Unrevealing culture-negative severe sepsis
Unrevealing culture-negative severe sepsis
Nicolas de Prost 0
Keyvan Razazi 0
Christian Brun-Buisson 0
0 Service de Réanimation Médicale, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny , 94010, Créteil, Cedex , France
Sepsis involves a wide array of sources and microorganisms, only a fraction of which are microbiologically documented. Culture-negative sepsis poses special diagnostic challenges to both clinicians and microbiologists and further questions the validity of sepsis definitions.
According to the 2012 Surviving Sepsis Campaign, sepsis
is a ‘systemic, deleterious host response to infection’,
characterized as ‘suspected or documented’, which can
lead to severe sepsis as defined by an ‘acute organ
dysfunction secondary to infection’ . Central to this
definition is the presence of an infectious process, which
differentiates sepsis from other causes of severe
inflammation. However, only about 40 to 60% of patients with
severe sepsis or shock have a microbiologically
documented infection. In a substantial proportion of patients,
sepsis will remain only clinically suspected, raising the
possibility of a non-infectious cause (that is, of severe
systemic inflammatory response syndrome).
In this issue of Critical Care, Phua and colleagues
reported on a large prospective cohort study of patients
(n = 1,001) presenting with severe sepsis on ICU
admission and compared the characteristics and outcomes of
culture-negative versus culture-positive episodes .
Their main findings were that culture-negative sepsis
occurred in 41.5% of the cohort, was associated with
female gender, less comorbidities or organ failures, and
more lung infection (74.5% vs. 59.9%) than their
counterparts, and included lower serum procalcitonin levels
and ICU mortality; however, identification of a pathogen
was not independently associated with mortality in
Sepsis is a highly heterogeneous syndrome, affecting
patients with various underlying conditions, and
involving an array of infectious sources and
microorganisms. Although the characteristics of infection were
retained in attempts to better characterize sepsis
through the PIRO (predisposition, infection, response
and organ failure) concept , data are conflicting
regarding their impact on outcome of patients [4,5]. The
observations by Phua and colleagues  tend to confirm
earlier epidemiological studies showing that patients
with or without microbiological documentation were at
similarly high risk of death [6-8]. Despite this apparent
lack of influence on outcome of patients,
nondocumented sepsis challenges both our
understanding of sepsis and management strategy. Indeed, the
highest possible rate of documentation is desirable, as
this would allow for a more targeted therapy in many
patients, possibly avoiding unnecessary prolonged
administration of broad-spectrum antibiotics .
Why should patients presenting with a clinical
syndrome of severe sepsis have nondocumented infection?
Firstly, patients may have received antibiotics prior to
the onset of organ dysfunction, thus obscuring
conventional cultures. For example, patients with
communityacquired respiratory tract infection often receive
antibiotics before ICU admission, and not surprisingly Phua
and colleagues report that respiratory tract infection was
associated with culture-negative sepsis . They did not,
however, record information on prior antibiotic
treatment, and this hypothesis cannot be substantiated.
Secondly, the diagnostic workup may be insufficient or
incomplete, which does seem to apply to the current
study because patients with positive or negative cultures
appeared to have a similar number of samples taken .
A third possible explanation is sepsis caused by
unusual organisms that are difficult to identify in routine
practice. Conventional microbiological methods
frequently fail to indentify a microorganism due to various
reasons related to technical issues or intrinsic to the
microorganism. Promising studies using PCR methods
showed that microbial DNA could be rapidly detected in
blood of septic patients , and could detect potentially
significant bacteria and fungi not retrieved from blood
culture [9,10]. In a recent meta-analysis, the overall
sensitivity and specificity for such methods to detect bacterial
or fungal DNA were 0.75 and 0.92 . However, even in
patients with severe sepsis, the rate of positive blood PCRs
was only 34.7% . Patients with culture-negative sepsis
described by Phua and colleagues  having lower serum
procalcitonin levels than others also suggests that at least
some of them may have had severe viral infections.
Indeed, a recent study showed that approximately one-third
of ICU patients with severe pneumonia had viruses found
by PCR assays on nasopharyngeal swabs or
bronchoalveolar lavage fluid .
A fourth explanation is that some patients having
culture-negative sepsis might actually have a noninfectious
cause for the clinical syndrome. Indeed, Phua and
colleagues report a few (n = 18) patients with
culturenegative sepsis having an unknown source of infection ,
raising the question of whether these patients with severe
systemic inflammatory response syndrome truly had an
underlying infection. Indeed, numerous differential
diagnoses of severe sepsis have been previously described,
including various tissue injuries (for example, surgery/trauma,
ischemia, and so forth), metabolic disorders (for example,
thyroid storm), adverse effects of drugs, inflammatory
diseases (for example, systemic lupus erythematosus, DRESS
syndrome, and so forth), malignancies and subarachnoid
hemorrhage [13,14]. One could reasonably hypothesize
that some of these mimickers of sepsis accounted for some
of the culture-negative severe sepsis in the study from
Phua and colleagues .
Although the study by Phua and colleagues leaves
several questions unanswered, it highlights the persisting
gaps in our current understanding of sepsis and provides
insightful information on the clinical features of
nondocumented sepsis . In the future, clinicians
should strive to formalize strategies for managing such
patients, probably combining clinical findings, imaging,
and conventional bacterial cultures, but also the use of
biomarkers and perhaps multiplex PCR-based assays to
enhance our diagnostic ability.
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