapidly fatal if not detected and treated early. Neisseria meningitidis infections occur both endemically and epidemically. Sporadic disease occurs more commonly during winter and early spring months, and affects predominantly children. The highest rate of infection is in infants six months to one year, with a steady decline in infection rate with age. This is likely explained by passive maternal immunity providing protection in the first six months, and gradual onset of acquired immunity with age. Approximately two-thirds of invasive meningococcal disease occurs in children (1). The human bacterial reservoir is the upper respiratory tract. In the general popula tion, the carrier state is quite common, but in only rare cases do carriers develop invasive disease. There are many different serotypes of Neisseria meningitidis, but types A, B, C, W-135, and Y account for nearly all invasive disease. Worldwide, type A is responsible for most large epidemics, but in the United States, serotypes B and C account for approximately 90% of invasive infections. Most people exposed to an infected individual will become colonized in the upper respiratory tract. There is an approximately 5% chance of invasive infection developing in household contacts in the first 60 days after exposure. Most of these occur in the first week (2). Thus, treatment of close contacts of those with invasive infection is warranted.

The carrier state for Neisseria meningitidis is common, but invasive infection occurs in few individuals. The organism is able to survive in a carrier state by a number of different mechanisms. It may adhere to epithelial cells by pili and may produce IgA proteases—factors that inhibit ciliary activity. The bacterial polysaccharide capsule assists in adherence and inhibits phagocytosis (3). Invasive disease may be precipitated by antecedent viral infections, inhalation of dry, dusty air, or passive smoke inhalation, all factors that may disrupt the integrity of mucosal epithelium (3). Immunologic response to meningococcal disease utilizes all three components of the complement pathway, the classical pathway, the alternative pathway, and the mannose-binding lectin pathway. Patients with inherited defects of the terminal components of complement C6-C8 (4,5), properdin (6), and genetic variants of mannose-binding lectin (7) are susceptible to Neisserial infections, including fulminant or chronic meningococcemia. Acquired deficiencies of complement as may occur in chronic liver disease, systemic lupus erythematosus, and multiple myeloma also predispose to invasive meningococcal infection (4,8). In one series of patients presenting with a first episode of meningococcemia, 30% had either inherited or acquired deficiencies of complement (4). In addition to complement deficiencies, deficiencies of immunoglobulin IgG, IgG subclass 2, and IgA have been described in patients with meningococcal infections (9,10).

The clinical manifestations of meningococcal infection are varied. Tracheobronchitis, conjunctivitis, genital tract infection, pneumonia, and meningitis may all occur, with or without septicemia. Bacteremia may be occult. Acute meningococcemia usually begins with upper respiratory tract symptoms, progressing to fever, chills, myalgias, arthralgias, headache, and nausea and vomiting. Menin-gococcal meningitis usually presents without distinctive clinical features. It may closely resemble viral meningitis. Bacteremia is not necessarily present.

Cutaneous findings in meningococcemia are not consistently present. In one series of adult patients, 50% had no cutaneous findings or clinical evidence of meningitis (1). When present, skin findings are not specific. They may include a morbilliform eruption, urticarial papules and plaques, petechiae, or purpuric patches (Figure 29.1). Morbilliform eruptions, papules and urticarial plaques may occur early in the disease, and then purpura subsequently develops. Small purpuric necrotic papules and vesicles may occur in any anatomic site. These usually represent septic or immune complex vasculitis. Broad areas of purpura and necrosis are more likely to be manifestations of purpura fulminans, an ominous presentation

Photos Extensive Petechiae
Figure 29.1. Meningococcemia: purpuric papules of the leg extremities.
Purpuric PatchesHealthcare Sepsis
Figure 29.2. Purpura fulminans: extensive purpuric necrotic patches.
Purpura Fulminans

of sepsis-associated disseminated intravascular coagulation (Figure 29.2). Such cases may be rapidly fatal, and in the setting of adrenal hemorrhage are referred to as Waterhouse-Friderichsen syndrome. Early literature mistook manifestations of sepsis for adrenal insufficiency due to adrenal hemorrhage. Most patients with this syndrome have elevations in cortisol (2).

In the child presenting with fever and a purpuric eruption, one must be vigilant for the possibility of meningo-coccemia. However, in a series of such patients, bacterial sepsis comprises about 12% of the total, and of those, meningococcemia accounts for approximately two-thirds (2). Most children with fever and purpura have viral infections, particularly enterovirus. Enterovirus may cause aseptic meningitis, resulting in a clinical presentation similar to that of meningococcemia. The differential diagnosis also includes infection with parvovirus B19, Epstein-Barr virus, cytomegalovirus, as well as endocarditis, gonococcemia, typhus, drug eruption, and other forms of systemic vasculitis such as Henoch-Schonlein purpura.

A chronic form of meningococcemia also occurs, and generally presents with a less fulminant course and variable skin findings. These include macules, papules, erythema-nodosum-like lesions, or palpable purpura due to small vessel neutrophilic vasculitis. However, cutaneous involvement is not a constant feature of the disease, particularly in adults. Other manifestations include fever, malaise, myalgias, and arthralgias. Symptoms may persist for weeks prior to diagnosis. Chronic meningococcemia may occur in immunocompetent individuals or those with HIV infection or deficiencies of complement or immunoglobulin (11,12).

The diagnosis of meningococcal infection is made from isolation of the organism from usually sterile sites such as blood or cerebrospinal fluid. Surface cultures, especially those from oropharynx, are not useful because of high rates of carriage in the general population. Blood drawn from puncture wounds of purpuric lesions is reported to have a high yield for organisms by Gram's stain (13). The organism may be found in Gram's stains of biopsy specimens of skin lesions or even on the peripheral blood smear (14). Rapid serologic tests are available to detect Neisseria meningitidis capsular polysaccharide antigen. These may be particularly useful for CSF or if treatment has been instituted.

Fulminant sepsis may develop rapidly in meningococcemia. Endotoxin is a critical component of host immune activation, and its levels correlate with the severity of disease. Serotype C frequently has fulminant manifestations, probably because it has the highest production of endotoxin of any of the serotypes. In the circulation, CD14 on the surface of monocytes and endothelial cells is the principal receptor for endotoxin. The interaction causes production of pro-inflammatory cytokines such as TNF-a and IL-1P, which are important inflammatory mediators in sepsis (3). Neutrophils are activated via endotoxin and complement to produce proteases that result in tissue damage.

Complications of meningococcal sepsis may include septic arthritis, pericarditis, and endocarditis. One particularly deadly complication of meningococcemia is purpura fulminans, which occurs in 15% —25% of patients with meningococcemia (15). Patients develop a severe form of disseminated intravascular coagulation, clinically manifested by purpuric patches with extensive cutaneous necrosis, accompanied by high mortality rates. Purpura fulminans is not specific to meningococcemia, and occurs in several clinical settings.

Purpura Fulminans

Purpura fulminans (PF) oeeurs in three different elinieal settings: neonatal homozygous protein C or S deficiency, after infection, and with bacterial sepsis. Homozygous protein C or S deficiency causes spontaneous intravascular coagulation in the neonatal period, clinically presenting as PF. Postinfectious PF usually occurs 7 to 10 days after an infectious trigger. Possible triggers include varicella, scarlet fever, viral exanthem, or even hypersensitivity reactions. This form is usually less severe than other forms, with disease more frequently limited to the skin. At least some cases seem to be mediated by autoantibodies induced against protein S (16). The third type of PF occurs in the setting of sepsis with endotoxin-producing bacteria. The majority of these cases are due to meningococcemia, but some occur in association with infection by Streptococcus pneumoniae, group A or B Streptococcus, and Haemophilus influenzae, among others. PF has also been induced by septicemia with Capnocytophaga canimorsus (DF-2), a complication of a dog bite (17). Hypercoagulable states such as Factor V Leiden mutation may predispose to some sepsis-induced PF (18).

Purpura fulminans likely represents a phenotype with multiple causes. A consumptive coagulopathy causes disseminated intravascular coagulation. In sepsis, circulating bacterial endotoxin and complement attack sequence disrupt endothelium, resulting in release of tissue factor. Tissue factor binds to coagulation factor VII, and the complex causes activation of factors V, X, VIII, and IX, with consequent formation of thrombin and other procoagulant proteins. Protein C is a vitamin K-dependent glycoprotein that circulates in plasma in an inactive form. In a prothrombotic state, thrombin forms a complex with endothelial membrane-bound thrombomodulin. Circulating inactive protein C binds to that complex and to membrane-bound endothelial protein C receptor, resulting in activated protein C. Once it is activated, it acts with its cofactor protein S to inactivate activated factors V and VIII, thus exerting an anticoagulant effect.

A dysfunctional protein C activation system likely contributes to PF in meningococcal sepsis. In meningococcal sepsis with PF, activated protein C in plasma is undetectable in most patients, and infusions of unactivated protein

C concentrate do not increase activated protein C levels. Additionally, thrombomodulin and endothelial protein C receptor expression are reduced, theoretically leaving less available for use in protein C activation. The result of this imbalance in coagulation homeostasis is a thrombotic state (19).

The classical clinical presentation of purpura fulminans is acute onset of painful purpuric papules, plaques, and patches with a rim of erythema. Necrosis quickly ensues, sometimes with formation of vesicles and bullae, and subsequent eschar. Distal extremities are most commonly affected. Proximal involvement also occurs, but is more common in the postinfectious variant (15). Similar involvement of internal organ systems occurs. A consumptive coagulopathy develops in PF, which helps distinguish it from heparin and coumadin necrosis, thrombotic thrombocytopenic purpura, cryoglobuline-mia, and thrombotic states associated with antiphospho-lipid antibody. Laboratory evaluation reveals reduced fibrinogen, platelets, factor V and VIII, protein C, S, and antithrombin III levels. There is a prolongation of PT and PTT, and an elevation in fibrin degradation products such as D-dimers. Histopathologic evaluation reveals thrombi of vessels, with fibrin, platelets, leukocytes, and, in the case of meningococcemia, sometimes gram-negative dip-lococci (Figures 29.3 and 29.4). In cases of PF associated with bacterial sepsis, a neutrophilic vasculitis may accompany the thrombi, distinguishing it from noninfectious causes (15).

The treatment of purpura fulminans is aimed at reversing the underlying cause, but may also include a variety of measures to counter the hypercoagulable state. Early surgical consultation is advised. Patients should be monitored for compartment syndrome, particularly if aggressive fluid resuscitation is implemented. "Compartments" are fascially delineated anatomic regions susceptible to ischemic necrosis in the setting of edema and low blood flow. Urgent fasciotomy may be necessary if compartment syndrome develops (20). Postinfectious PF may be induced by autoantibodies to protein S. These patients may benefit from plasmapheresis or intravenous immunoglobulin in addition to other therapies (16). Treatment for sepsis-induced purpura fulminans is discussed below.

Treatment in suspected cases of meningococcemia should be instituted immediately after cultures are obtained, because prognosis is dependent upon early intervention. Generally, intravenous treatment with a third-generation cephalosporin is given until cultures and susceptibilities allow narrowing the coverage. Fluid and inotropic support are given as needed. In patients who develop purpura fulminans, extensive cutaneous involve

Fasciotomy Compartment Syndrome

ment portends a poor prognosis. Beneficial effects in severe sepsis have been seen with infusions of activated protein C, and also bactericidal permeability increasing protein (which binds endotoxin, preventing the proinflammatory cascades), both in randomized controlled trials (21,22). In case reports, additional therapeutic mea sures reported to be of benefit include anti-endotoxin antibody, systemic steroids, anti-TNF-a antibody, anti-IL-1-P antibody, unactivated protein C infusion, fresh frozen plasma, antithrombin III, heparin, tissue plasminogen activator, plasmapheresis, and extracorporeal membrane oxygenation (3). Anticoagulation agents may be

Figure 29.4. Purpura fulminans: prominent intravascular coagulation with occasional neutrophils and superficial necrosis.

Figure 29.4. Purpura fulminans: prominent intravascular coagulation with occasional neutrophils and superficial necrosis.

Purpura Fulminans

associated with bleeding complications, so if used, it should be with great caution.

Poor prognostic features in meningococcemia include petechiae present for less than 12 hours prior to admission, hypotension (systolic blood pressure <70 mm Hg), absence of meningitis, peripheral WBC count <10,000, erythrocyte sedimentation rate <10 mm/hr, difference between rectal and skin temperature >3°C, and parental opinion that child's condition has deteriorated in the previous hour (23,24). The mortality rate is 8%—10% (2). Long-term complications usually result from ischemia during acute infection, and consist of amputations and abnormal bone growth. In those patients surviving the acute infection, evaluation for complement and immuno-globulin deficiency should be performed to determine if ongoing replacement therapy is needed.

Household and other close contacts should be treated prophylactically because of the potential for epidemic spread of invasive meningococcal disease. Meningococcal vaccine consists of tetravalent purified capsular poly-saccharide with groups A, C, Y, and W-135. Group B is excluded because of its poor immunogenicity. Vaccine is routinely used in the military because of the potential for epidemics, and should be given to those with asplenia and complement deficiencies, both acquired and inherited.

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