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Published Date: 2011-08-27 16:24:20
Subject: PRO/AH> E. coli O104 - EU (36): intervention strategies
Archive Number: 20110827.2617

E. COLI O104 - EUROPEAN UNION (36): INTERVENTION STRATEGIES
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Date: Wed 24 Aug 2011
Source: Medscape [edited]
http://www.medscape.com/viewarticle/748532

Early plasma exchange may hold promise in managing diarrhea-associated
hemolytic uremic syndrome, a rare but potentially fatal complication
of _E. coli_ infection, according to results from a small study
carried out in Denmark and published online today in The Lancet. The
study is one of the first to appear after the _E. coli_ outbreak
earlier this summer in Europe. Most cases in that outbreak were
reported in Germany, but residents of other countries sought treatment
as well.

Senior author Martin Tepel, MD, from the Department of Nephrology,
Odense University Hospital, Denmark, and colleagues point out that
diarrhea-associated hemolytic uremic syndrome (HUS) is rare in adults
(0.5 - 2.1 cases per 100 000 people per year) but is seen more
frequently in children (6.1 cases per 100 000 children younger than 5
years per year).

HUS is characterized by acute hemolytic anemia, thrombocytopenia, and
renal insufficiency. Most cases are associated with enteritis
resulting from a Shiga toxin that is released by certain serotypes of
_E. coli_. One such serotype is 0104:H4, the pathogen most often
identified in May's outbreak. More than 40 people have died as a
result of the outbreak, and some reports indicate HUS may have been
much more common this time than in previous outbreaks.

Dr. Tepel and his group point out that plasma exchange has been tried
previously, but the benefit of that management strategy remains
controversial. They add that as HUS is rare, it would be unlikely that
a randomized controlled trial could be carried out to assess the
relative efficacy of various treatments. "However, we were able to
assess the benefit of plasma exchange in a large outbreak, providing
the opportunity to study at least several cases at the same time,"
they write.

In late May 2011, Dr. Tepel and his group used plasmapheresis to treat
4 women and 1 man (aged 44 - 70 years) who had symptoms of HUS
associated with _E. coli_, including enteritis, bloody diarrhea, acute
hemolytic anemia, thrombocytopenia, acute kidney injury, and
progressive central nervous dysfunction. All the patients had recently
visited northern Germany.
Each of the patients was treated daily with plasma exchange by
centrifugation and substitution with fresh frozen plasma.
After treatment, median platelet counts and glomerular filtration
rates increased and median lactate dehydrogenase concentrations
decreased. Neurological status also improved, the authors say.

The researchers found an association between time to initiation of
therapy and how soon the treatment showed effect. "The time interval
from onset of bloody diarrhea to start of plasma exchange had an
inverse correlation with reduction of lactate dehydrogenase
concentrations by plasma change (p=0.02)," the researchers write. All
5 patients were discharged from hospital with normal neurological
status between 5 and 8 days after beginning treatment. The authors
conclude: "Early plasma exchange might ameliorate the course of
diarrhea-associated [HUS] in adults, but this finding should be
verified in randomized controlled trials."

A comment accompanies the Tepel study, in which coauthors Piero
Ruggenenti, MD, from Mario Negri Institute for Pharmacological
Research, Bergamo, and Giuseppe Remuzzi, MD, from Azienda Ospedaliera
Ospedali Riuniti di Bergamo, Italy, point out that treatment with the
monoclonal antibody eculizumab has been tried during the outbreak as
an adjunctive therapy with plasma exchange. However, they say, results
with that approach have not demonstrated consistency. They add that it
could be that early treatment with carbapenems or antimicrobials that
are electively effective against extended-spectrum beta-lactamase
producing _E. coli_ (eg, fosfomycin) might help stop enterocolitis
from progressing to HUS, and that such approaches merit further study.
However, they conclude, "At present, early plasmapheresis, with or
without eculizumab, remains the cornerstone of treatment."

[Byline: Steven Fox]

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[These 2 articles, published online in the British journal The Lancet,
represents the 1st after-epidemic observations on potential
therapeutic interventions for this chimeric organism which combines
virulence factors of the pathotypes, enterohemorrhagic and
enteroaggregative, of _E. coli_. Whether the observations, anecdotal
at best at this time, are applicable to the more typical
enterohemorrhagic strains represented by _E. coli_ O157:H7 is not
truly established.

Martin Tepel's study (1) reported on 5 patients in Denmark, all who
had traveled to Germany, receiving plasmaphoresis and seemed to have a
prompt response to the intervention. Although the technique has been
used commonly in thrombotic thrombocytopenic purpura (TTP), a close
relative of HUS in the group of thrombotic angiopathies, and in
non-diarrhea-associated HUS, its use in _E. coli_-associated disease
has remained controversial. Although the intervention seemed
successful, the authors appropriately interpreted their finding as
"early plasma exchange might ameliorate the course of
diarrhea-associated HUS in adults. However, this finding should be
verified in randomized controlled trials."

>From this moderator's perspective, since such large outbreaks of such
an entity are unusual, this outbreak may well have been the best
opportunity to do such as trial. Many clinicians may take the Tepel
study as a testimonial for plasmaphoresis in this entity but, as the
authors had stated, it is not. Again, even if clearly effective in
this unique _E. coli_ O104:H4 outbreak, whether it applies to O157:H7
and other EHEC strains is even less clear.

The 2nd report (2) is a commentary on the Tepel study and adds little
to the two other inventions that were explored, the humanized,
monoclonal antibody eculizumab and early treatment with a carbapenem.
They state that about 300 patients were treated with eculizumab during
the outbreak "apparently less consistent effects". No data is
available as yet how the study was designed so any meaningful
conclusions whether the monoclonal antibody was useful is totally
lacking. Likewise, whether the use of a carbapenem antimicrobial
agent can prevent progression is not at all established especially
since, as in the Tepel study, most antimicrobials used early in
disease are detrimental.

References:
1. Colic E, Dieperink H, Titlestad K, Tepel M: Management of an acute
outbreak of diarrhoea-associated haemolytic uraemic syndrome with
early plasma exchange in adults from southern Denmark: an
observational study. Lancet doi:10.1016/S0140-6736(11)61145-8.
2. Ruggenenti P, Remuzzi G:A German outbreak of haemolytic uraemic
syndrome. Lancet doi:10.1016/S0140-6736(11)61217-8. - Mod.LL]

See Also