Triple diagnostics for early detection of ambivalent necrotizing fasciitis
Hietbrink et al. World Journal of Emergency Surgery
Triple diagnostics for early detection of ambivalent necrotizing fasciitis
Falco Hietbrink 0
Lonneke G. Bode
Luke P. H. Leenen 0
Marijke R. van Dijk
0 Department of surgery, University Medical Center Utrecht , Utrecht , The Netherlands
Background: Necrotizing fasciitis is an uncommon, rapidly progressive and potential lethal condition. Over the last decade time to surgery decreased and outcome improved, most likely due to increased awareness and more timely referral. Early recognition is key to improve mortality and morbidity. However, early referral frequently makes it a challenge to recognize this heterogeneous disease in its initial stages. Signs and symptoms might be misleading or absent, while the most prominent skin marks might be in discrepancy with the position of the fascial necrosis. Gram staining and especially fresh frozen section histology might be a useful adjunct. Methods: Retrospective analysis of 3 year period. Non-transferred patients who presented with suspected necrotizing fasciitis are included. ASA classification was determined. Mortality was documented. Results: In total, 21 patients are included. Most patients suffered from severe comorbidities. In 11 patients, diagnoses was confirmed based on intra-operative macroscopic findings. Histology and/or microbiotic findings resulted in 6/10 remaining patients in a change in treatment strategy. In total, 17 patients proved to suffer necrotizing fasciitis. In the cohort series 2 patients died due to necrotizing fasciitis Conclusion: In the early phases of necrotizing fasciitis, clinical presentation can be ambivalent. In the present cohort, triple diagnostics consisting of an incisional biopsy with macroscopic, histologic and microbiotic findings was helpful in timely identification of necrotizing fasciitis.
Necrotizing fasciitis; Early recognition; Triple diagnostics; Histology; Fresh frozen section
Necrotizing fasciitis is a relatively rare disease, which
describes a group of infections that comprises skin, soft
tissue and muscle and swiftly can spread through fascial
planes [1–3]. The disease can be rapidly progressive
and can have devastating outcome with many patients
not surviving the infection (up to 70 % mortality rate
reported in past series) . Early diagnosis followed by
immediate and thorough surgical debridement of affected
tissue is necessary to prevent mortality and curb the
systemic effects from resultant sepsis. However, diagnosis
in the early stages can be challenging [4, 5]. Patients with
necrotizing fasciitis might be brought to the ICU because
of their sepsis without known cause and later prove
unresponsive to resuscitation therapy [6, 7]. In a systematic
review, a close correlation between the percentage of
initially missed cases and the mortality rate in the
presented cohort series has been described . A 75 %
mortality reduction has been reported if operated within 12 h
after onset [9–13]. Moreover, a mismatch between
external signs and affected fascia has been mentioned. Thus,
early recognition, timely surgery and thorough initial
debridement are mandatory for survival [6, 8].
Over the last decade, mortality rate has decreased to
20-40 % in reported series [14–17]. Some have attributed
this to the improved awareness for necrotizing fasciitis
at general practitioners and ED-physicians, probably due
to the attention that has been given to this disease in
medical journals and general media . Due to this
improved awareness, patients are presented to the different
surgical specialties in more early stages of their disease.
This is a challenge for the treating surgeon, as local signs
can be minimal and only become more prominent as
the disease progresses . In these early stages of
necrotizing fasciitis, triple diagnostics is suggested to be a
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useful adjunct in obtaining a diagnosis . We provide
an algorithm that contributes in the early phases of these
patients in which a fresh frozen section and Gram
staining can be of paramount importance to the treating
surgeon. Implementation of this algorithm was analysed.
A retrospective analysis was performed of all
non-transferred patients, presented to the emergency department
of the University Medical Centre Utrecht with suspected
necrotizing fasciitis. Inclusion criteria were age >18 and
incisional biopsy or operation performed under the
suspicion of necrotizing fasciitis. No exclusion criteria were
formulated. A waiver was granted by the Ethical
Committee for retrospective data collection.
Comorbidity severity was scored according to the ASA
(American Society for Anesthesiologists) classification.
Patients are scored grade 1–4 in our hospital describing
the pre-hospital situation, with the addendum that grade 5
and 6 (created for emergency surgery settings) are not used
in our hospital as all critical ill patients will be in those
categories upon presentation. Mortality was recorded.
Deep tissue pain, hypoesthesia, purple skin changes,
ecchymotic changes of intact skin indicate neural and
vascular involvement and signify the need for immediate
operative intervention without biopsy . All other
patients undergo incisional biopsy. Macroscopic findings that
are suggestive for necrotizing fasciitis are summarized in
Table 1. Findings that are suggestive for necrotizing fasciitis
in fresh frozen sections or Gram stain are listed (Table 1).
Only few studies describe their results on triple diagnostics,
which makes a meta-analysis of this procedure not possible
[20, 21]. To endorse the usefulness of triple diagnostics in
necrotizing fasciitis, we questioned in what frequency its
use had led to an altered treatment strategy in our hands.
Triple diagnostics: macroscopic findings
When necrotizing fasciitis is suspected, an incisional
biopsy over the most suspected area is obtained via an
longitudinal or incision in the Langer lines [6, 22, 23].
Classical signs indicative for necrotizing fasciitis are
swollen tissue, dull grey necrotic tissue, grey fascia,
lack of bleeding, small vessel thrombosis, “dishwater”
pus, non-contracting muscle fibres and a positive “finger
test” [24–26]. These macroscopic findings are
pathognomonic and should prompt aggressive surgical debridement
(Table 1). However, especially in the early phases of
necrotizing fasciitis or immunocompromised patients,
classical signs may not be present during biopsy at all
or are present on a distant site from the external signs
. Merely oedema is no reason for thorough
debridement. In these cases, triple diagnostics by biopsy might
be an adjunct for both diagnosis and treatment. This
was first coined in the early eighties for ambivalent
cases of necrotizing fasciitis [19, 20]. Since then, it has
been mentioned occasionally, but has not been given the
place in diagnostics it deserves and even neglected in
recent guidelines due to lack of large scale studies . In
ambivalent cases microbiological findings by urgent Gram
staining and histopathological analysis by fresh frozen
section of soft tissue should be obtained [6, 20, 22]. The
sample should contain infected subcutaneous tissue, fascia
and muscle of the affected area.
Triple diagnostics: Gram staining
Fascia biopsy material is transported to the lab in a sterile
container. For Gram staining, the tissue is fixed to a glass
slide by alcohol or heating. For microscopy, x1,000
magnification (using an oil immersion objective lens (100×)) is
used to assess the presence, Gram staining, characteristic
arrangements and morphology of microorganisms.
Group A Streptococci (GAS, also called Streptococcus
pyogenes) are Gram positive spherical cocci. In clinical
specimens such as fascia biopsy material, they may appear
as pairs or short chains. However, when they are grown in
liquid media, they form the typical long chains.
Polymicrobial infections are usually mixtures of aerobic and anaerobic
bacteria, and therefore, many morphologically different
microorganisms can be seen. Gram staining may even show
more different microorganisms than are cultured
eventually, as culturing anaerobic bacteria can be difficult due to
specific growth requirements. Antibiotic therapy can be
modulated according to the results of the Gram stain.
Gram staining and microscopy can be performed rapidly
after arrival of the tissue in the lab, with a
turn-aroundtime of approximately 30 min depending on the techniques
used in the lab and the skills of the microscopist. Negative
Table 1 Characteristic findings suggestive for necrotizing fasciitis. Typical findings that can indicate necrotizing fasciitis during
incision biopsy for macroscopic findings and findings on the fresh frozen section and Gram staining
Necrosis of superficial fascia
Polymorphonuclear infiltration of the deep dermis and fascia
Fibrinous trombi of arteries and veins passing through the fascia
Angiitis with fibrinoid necrosis of vessel walls
Microorganisms within the destroyed fascia and dermis
microscopy does not rule out the presence of
microorganisms in tissue however; tissue should therefore be cultured
as well. This also facilitates antimicrobial susceptibility
testing on the causative microorganisms. Special care should
be given to anaerobic microbes.
Triple diagnostics: fresh frozen section
Especially in cases with only peri-fascial oedema and
absence of macroscopic necrosis, a fresh frozen section is
of the upmost importance. Fresh, non-fixed tissue from
a true cut section including fascia is embedded in gel
and frozen rapidly to about −20° C. With a cryostat
sections of 6 to 9 micrometer are produced and stained
with hematoxylin and eosin (H&E). This procedure takes
10 to 15 min. The most specific predictive finding is
necrosis of the superficial fascia with fibrinous trombi of
arteries and veins located in the fascia. The vessels walls
can show signs of angiitis with fibrinoid necrosis of the
walls. Both the fascia and the deep dermis often show
infiltration of polymorphonuclear cells. If bacteria are
present in large numbers, they can often be seen in the
H&E staining [20, 28]. In macroscopically obvious cases
of necrotic fascia, histology will only demonstrate
nonspecific necrosis and is not indicated. No data is
available about under and over diagnosis using this method
and microbiology and pathology findings should not
replace clinical parameters. Nevertheless, the combination
of the 3 modalities might provide the surgeon sufficient
data to identify the correct patients as early as possible
or to extent the exploration of the suspected area.
A treatment algorithm that might help in the management
of these patients with ambivalent cases is postulated
(Fig. 1). When there is a suspicion of necrotizing
fasciitis, skin lesions are marked, blood cultures are drawn and
laboratory tests are performed. Thereafter, broad spectrum
antibiotics are initiated and should cover Streptococcus
(Penicillin or 2nd/3rd generation Cephalosporin),
Clindamycin (as toxin scavenger) and Gentamicin. The surgeon
is consulted. Sepsis is treated immediately according to the
Surviving Sepsis Campaign guidelines . If clinical signs
and symptoms in combination with laboratory tests are
not suspicious, the patient is re-examined on set time
points. However, if necrotizing fasciitis is suspected or
cannot be ruled out, the patients consent is obtained for
all possible scenario’s (debridement, amputation, intensive
care and ventilator support and dialysis) and the patient is
brought to the operation room for biopsy as soon as
An incision is made over the most prominent skin marks
or spot that is most painful. If during this procedure the
diagnosis can be confirmed macroscopically, this prompts
aggressive debridement. An incision biopsy for Gram stain
Fig. 1 Clinical algorithm for suspected fasciitis. The algorithm used for gate specialties in patients with suspected necrotizing fasciitis. It consists
of awareness, early surgical consultation and early initiation of treatment. When incision biopsy is indicated, the patient is transported to the
operation room for further treatment. Treatment and aftercare is multidisciplinary
is obtained, but should not delay further surgical control of
the tissue when there are macroscopic findings of necrosis.
Macroscopic necrosis frequently hampers the
interpretation of histology and fresh frozen section is considered
less useful in these cases.
However, if the diagnosis is indistinct by macroscopic
findings (i.e. merely oedema), the biopsy is used for a
Gram stain and fresh frozen section. If either one of
them is suggestive for necrotizing fasciitis this prompts
longitudinal extension of the incision. Skin marks can be
misleading and necrotic lesions of the fascia can be found
at distance after extension of the incision(s). When
indicated by findings on histology of microbiology, aggressive
debridement should follow of the entire affected area.
Because either a positive or ambivalent macroscopic finding
prompts further surgery, we prefer to perform the incision
biopsy in the operation room.
After debridement, the wounds are left open, the
patient is transported to the ICU for resuscitation and
reevaluated at set time points. When there are no
indications for necrotizing fasciitis by macroscopy, Gram stain
and fresh frozen section, the wound is either closed or left
open when there is reasonable doubt. Re-evaluation takes
place at set time points. Supportive therapeutic measures
are initiated when indicated and based on mainly the
Gram stain, such as immunoglobulins for GAS and
hyperbaric oxygen in clostridium. Thereafter the patient is
further treated by a multidisciplinary team, consisting
of a surgeon, intensivist, microbiologist, physiotherapist,
social worker, dietician and additional specialties
depending on the location of the disease (i.e. plastic surgery,
ophthalmologist, ENT-physician) . When progression
of necrosis is controlled, wounds are usually covered by
vacuum devices until closure can be achieved.
In a three year period, 21 non-transferred cases were
presented to the emergency department who underwent
incision biopsy or operative debridement. Their average
age was 53 (range 34–75) and most patients suffered
from severe comorbidities (6 ASA I, 4 ASA II, 2 ASA III
and 9 (47 %) ASA IV patients). In 11 patients, diagnoses
was confirmed based on intra-operative macroscopic
findings of fascial necrosis. There were 10 ambivalent
cases with only macroscopic peri-fascial oedema or
necrosis of the subcutaneous fatty tissue, in which fresh
frozen section and Gram staining resulted in a change in
treatment strategy in six patients. Based on macroscopic
findings the surgeon would have ended the surgical
procedure, but instead extended the incisional area and
focal necrosis was found at a distant side in all 6 patients.
Follow-up proved that 4/21 patients did not have
necrotizing fasciitis (Fig. 2). Group A Streptococcus were found
in 8 of the 17 patients with confirmed necrotizing fasciitis.
Mortality due to necrotizing fasciitis was the outcome in
two patients (12.5 %) and 2 additional patients died within
the first 30 days after admission due to other pre-existing
conditions (25 % total 30 day mortality).
In this cohort series we present the results of an algorithm
which uses triple diagnostics for ambivalent cases of
Fig. 2 Patient flow. The flow of patients is depicted and decision making was based on macroscopic, histologic and microbiotic findings
necrotizing fasciitis in the very early stages of the disease.
In patients with an ambivalent presentation and no clear
macroscopic necrosis of the fascia during incisional
biopsy, the combination of a fresh frozen section and Gram
staining altered treatment in 60 % of the cases. All of
which later proved to be necrotizing fasciitis based on
clinical follow-up. Mortality due to necrotizing fasciitis in
this series was 12.5 % and overall mortality was 25 %,
which is a fair result considering the large number of ASA
IV classified patients.
The mortality rate in the present series is identical to
the first report (12.5 %) on the use of histology in
necrotizing fasciitis . It was discussed if the relative low
mortality was the result of the early operative debridement
or could be attributed to the histology . We feel that
the use of histology and Gram staining results in more
timely decision making and therefore early debridement
and source control.
Necrotizing fasciitis is rare and heterogeneous in its
presentation for body region as it can occur in every fascia
and mimic many other infectious and non-infectious
diseases. As a result, numbers per treating physician
and expertise gained with this disease are often limited.
In addition, physicians frequently find it a “scary” disease,
because of its rapid progression and the necessary
thorough debridement that might result in bad function and
Awareness is advocated in patients with sudden onset
and rapid progression of a suspected infectious disease.
Disproportional pain is often referred to as the common
denominator in this disease and should trigger further
investigation. More classical symptoms for necrotizing
fasciitis, such as erythema, oedema, blisters, crepitus, and
skin necrosis have been described in only 10–40 % of the
cases and are seldom seen within the first 24 h [22, 32, 33].
The difficulty in recognition is further stretched by
underlying conditions, for instance trauma, vascular disease,
diabetic wounds or drug abuse . Co-morbidities are found
in nearly 50 % of patients with necrotizing fasciitis and
frequently some form of trauma (blunt or penetrating)
preceded symptoms. In the present series 55 % suffered severe
co-morbidities such as congestive heart failure, renal
insufficiency or acute leukemia. Although heterogeneous in its
presentation, the philosophy of early identification and
aggressive holistic treatment is uniform. This is often referred
to as the “search and destroy” strategy [7, 21, 31, 34, 35]. In
the presented cohort, a total of 4 patients were brought to
the operation room based on clinical suspicion, who did
not prove to have necrotizing fasciitis, This demonstrates
the low threshold for incisional biopsy when necrotizing
fasciitis is suspected, leading to a relative over treatment of
patients with a less severe condition (i.e. erysipelas).
Proposed classifications are universal and either based
on location or microbiology [36, 37]. Locations which
are often affected are the trunk, extremities and the
maxillofacial region. Frequently encountered specific
locations include Fournier (perineum), Ludwig’s angina
(submandibular) and Meleney’s synergistic gangrene
(abdominal wall and/or post-operative) [24, 25, 38].
Classification by microbiology covers all locations,
although some locations are more associated with a specific
type than others. Type 1 accounts for 55–90 % of all cases
and consists of a polymicrobial flora [24, 26, 38, 39].
Fournier is often associated with type 1 necrotizing fasciitis.
Type 2 consists of a mono-microbial flora, of which
necrotizing fasciitis with Group A Haemolytic Streptococcus
(GAS, also called Streptococcus pyogenes) is the most
important one. Other suggested classification groups are type
3 for virulent Gram negative bacilli (i.e. Vibrio species) and
type 4 for fungi and yeasts (i.e. Cryptococcus or Candida
species) . Microbiological findings, and thus
classification types, are highly geographically dependant. For
instance, Vibrio species is mostly situated in Asia, while
methicillin-resistant Staphylococcus aureus (MRSA) is
seldom seen in the northern region of Europe [41, 42].
In order to combine multiple aetiologies, it has been
proposed to integrate all types of necrotizing fasciitis like
entities in the diagnose of severe necrotizing soft tissue
disease as therapy is similar . In addition, the potential
whole body presentation causes many different medical
specialties to be confronted with necrotizing fasciitis,
resulting in more scattered experience. This stretches the
need for a universal treatment algorithm [34, 44, 45].
To aid in the identification of patients with necrotizing
fasciitis, several adjuncts have been described. A large base
deficit or high Laboratory Risk Indicator for Necrotizing
Fasciitis (LRINEC) score have been suggested to increase
the possibility of a patient having necrotizing fasciitis,
however, they are not tools to provide a definitive
diagnosis [16, 32, 33, 46, 47]. Their values may provide insight
in the severity of disease, however, sensitivity remains
low [7, 48, 49].
Imaging studies might provide additional information.
Although air in the fascial planes is seldom present in
the early stages and fascial fluid collections are not always
seen. Moreover, CT-scanning might provide information
about underlying conditions in cases for necrotizing
fasciitis in the maxillo-facial area or trunk (Fournier), such as
diverticulitis or abscesses. Some clinics have incorporated
CT-scanning in their standard work-up for hemodynamic
stable patients with fasciitis to screen for underlying
pathology. In certain cases CT helps to evaluate the extent of
tissue infection showing swelling, inflammation and gas
MRI scanning proves to have the highest sensitivity
and specificity . However, MRI scanning may not be
desirable in all patients or available in all hospitals.
Furthermore, the exact contribution of imaging modalities
in the early stages of necrotizing fasciitis is still under
debate and should always be correlated with the clinical
presentation [48, 51, 52]. In more advanced cases
treatment should not be delayed for imaging. Taken together,
clinical suspicion should outweigh both laboratory and
imaging adjuncts for the diagnosis of necrotizing
fasciitis, especially in the early stages of the disease, where
the therapeutic yield of debridement is the greatest .
Clinical suspicion can be supported by fresh frozen
section and Gram staining during incisional biopsy and might
result in more timely identification of this life threatening
With improved awareness, a challenge arises with the early
and correct identification of necrotizing fasciitis. Signs and
symptoms might be absent or misleading, as prominent
skin marks might not be the place of fascial necrosis. This
emphasizes the importance of adequate algorithms and
treatment protocols for all medical specialties that might
encounter necrotizing fasciitis. Identification and
debridement as soon as possible and aggressive enough are the
major contributors for survival. Therefore, triple
diagnostics which include a fresh frozen section and Gram staining
might be an important adjunct in early ambivalent stages
of suspected necrotizing fasciitis.
Availability of data and materials
Data sharing not applicable to this article.
FH, MvD and LB prepared the first draft. FH analysed database. FH, MvD, LB,
LL, LR critically reviewed and drafted the manuscript until its final version. All
authors read and approved the final manuscript.
Consent for publication
No consent for patient material was needed: not applicable.
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