Immunotherapy for Infectious Diseases

278 Donta
antibody preparation (HA-1A) against the same J5 mutant, showed that both mortality
and morbidity (i.e., shock) could be prevented in patients with documented Gramnegative
bacteremia (24,25). A number of other clinical trials also showed therapeutic
or prophylactic benefit of immunoglobulin preparations (26–28), although other trials
did not show any benefit of core-endotoxin hyperimmune globulin over that of standard
IVIG preparations (29,30). Because overall mortality of patients was not reduced
in control patients in the HA-1A trial, implying an adverse effect of the antibody preparation
in patients with Gram-positive bacteremia or with no defined etiology, because
two other trials failed to show a beneficial effect against Gram-negative sepsis, and
because of a number of other issues, including the use of subanalyses, and the potential
costs of this therapy, the HA-1A preparation did not receive U.S. Food and Drug
Administration approval for use in patients with suspected Gram-negative sepsis. The
various issues, however, remain unresolved, as argued by Cross et al (31), and it is
hoped that this approach will be re-examined and refined, not abandoned.
Another series of trials directed against infections caused by Klebsiella species and
Pseudomonas aeruginosa ended without definitive conclusions. In these trials, patients
in intensive care units in Department of Veterans Affairs hospitals in the United States
were given hyperimmune sera derived from immunized human volunteers to determine
whether these preparations were more effective than an albumin placebo in preventing
infection, mortality, and morbidity caused by these important pathogens. In the first
trial, it appeared that Klebsiella infections were being prevented and modified, but
because there was no effect against Pseudomonas infections, that trial was stopped by
the Data Monitoring Board (DMB) and a new trial begun using greater concentrations
of hyperimmune sera (32). The second trial was never completed, however, because of
the many adverse effects (e.g., hypotension, fever) of the hyperimmune IVIG preparation
and because the DMB was not convinced that the trial would yield significant differences
when and if sufficient patient enrollment could be achieved. Subsequent
analyses suggested that the hyperimmune preparation had a therapeutic effect on
patients who were already infected at the time of patient entry into the study, but the
numbers did not achieve statistical significance. No subsequent studies were considered
by the manufacturer or by the Department of Veterans Affairs, leaving the possibility
of therapeutic and/or prophylactic benefit unresolved.
Miscellaneous Observations
Limited, anecdotal, studies in various other settings have suggested some therapeutic
and prophylactic benefit of standard IVIG preparations. These include sepsis following
cardiac surgery in high-risk patients (33), patients with cerebrospinal fluid shunt infections
(34), and patients with multiple myeloma (35). No effect was found in preventing
infections in pediatric head trauma patients (36). One report suggested that early treatment
with IVIG prevented polyneuropathy following multiple organ failure and Gramnegative
sepsis (37). Another report suggested that IVIG facilitated the recovery of
lymphocytic meningoradiculitis associated with Lyme disease (38). Experimentally, the
use of human IVIG protected rabbits from diarrhea and death associated with E. coli
shiga-like toxin (39).