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Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe
M Levin1, P A Quint, B Goldstein
1Imperial College School of Medicine, Norfolk Place, London, UK.
Insights
Recombinant BPI21 (rBPI21) shows promise in treating severe meningococcal sepsis in children. While not significantly reducing mortality, rBPI21 trended towards fewer amputations and improved functional outcomes, suggesting it is beneficial in decreasing disease complications.
Area of Science:
- Pediatrics
- Infectious Diseases
- Critical Care Medicine
Background:
- Meningococcal sepsis is a life-threatening condition triggered by endotoxin.
- Bactericidal/permeability-increasing protein (BPI) neutralizes endotoxin effects.
- A recombinant fragment, rBPI21, was investigated for its efficacy in severe meningococcal sepsis.
Purpose of the Study:
- To evaluate the effectiveness of recombinant 21-kDa modified fragment of human BPI (rBPI21) in reducing mortality and long-term disability in children with severe meningococcal sepsis.
- To assess the impact of rBPI21 on amputation rates and functional outcomes (Paediatric Overall Performance Category - POPC).
Main Methods:
- A randomized, double-blind, placebo-controlled trial was conducted in 22 UK and US centers.
- Children aged 2 weeks to 18 years with severe meningococcal sepsis received either rBPI21 or placebo alongside standard medical therapy.
- Primary outcomes included mortality, amputations, and POPC at day 60; intention-to-treat analysis was performed.
Main Results:
- Mortality rates were 7.4% for rBPI21 and 9.9% for placebo (p=0.48).
- Fewer patients receiving rBPI21 experienced multiple severe amputations (3.2% vs 7.4%, p=0.067).
- A significantly higher proportion of patients on rBPI21 achieved pre-illness functional status by day 60 (77.3% vs 66.3%, p=0.019).
Conclusions:
- The trial was underpowered to demonstrate a significant reduction in mortality due to lower-than-predicted placebo group deaths.
- rBPI21 demonstrated a trend towards improved outcomes across all primary variables.
- Results suggest rBPI21 is beneficial in mitigating complications associated with severe meningococcal sepsis.
Background:
Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis.
Methods:
We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat.
Findings:
Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019).
Interpretation:
Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.
