New Approaches to the Treatment of Severe Meningococcal Sepsis
ABSTRACTS & COMMENTARY
Synopsis: Bactericidal/permeability-increasing protein infusion may reduce mortality in severe meningococcal sepsis, while a separate study suggests that a combination of interventions, including the administration of protein-C concentrate, may improve survival in meningococcal purpura fulminans. Both observations require confirmation in a controlled clinical trial.
Sources: Giroir BP, et al. Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis. Lancet 1997;350:1439-1443; Smith OP, et al. Use of protein-C concentrate, heparin, and haemofiltration in meningococcus-induced purpura fulminans. Lancet 1997;350: 1590-1593.
At six hospitals, giroir and colleagues enrolled 26 patients ages 1-18 years in an unblinded, dose-escalating trial of the safety and efficacy of recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein (rBPI21) infusion in the treatment of severe meningococcal sepsis. Entry into the study required a presumptive diagnosis of meningococcemia based on at least one of the following: a) petechiae or purpura, fever, and hemodynamic instability; b) gram-negative diplococci in blood, CSF, or skin lesions; c) evidence of meningococcal antigens in a compatible clinical context. A Glasgow meningococcal septicemia prognostic score (GMPS) of more than 8 was required, as was the administration of rBPI21 within eight hours of the initiation of antibiotic therapy, which was, of course, administered to all patients. Peculiarly, given the disease being studied, one of the reasons for exclusion from the study was: "Any condition which would, in the attending pediatric intensivist’s opinion, make the patient unsuitable, including imminent death."
Meningococcal disease was microbiologically confirmed in 21 of the 26 patients. Plasma concentrations of lipopolysaccharide (LPS), TNF, and IL-6 were elevated at entry. BPI infusion was well tolerated. Although the predicted mortality, based on their GMPS, for this group of patients was 30%, only one (4%) patient died. Seven (27%) of the survivors required amputations. Although none of the survivors was left comatose or in a vegetative state, three (12%) were left with severe disability.
Separately, Smith and colleagues assessed the effects of early replacement therapy with protein-C concentrate together with continuous veno-venous hemodiafiltration and conventional treatment in 12 patients with meningococcal purpura fulminans. The patients, ages 3 months to 27 years, all had microbiological confirmation of meningococcemia and septic shock, purpura fulminans, skin necrosis, and DIC. Protein-C concentrate was administered, after a test dose, by continuous infusion with maintenance of the plasma concentration between 0.8 and 1.2 IU/mL. Nine of the patients also received continuous veno-venous hemofiltration, and 11 patients received heparin to maintain their APTT ratios between 1.5 and 2.0. One patient received antithrombin III concentrate.
The time from admission to the start of the protein-C infusion, which was well tolerated in all patients, ranged from 8 to 72 hours but was less than 18 hours in 10 of the 12 patients. The target range of plasma protein-C concentration was readily maintained and was associated with a reduction in plasma concentration of fibrin d-dimer. Veno-venous hemofiltration was begun within 12 hours of admission in eight of the nine patients who received this therapy. Although the GMPS-predicted mortality was 80% and the pediatric risk score of mortality was 57%, all 12 patients survived. Two patients, one of whom also had a thrombotic CVA, underwent lower extremity amputations.
COMMENT BY STAN DERESINSKI, MD, FACP
The mortality rate of severe meningococcemia, particularly that associated with purpura fulminans, a syndrome of rapidly progressive, hemorrhagic skin necrosis due to dermal vascular thrombosis associated with hemodynamic collapse and DIC, remains extraordinarily high. The pathophysiology of purpura fulminans in meningococcemia involves triggering of the inflammatory response by products of the microbial organism, including endotoxin. A by-product of this response is the acceleration of blood clotting with subsequent dissolution of the fibrin clot. In the course of these events, DIC, potentially characterized by both vascular thrombosis and bleeding, may occur. Thus, defects in both coagulant and anti-coagulant activities are present, with the clinical manifestations (thrombosis and bleeding) dependent upon their relative degrees of abnormality. Normally, when coagulation is initiated, systems to prevent excess clotting must be activated. Anticoagulant (or "pre-anticoagulant") molecules normally present include antithrombin III, protein S, and protein C. Deficiency, hereditary or acquired, of protein C leads to pathological thrombosis. Thus, homozygous deficiency of protein C or protein S is associated with catastrophic neonatal purpura fulminans.
Meningococcemia is a cause of acquired protein C deficiency, as well as protein S and antithrombin III deficiencies. The risk of purpura fulminans in patients with severe meningococcemia is highest in those with platelet counts less than 50,000 cells/mm3 and low protein C levels.1 The inflammatory response elicited by meningococcal infection is presumably linked to the protein-C system by the presence of specific receptors for the latter that are present on endothelial cells and mononuclear phagocytes. The study by Smith and colleagues reviewed here demonstrates, as do some previous studies, that protein C concentrate infusion is safe in patients with meningococcemia, a target range of plasma concentrations can be maintained, and that this is associated with a decrease in plasma d-dimer levels.2
Antithrombin III levels were low in 11 of 12 patients on entry to the study by Smith and colleagues. Antithrombin III has been administered to patients with meningococcal purpura fulminans with reportedly favorable results.3 Heparin has also been commonly recommended for patients with purpura fulminans and other thrombotic complications of DIC. In the Smith study, 11 of 12 patients received heparin in addition to protein-C concentrate. One of these also received antithrombin III concentrate because heparin is ineffective in the presence of severe antithrombin III deficiency since this is its target molecule. Heparin, a highly acidic molecule, binds to positively charged lysine residues in antithrombin III, accelerating the rate of inactivation of pro-coagulation serine proteases by the latter.
The use of hemofiltration in the Smith et al study is based upon the possibility of clearing molecules from the plasma such as TNF and IL-1, which are believed to contribute to the pathophysiology of this disease. However, no evidence is presented to indicate that such removal occurred.
BPI is one of a large group of natural cationic peptide antibiotics that inhibit bacterial and fungal growth by forming channels in the cell membranes similar to those created by amphotericin B in fungal cell membranes.4 BPI is a 55 kDa protein present in the azurophilic granules of human neutrophils. BPI also binds to bacterial endotoxin and inhibits endotoxin-mediated inflammatory responses.
Each of these studies is intriguing, but it is important that the results not be taken as definitive. Both studies were small, and the outcomes were compared to those expected based on previously devised scoring criteria. Small differences in outcome could, as a result, have markedly biased the interpretation. One aspect of this is that neither study provides any information about patients considered but rejected from the study. At any rate, based on the delay in receiving protein-C concentrate in the Smith et al study and the vaguely described reasons for exclusion by the intensivist in the study by Giroir and colleagues, one must consider the possibility that there was a selection biasin the latter case the possible subjective bias of the intensivist and in the former the possible bias introduced by the fact that patients had to survive long enough to receive the concentrate in order to enter the study.
At any rate, studies such as these are important to the extent that they provide hypotheses that can be tested in appropriate trials, encourage proceeding to those trials, and point to the appropriate design of those clinical protocols describing those trials. The study by Giroir and colleagues is straightforward, and the hypothesis to be tested in future trials seems clear. In contrast, the study by Smith and colleagues used a variety of interventions (protein-C concentrate, heparin, and hemofiltration), and it is impossible to dissect the relative contribution, if any, of each of these. It would make much more sense to evaluate each of these interventions separately.
References
1. Powars D, et al. Epidemic meningococcemia and purpura fulminans with induced protein C deficiency. Clin Infect Dis 1993;17:254-261.
2. Rivard GE, et al. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 1995;126:646-652.
3. Fourrier F, et al. Meningococcemia and purpura fulminans in adults: Acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates. Intensive Care Med1990;16:121-124.
4. Hancock RE. Peptide antibiotics. Lancet 1997;349: 1026-1027.
Which of the following is correct?
a. Heparin binds to and inactivates antithrombin II.
b. Plasma protein C concentrations increase in patients with severe meningococcemia.
c. The risk of purpura fulminans in patients with severe meningococcemia is highest in those with platelet counts lower than 50,000 cells/mm3 and low protein C levels.
d. Bactericidal/permeability-increasing protein promotes endotoxin activity.
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