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Eur J Clin Microbiol Infect Dis (2015) 34:633–639
DOI 10.1007/s10096-014-2277-6
REVIEW
Ecthyma gangrenosum and ecthyma-like lesions: review article
M. Vaiman & T. Lazarovitch & L. Heller & G. Lotan
Received: 11 October 2014 / Accepted: 4 November 2014 / Published online: 19 November 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract The generally accepted definition of ecthyma
gangrenosum (EG) states that this condition is pathognomonic
of Pseudomonas septicemia (Pseudomonas aeruginosa) and
that it should usually be seen in immunocompromised patients, particularly those with underlying malignant disease.
The cases described in the literature present a somewhat
different picture. Our objective was to analyze this controversy. The review analyzes 167 cases of EG that were described
in the literature from 1975 to 2014. All articles on EG cases
with EG-specific tissue defect that had signs of general and/or
local infection and skin necrosis were included and analyzed,
whatever the etiology detected. Necrotic lesions of the skin
diagnosed as EG have various microbiological etiology, can
occur in immunocompetent or even healthy persons, and are
not necessarily connected with septicemia. In published cases,
P. aeruginosa was detected in 123 cases (73.65 %); of them,
M. Vaiman
Department of Otolaryngology, Assaf HaRofeh Medical Center,
Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel
T. Lazarovitch
Department of Microbiology, Assaf HaRofeh Medical Center,
Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel
L. Heller
Department of Plastic Surgery, Assaf HaRofeh Medical Center,
Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel
G. Lotan
Pediatric Surgery Department, Assaf HaRofeh Medical Center,
Affiliated to the Sackler Medical School, Tel Aviv University,
Zerifin, Israel
M. Vaiman (*)
33 Shapiro Street, Bat Yam 59561, Israel
e-mail: [email protected]
there were only 72 cases (58.5 %) with sepsis. Other bacterial
etiology was detected in 29 cases (17.35 %) and fungi were
detected in 15 cases (9 %). While the clinical picture of the
disease and the treatment strategy remain the same, there is no
need to invent two separate definitions for Pseudomonas and
non-Pseudomonas cases. We suggest accepting a broader
definition of EG.
Introduction
Ecthyma gangrenosum (EG) is a relatively uncommon condition. The clear description of the disease was given by L.
Barker in 1897 and the term itself was generally accepted in
the 1950s [1, 2]. Up to the 1970s, it was postulated that this
condition is pathognomonic of Pseudomonas septicemia
(Pseudomonas aeruginosa) and that it should usually be seen
in immunocompromised patients, particularly those with underlying malignant disease [3, 4]. P. aeruginosa is a Gramnegative, aerobic, coccobacillus bacterium that was previously known as Bacterium aeruginosum, Bacillus pyocyaneus,
and Bacterium pyocyaneum. The name P. aeruginosa became
generally accepted since the 1940s. The importance of this
bacterium in dermatology was well described [5].
Since the 1980s, more and more data have been accumulated that various bacteria like Escherichia coli, Citrobacter
freundii, Klebsiella pneumonia, various other Pseudomonas
species, and Morganella morganii can be etiologic agents for
EG, as well as some fungi (Candida albicans, Fusarium, and
others) [6–8]. It was also reported that EG can manifest in
immunocompetent patients as well [9]. Finally, it was reported
that EG can affect an otherwise healthy person and the whole
concept that EG is a skin manifestation of severe systemic
Pseudomonas infection was questioned [10]. Cases of EG
diagnosed in healthy newborn infants added more to this
unclear situation [11, 12].
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The clinical picture of EG is well described as hemorrhagic
pustules evolving into necrotic ulcers. The evolved EG gangrenous ulcer has a black scab and can be surrounded by a red
halo. While generally accepted, the exact clinical manifestations also have their own unanswered questions. For example,
most of the researches agree that the skin lesions usually occur
in the gluteal and perineal regions (57 %) or extremities
(30 %) [13, 14]. The lesions, however, may appear on the
face, chest, arms, neck, and other parts of the body [10, 15]. At
present, the knowledge about EG is still incomplete. In the
emerging literature, authors have tried to overcome this confusion, suggesting two definitions: EG and EG-like lesions
[12, 16, 17] or “mimicking ecthyma gangrenosum” lesions
[18]. The current review analyzes the above-described
controversies.
Search strategy and selection criteria
An extensive search for relevant data was performed through
the PubMed, MEDLINE, and ScienceDirect search tools. The
articles on the subject published from 1975 till 2014 were
analyzed. The search started from the 1940s, when the first
relevant articles appeared, but the selection of relevant articles
started from 1975, when the diagnosis of P. aeruginosa infection was completely developed. Current microbiologic analysis includes the usage of blood agar or eosin-methylthionine
blue agar, Gram morphology, ability/inability to ferment lactose, a positive/negative oxidase reaction, odor, ability/
inability to grow at 42 °C, and fluorescence under ultraviolet
light. Fluorescence is also used to detect the presence of
P. aeruginosa in wounds. The articles that appeared before
the 1970s frequently lack this complete set of tests.
Inclusion criterion: all articles on EG cases with EGspecific tissue defect that had signs of general and/or local
infection and skin necrosis were included and analyzed, whatever the etiology detected. Exclusion criteria: articles on the
subject dealing with EG-like tissue defects that appeared after
burns were excluded from the analysis. Articles with incomplete description of differential diagnosis were excluded from
the analysis, as well as articles with an unclear description of
the microbiologic laboratory diagnostics.
In addition to the location of the lesion, clinical picture, and
treatment, three main variables were analyzed: etiology, presence or absence of septicemia, and the immune status of the
patients.
Results
From 1975 to 2014, 85 articles on EG were published that met
the requirements of the inclusion criteria. These articles described 167 cases of EG of various etiology. Most of the
Eur J Clin Microbiol Infect Dis (2015) 34:633–639
articles described 1–3 cases as case reports. Few articles
described several cases, i.e., eight [19, 20], six [21, 22], and
seven cases [23]. The most recent article of Chuang et al. in
2014 described 17 cases of EG that were found among 27
cases of Shanghai fever of P. aeruginosa etiology [24].
Etiology
Of the 167 published cases, P. aeruginosa was detected in 123
cases (73.65 %) (Table 1). Various other bacterial etiology was
detected in 29 cases (17.35 %), fungi were detected in 15 cases
(9 %). Pseudomonas cepacia, Pseudomonas maltophilia,
Pseudomonas stutzeri, Aeromonas hydrophila, Escherichia
coli, Klebsiella pneumoniae, Citrobacter freundii, Staphylococcus aureus, Staphylococcus epidermidis, and
Stenotrophomonas maltophilia were described as etiology of
non-P. aeruginosa cases, as well as disseminated nontuberculous mycobacterial infection and streptococcal infection. The most frequent agents were A. hydrophila (seven
cases), P. maltophilia (Xanthomonas maltophilia) (four
cases), and E. coli (four cases). Among fungal infections, the
authors indicated Mucor pusillus [25], Candida tropicalis
[26], Fusarium solani [27], Scytalidium dimidiatum [28],
Metarhizium anisopliae [29], and Candida albicans as the
EG etiology [8, 12].
The viral etiology remains unclear and poorly described.
Two articles described non-bacteremic EG in patients with
acquired immune deficiency syndrome (AIDS; three cases),
but the connection between EG and human immunodeficiency virus (HIV) remains very unclear [30, 31]. Herpes simplex
was indicated among the possible viral etiological agents, but
its connection with EG is also unclear [32]. The infection is
not necessarily a monoculture and, for example, Fusarium
spp. can coexist with P. aeruginosa in the same patient [16].
General clinical picture
As a rule, P. aeruginosa or other etiological agents invade
the venules, resulting in secondary thrombosis of the arterioles, tissue edema, and separation of the epidermis that
leads to a specific clinical picture of EG. Almost all of the
analyzed reports and articles describe the same clinical
manifestation of EG, with very slight variations. The skin
lesions begin as an erythematous nodule or hemorrhagic
vesicle, usually macule first and then papule, which evolves
into a necrotic ulcer with eschar [4–15]. The skin lesions
can be single or widespread over the body. In the analyzed
literature, we detected no difference in the descriptions of
the clinical picture, time from nodule to ulcer, lesion location, and number of lesions per person between
Pseudomonas and non-Pseudomonas cases.
Eur J Clin Microbiol Infect Dis (2015) 34:633–639
Table 1 Distribution of 167
ecthyma gangrenosum (EG) cases
described in the literature since
1975
635
Etiology
Septicemia
P. aeruginosa
Other bacteria
Fungal
Immune status
Yes
No
Yes
No
Yes
No
Total
32
41
36
7
2
5
123 (73.65 %)
2
15
0
11
0
1
29 (17.35 %)
2
11
0
1
0
1
15 (9 %)
Immunocompromised
Immunocompromised
Immunocompetent
Immunocompetent
Healthy
Healthy
EG with and without septicemia
Diagnosis and differential diagnosis
Of the 123 EG cases of P. aeruginosa etiology, sepsis/septicemia/bacteremia were described in 72 cases (58.5 % of
Pseudomonas cases or 43.1 % of all cases) and an absence
of septicemia was detected in 51 cases (41.5 % of
Pseudomonas cases). Any age can be affected, starting from
a case of neonatal P. aeruginosa sepsis [33]. In older patients
(72 years), Pseudomonas bacteremia can coexist with disseminated fusariosis in wounds [16]. Up to the 1980s, it was
generally accepted that EG complicating Pseudomonas
bacteremia/sepsis is fatal to most patients, especially infants
[3, 34]. Further development of antibiotic therapy helped to
reduce the number of fatalities. At present, even a newborn
with EG and neonatal sepsis associated with significant leukopenia, thrombocytopenia, and alteration of the coagulation
profile can be saved by intravenous antibiotic treatment [33].
When EG was caused by other bacteria species, bacteremia
was detected in a much lower number of cases. Of the 29 EG
cases with various bacterial etiology, only two cases (6.9 % of
bacterial etiology or 1.2 % of all cases) had positive blood
cultures. Blood cultures were positive for Pseudomonas stutzeri
[35] and Escherichia coli [36, 37]. Fungal flora can also be
cultured from the blood of patients with EG, as well as from the
lesions. Two case reports described that blood culture grew
Scytalidium dimidiatum and Candida albicans [8, 28]. These
two cases represent 13.33 % of 15 cases with fungal etiology.
During the period from 1975 to 2014, the basics of EG
diagnostics remained generally the same. Blood cultures and
skin biopsy are optimal for precise diagnosis. A skin biopsy
should be sent for tissue culture for bacteria, fungi, yeasts, and
mycobacteria. Sensitivity tests should be performed on any
isolated organisms. Specimen processing includes the detection of bacteria by culturing, biochemical identification, and
susceptibility testing.
The majority of case reports do not describe microbiological
procedures in detail, indicating only the microorganism that the
wound cultures grew. The present protocol indicates that the
specimens should be inoculated into MacConkey agar and
blood agar. Cultured plates should be examined after overnight
incubation at 37 ° C. If no growth was obtained in the plates,
they should be reincubated for another 24 h. The identification
of Pseudomonas aeruginosa and antibiotics susceptibility tests
are performed by using a VITEK 2 (bioMérieux) or similar
instrument, according to the interpretive standards of the Clinical and Laboratory Standards Institute (CLSI) [38–40].
While in the majority of cases the clinical picture is specific
and convincing, the differential diagnosis should be performed between EG and warfarin-induced skin necrosis,
cocaine-induced skin necrosis, calciphylaxis, septic emboli,
loxoscelism, diabetic microangiopathy, disseminated intravascular coagulation, paraneoplastic extensive necrotizing vasculitis, pyoderma gangrenosum, livedoid vasculopathy,
antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cutaneous necrotizing vasculitis as a manifestation of
familial Mediterranean fever, and necrosis secondary to the
use of vasoactive drugs [41, 42].
EG and the immune status of the patients
The immunocompromised status is not obligatory for the
patients with EG. Among 123 patients with P. aeruginosa
EG, only 73 (59 % of Pseudomonas cases) were immunocompromised and the remaining 50 (41 %) were immunocompetent. EG cases of various other bacterial etiology present approximately the same picture: 17 immunocompromised
vs. 12 immunocompetent out of the total of 29 cases (58.62 vs.
41.38 %). In contrast, fungal EG can be found in immunocompromised patients almost always (13 cases out of 15,
86.66 %).
Underlying diseases
The analysis of 85 selected articles indicates that a broad
spectrum of diseases might be associated with EG. Malignancy, specific infectious diseases, connective tissue diseases,
diabetes, AIDS, and other immunocompromising pathologies
are common for the patients with EG, irrespective of the
636
etiological agent. Species other than P. aeruginosa can easily
infect an immunocompromised patient. For example, a patient
with acute myelocytic leukemia developed EG caused by
Citrobacter freundii [43]. In another case, disseminated invasive infection due to Metarhizium anisopliae in an immunocompromised child (acute lymphoblastic leukemia) also produced EG [29]. The majority of immunocompromised patients usually suffer from leukemia, lymphoma, other malignant diseases, severe burns or organ transplant [44], or might
be receiving immunosuppressive therapy.
In the 1980s, it was generally accepted that P. aeruginosa
can cause green nail syndrome, toe web infections, hot tub
folliculitis, infectious eczematoid dermatitis, and other mild
cutaneous infections in healthy individuals, while
Pseudomonas septicemia causes EG [45]. At present, we
detect a growing number of reports describing EG in healthy
individuals [10, 46–52].
An underlying disease does not necessarily affect the immune status of a patient. For example, P. aeruginosa EG was
described in a woman with recurrent Graves’ disease who had
normal white blood cell count, immunoglobulins, and lymphocyte subsets [53].
Location of the lesions
Of the 167 described cases, the buttocks and/or lower extremities were affected in 110 cases (65.8 %), but the remaining 57
cases (34.2 %) presented lesions in various parts of the body,
including the face. The face and the whole head and neck
region are affected much more often than is usually thought.
At least 14 cases of EG lesions were described as being
located within the head and neck region [11, 33–35, 53–61].
The last two references are case reports describing EG of the
nasal cavity. Several more similar case reports were published,
but the differential diagnosis between EG and noma remained
unclear, and we do include these data in the present review. An
EG lesion of the genital area was also described [62].
Severe perineal ecthyma gangrenosum can result in a cloacalike deformity [63]. Cases with affected buttocks, anogenital
area, and/or lower extremities are numerous and blood cultures
can be both positive and negative for P. aeruginosa or other
bacteria [64]. The route of infection is generally difficult to
establish and analysis of the topographic anatomy of the muscles, nerves, and arteries of the perineum does not present any
clear solution. Both physically active and immobile patients
with severe diseases that can cause inadequate blood supply to
the buttocks and perineum may have EG of these areas. Further
studies are needed in order to clarify the picture.
Eur J Clin Microbiol Infect Dis (2015) 34:633–639
etiology is established, aggressive antibiotic or antifungal
treatment is prescribed, but because EG manifests as a necrotizing soft-tissue lesion, (3) surgical excision is often
necessary.
During the period from 1975 to 2014, empiric antibiotic
therapy experienced significant changes that do not permit
precise evaluation. In general, ceftazidime, ampicillin, amoxicillin–clavulanate, and conventional amphotericin B were used
more often. Specific therapy should be administered upon the
availability of results from the microbiological department. As
can be seen from the 167 analyzed cases, there is no uniformity
in these results. For example, 28 isolates in P. aeruginosa cases
were resistant to cefazolin, and another 21 isolates were resistant to ampicillin but susceptible to cefazolin. Following bacteriological results, the administered antibiotic treatment in
P. aeruginosa EG cases (n=123) included gentamicin (22
cases), ampicillin (39 cases), carbenicillin (five cases), ceftazidime (11 cases), ciprofloxacin (17 cases), doxorubicin+vincristine (seven cases), cefazolin (11 cases), and clindamycin+
ciprofloxacin (seven cases) that were administered as standard
protocols require. In four cases, the specific therapy was not
administered because the patients died before the culture results were received from the laboratory.
As for non-Pseudomonas cases, various specific treatments
were administered. Aeromonas hydrophila (six cases) had
different antibiotic sensitivities and was treated mainly with
cephalosporin. The case caused by Pseudomonas stutzeri was
successfully treated with chlorhexidine. Escherichia coli can
be successfully treated with ampicillin. Cases due to Fusarium
solani were treated with local debridement and topical
amphotericin B. Another fungal case, in which Candida
albicans was involved, was successfully treated with
amphotericin B and caspofungin. If treatment is successful,
the ulcer diminishes and disappears (Fig. 1a, b).
The surgeries vary from aggressive surgical debridement
and skin grafting to relatively mild plastic surgeries. Irrespective of the etiological agent, surgical procedures were needed
in 128 cases out of 167 (76.6 %), but in most of the cases
(n=99; 59.3 %), surgical debridement was enough. Minor
plastic surgery and/or skin grafting was performed in 29 cases
(17.4 %). Standard wound care included wet to dry dressing
changes. Among these 29 surgical cases, acute inflammatory
cell infiltration and vascular proliferation were seen in the
dermis in 20 cases, but in nine cases, the process involved
the subcutaneous tissue as well. The surgical approach to
Pseudomonas and non-Pseudomonas cases was similar.
Treatment
Discussion
There are three stages of the treatment of EG: (1) empiric
antibiotic therapy is administered initially, (2) when the
Descriptions of EG cases of various etiology, in immunocompetent and even healthy individuals, started from the 1960s
Eur J Clin Microbiol Infect Dis (2015) 34:633–639
637
Fig. 1 Ecthyma gangrenosum
(EG) of the face before (a) and
during successful treatment (b).
The pictures were taken by the
authors
and 1970s. As stated in the introduction to this review, the
present definition of EG as a bacterial skin infection caused by
P. aeruginosa that appears with P. aeruginosa sepsis in immunocompromised patients cannot be applied to all EG cases.
In fact, as can be seen from Table 1, the complete triad
P. aeruginosa in the lesion+P. aeruginosa sepsis+immunocompromised status was indicated only in 32 cases out of the
167 described cases (19.2 %). This percentage, however, does
not reflect the real picture. With rare exceptions, the analyzed
1975–2014 publications were case reports. A case report is
designed to present some rare or even unique case. Therefore,
we believe that the majority of the “normative” EG cases were
not reported.
With new case reports being published, the initial reports
on EG of non-Pseudomonas etiology presented as “unique”
are no longer unique. At present, for example, 12 cases were
published in which E. coli was detected as an etiological agent
for EG. EG caused by E. coli can occur following spontaneous
bacterial peritonitis due to the same organism and Shiga toxinproducing E. coli can cooperate with P. aeruginosa sepsis in
producing EG [65, 66]. Such cases are usually associated with
E. coli bacteremia [36, 37, 65–67].
As P. aeruginosa is not the only etiological agent for EG,
attempts were made to separate “real” EG from “EG-like” or
“EG-mimicking” lesions. The first definition should be applied to P. aeruginosa EG cases and the second definition to
all EG cases of different etiology. The term “nonpseudomonal
ecthyma gangrenosum” was suggested as well [68].
Scrupulous analysis of the cases that were described in the
literature do not indicate any clinical difference between
Pseudomonas and non-Pseudomonas EG cases. As the data
of Table 2 show, a more or less strong correlation exists only
between EG and the immunocompromised status of a patient
if etiology is not taken into account. One report even suggested that P. aeruginosa sepsis and EG might be initial
manifestations of primary immunodeficiency [69]. Clinically,
the authors describe the same disorder whatever the culture
obtained.
The authors of the analyzed articles described all possible
variations of the disorder: EG due to P. aeruginosa in an
immunocompromised patient with or without septicemia,
EG due to P. aeruginosa in an immunocompetent patient,
EG due to P. aeruginosa in a healthy patient, EG due to
various bacterial infections in immunocompromised and immunocompetent patients, fungal EG with and without septicemia, etc. [43].
Any attempt to change the definition is open for further
discussion. Analyzing reports in the emerging literature, we
suggest to define EG as a bacterial skin infection of various
etiology that leads to vasculitis and further local skin necrosis.
The disorder is more likely to appear in the presence of
P. aeruginosa and immunocompromised status of a patient.
Conclusion
Necrotic lesions of the skin diagnosed as ecthyma
gangrenosum (EG) have various microbiological etiology,
Table 2 Correlations between EG and the etiological agent, presence/
absence of septicemia, and the immune status of a patient
Correlations
Between Pseudomonas+septicemia and EG
Between Pseudomonas+immunocompromised and EG
Between Pseudomonas+septicemia+immunocompromised
and EG
Between any etiology+septicemia and EG
Between any etiology+immunocompromised and EG
r=0.43
r=0.44
r=0.2
r=0.45
r=0.62
638
Eur J Clin Microbiol Infect Dis (2015) 34:633–639
can occur in immunocompetent or even healthy persons, and
are not necessarily connected with septicemia. While the
clinical picture of the disease and the treatment strategy remain the same, there is no need to invent two separate definitions for Pseudomonas and non-Pseudomonas cases. We suggest accepting a broader definition of EG.
Conflict of interest Disclosure of potential conflicts of interest: the
authors state no potential conflict of interest.
Compliance with ethical standards
participants and/or animals: N/A.
Informed consent: N/A.
Research involving human
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