Lets get back to the facts...shall we>>>>>>>>>>>>>>>>>>>>>>>>>>
>>>Meningococcal sepsis remains an important cause of morbidity6 and
mortality in both children and adults. In North America, serogroup C
outbreaks have become more frequent and more virulent;[17] high rates of
endemic disease continue in Europe;[18] and in sub-Saharan Africa,
140000 cases of invasive meningococcal disease and at least 15000 deaths
were reported by WHO for the first half of 1996. Yet, despite medical
advances, there has been no significant, risk-stratified improvement in
outcome since the 1950s.[1,2] This lack of progress may seem
paradoxical: these patients are previously healthy, their disease is
easily identified, and the bacteria are susceptible to antibiotics. The
problem is that antibiotics neither interrupt nor rapidly reverse the
inflammatory processes associated with the gram-negative bacterial
infection, including shock, thrombosis, and multiorgan injury. Patients
are supported by all available pharmacological and technological means
until the underlying processes subside or the child experiences
cardiovascular collapse and dies.[3]
We hypothesised that children with meningococcaemia might benefit from
direct inhibition of the inflammatory processes which, in
meningococcaemia, are primarily initiated by bacteria and LPS.[4,7]
Plasma levels of endotoxin in meningococcaemia are 30-50 times higher
than those reported in other gram-negative infections and they correlate
with disease severity and clinical outcome.[19] LPS, present on the
outer bacterial membrane or released from bacteria, induces the
production of cytokines, hormones, and receptors and initiates
inflammatory cascades leading to thrombosis, myocardial dysfunction,
multiorgan failure, and circulatory collapse.[20]
rBPI21 is an N-terminal fragment of BPI, a protein which kills bacteria,
neutralises bacterial endotoxin, and enhances endotoxin clearance.[12,13,
21,22] rBPI21 itself exerts direct bactericidal or antibiotic-enhancing
effects on a wide range of gram-negative bacteria,8,23 and it is
bactericidal for all serogroups of meningococcus tested (A,B,C,W135).
Minimum bactericidal concentrations are 4-16 mg/mL and bacterial killing
is manifest after only brief incubations (<1 h) with the protein. In our
study, peak BPI levels, especially in the high-dose group, equalled or
exceeded the minimum bactericidal concentrations for many clinical
isolates of meningococcus.
Neither rBPI21 nor rBPI23 are immunogenic in healthy adults at any
dose.[15] We did not measure antibodies to rBPI21, largely because of
limitations on blood sampling in children. Autoantibodies to BPI have
been detected, however, in patients with vasculitis, inflammatory bowel
disease, and cystic fibrosis, suggesting that BPI can be an
antineutrophil cytoplasmic antibody (ANCA) antigen. However, these
antibodies seem to be directed against the C-terminal region of BPI and
do not react with rBPI21[24] (Dunn A, personal communication).
The rationale for inhibiting bacterial endotoxin has been intensely
scrutinised in large phase III trials in adults with sepsis, treated
with monoclonal antibodies directed against the lipid A portion of
LPS.[25,26] Although there was no effect on 28-day mortality, that does
not mean that the rationale should be discarded. The trials included
patients with diverse underlying diseases and a wide spectrum of
expected outcomes. Meningococcaemia is a single infectious disease which
primarily afflicts otherwise healthy children, and the outcome is
predictable. Also the sepsis trials included many patients who did not
have gram-negative disease and were not endotoxaemic, and thus less
likely to benefit from antibody therapy. All our 26 patients had
microbiologically proven meningococcaemia5 or had meningococcaemia on
clinical criteria. 18 of the 20 for whom pre-study samples were
available were endotoxaemic (>10 pg/mL). Finally, rBPI21, unlike the
antibodies used in previous trials, has bactericidal, antibiotic-
enhancing, and endotoxin-neutralising activities.
Since this was the first use of rBPI21 in sick patients and the first
use of rBPI21 in any children, the trial was designed as a small, dose-
escalation study to see if rBPI21 administration was feasible and to
obtain preliminary safety and efficacy data. In the absence of placebo
controls we looked at outcome in several ways. To predict mortality we
prospectively chose the GMSPS,[27,28] a scoring system that incorporates
clinical indices plus the base deficit from blood gas analysis. This
score has been validated, it is widely used and easy to perform, and it
correlated with disease outcome in the study centre initiating our
trial.[3] On the basis of GMSPS scores, predicted mortality for our 26
patients was at least 30% (eight deaths);[27-30] only one patient died.
We also predicted outcome on the basis of laboratory markers reported
elsewhere. Expected mortality might have been higher if blood samples
had been taken earlier than the average 5 hours after initiation of
antibiotics in our series; even so, baseline endotoxin, 4 IL-6,[31] and
coagulopathy[32] indices all predicted four to eight deaths. In 54
children who were admitted to the study centres between July, 1993, and
the beginning of our study of rBPI21, and whose GMSPS scores were
similar in distribution, there were 11 deaths (20%). These data for
historical controls and the predictions from GMSPS and laboratory
markers suggest that mortality in meningococcaemia patients treated with
rBPI21 was lower than expected. A phase III, randomised, double blind,
placebo-controlled trial has been initiated in the UK, Canada, and USA.
Above is excepted
Note AT LEAST 30% (very sick kids)
Note>30 to 50x higher in meningo vs gram negs
Note>e5 rational should not be discard
Note>inclusion criteria for e5 etc
Note this is not my "research area"
All IMO all disclaimers
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