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\begin{document}

\title{ECTHYMA GANGRENOSUM IN CHILDREN WITH CANCER: DIAGNOSIS AT A GLANCE. A
retrospective study form the Infection Working Group of Italian
Pediatric Hematology Oncology Association.}



\author[1]{Paola Muggeo}%
\author[2]{Daniele Zama}%
\author[3]{Nunzia Decembrino}%
\author[4]{Daniela Onofrillo}%
\author[5]{Stefano Frenos}%
\author[6]{Antonella Colombini}%
\author[7]{Katia Perruccio}%
\author[8]{Elisabetta Calore}%
\author[9]{Nagua Giurici}%
\author[10]{Monica Ficara}%
\author[11]{Milena La Spina}%
\author[12]{Rosamaria Mura}%
\author[13]{Raffaela De Santis}%
\author[14]{Nicola Santoro}%
\author[15]{Simone Cesaro}%
\affil[1]{University of Bari}%
\affil[2]{Sant'Orsola-Malpighi Hospital University of Bologna}%
\affil[3]{Pediatric Hematology Oncology, IRCCS Policlinico San Matteo, University of Pavia}%
\affil[4]{Hospital of Pescara, Pescara, Italy}%
\affil[5]{Azienda Ospedaliero-Universitaria Meyer, Oncoematologia Pediatrica}%
\affil[6]{MBBM Foundation, University of Milano-Bicocca, Monza, Italy}%
\affil[7]{Pediatric Oncology and Hematology Section}%
\affil[8]{Pediatric Hematology and Oncology}%
\affil[9]{Institute for Maternal and Child Health Care IRCCS Burlo Garofolo}%
\affil[10]{lScuola di Specializzazione in Pediatria, Università degli Studi di Modena e Reggio Emilia}%
\affil[11]{Policlinico di Catania}%
\affil[12]{Paediatric Haematology-Oncology, Ospedale Pediatrico Microcitemico, Cagliari, Italy}%
\affil[13]{Unit of Pediatrics}%
\affil[14]{Division of Paediatric Haematology-Oncology, Department of Pediatrics, Bari}%
\affil[15]{Pediatric Hematology and Oncology Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Integrata, Verona}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose. To describe ecthyma gangrenosum (EG) characteristics and
complications in a large multicenter pediatric retrospective collection
of children with malignancies or bone marrow failure syndromes. Methods.
EG episodes diagnosed in the period 2009-2019 were identified by a
retrospective review of clinical charts at centers belonging to the
Italian Pediatric Hematology Oncology Association. Results. EG occurred
in 38 children (male/female 16/22; median age 5.2 years) with
hematological malignancy (33), allogeneic stem cell transplantation (2)
or relapsed/refractory solid tumor (3). The involved sites were:
perineal region (19), limbs (10), trunk (6), head and the iliac crest
(3). Bacteremia was present in 22 patients. Overall, the germs isolated
were Pseudomonas aeruginosa (34), Stenotrophomonas maltophilia (3) and
Escherichia Coli (1); 31\% of them were MDR. All patients received
antibacterial treatment while surgery was performed in 24 patients
(63.1\%). Predisposing underlying conditions for EG were: severe
neutropenia (97.3\%), corticosteroid treatment (71\%), iatrogenic
diabetes (23.7\%). All patients recovered, but EG recurred in 5
patients. Nine patients (24\%) showed sequelae (deep scars, with muscle
atrophy in 2). Four patients (10.5\%) died, 1 due to relapse of EG with
KPC co-infection, 3 due to the underlying disease. Conclusions. EG
requires early recognition and a proper and timely treatment to obtain
the recovery and to avoid larger necrotic evolution. The occurrence of
scarring sequelae might affect the quality of life of patients.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Ecthyma gangrenosum (EG) is a relatively uncommon cutaneous infection
that mostly occurs in individuals with immunosuppression due to
different underlying diseases including hematologic disorders,
malignancies, lymphoproliferative disorders and autoimmune diseases.
However, it has also been reported among previously healthy
individuals\textsuperscript{1-4}, both adults and
children.\emph{Pseudomonas aeruginosa} ~is the most common cause of EG,
with or without bacteremia, although it is also known to be caused by a
variety of pathogens, including different bacteria, fungi and
viruses\textsuperscript{1}. Lesions first appear as painless papules
which rapidly evolve in gangrenous ulcers. The macroscopic appearance
corresponds to the microvascular thrombosis and subsequent dermal
ischemic necrosis\textsuperscript{5}. Single or multiple lesions might
involve one or more sites in the body, mainly the axillary and perineal
regions. Prompt recognition and timely adequate treatment are crucial
for the prognosis\textsuperscript{1}.

In patients with hematological malignancies and cancer, many factors
(immunosuppression, mucositis and epithelial damage, microbiome
dysbiosis and prolonged use of central venous devices) predispose to
bacterial infections, usually affecting integumental surfaces such as
respiratory tract, gastrointestinal tract and skin. The frequently
atypical clinical presentation of these infections makes the prompt
recognition often challenging\textsuperscript{6}.

There are scant reports describing the occurrence of EG in
onco-hematological patients, mainly as case reports or small case
series\textsuperscript{7-16}. We report the results of a large
multicenter pediatric retrospective collection of 38 cases of proven EG
diagnosed between 2009 and 2019 in children with hematological disease
and cancer. The aim is to describe the clinical picture and
characteristics of EG, to early recognize and diagnose it, since timely
treatment influences the outcome of this infection. In fact,
particularly in this setting of patients, prompt interventions may
change the course of both this serious infection and the underlying
disease. The wide spectrum of clinical pictures at different levels of
severity in our sample allowed a more complete evaluation of EG
infection at different stages, considering that cases reported in the
literature have mainly a devastating clinical presentation.

\textbf{PATIENTS AND METHODS}

This retrospective study was conducted in 14 Pediatric Oncology and
Hematology centers belonging to the Italian Association of Pediatric
Hematology and Oncology (AIEOP) over 11-year period from 01/01/2009 to
31/12/2019.

Eligibility criteria were a diagnosis of EG in patients affected by
hematologic/oncologic malignancies or bone marrow failure syndromes,
aged 0-18 years, microbiologically documented by demonstration of the
microorganism in positive culture from wound swab or skin biopsy and/or
in positive blood culture. The date of diagnosis corresponded to the
first microbiological evidence of infection. Disseminated infection was
defined when two or more noncontiguous sites were involved; associated
bacteremia was defined when blood culture was positive.

The following information were extracted from the clinical records of
the patients: demographic characteristics, type of malignancy,
adjunctive risk factors occurring until 7 days before the diagnosis of
infection (corticosteroid treatment, iatrogenic diabetes) clinical
symptoms and signs of infection, radiological findings, site of
infection, laboratory findings (e.g. neutrophil count, microbiological
isolates), treatments received and duration of treatment, outcome,
clinical status at last follow-up. Severe and prolonged neutropenia was
defined by an absolute neutrophil count \textless{}0.5 x
10\textsuperscript{9}/L for \textgreater{}10 days. Prolonged use of
corticosteroids was defined by a mean minimum dose of 0.3 mg/kg/day of
prednisone equivalent for \textgreater{}3 weeks\textsuperscript{17}.

Multi-drug resistance was defined in the presence of isolates with
non-susceptibility to at least 3 different drug classes, in accordance
with EUCAST international standards and breakpoints.

A descriptive analysis of the data was performed. Univariate analysis of
variables regarding clinical presentation between multi drug resistant
(MDR) e non-MDR infections was estimated by Fisher exact test. In all
analyses a probability value less than 0.05 was considered statistically
significant. Data were analyzed using the ``R'' language statistical
software (version 3.6.2).

Patients or parent informed consent was obtained. Data processing was in
accordance with Italian law for patient confidentiality and good
clinical practice. The study was conducted according to Italian policy
for retrospective studies and in accordance with local Ethical Committee
judgment.

\textbf{RESULTS}

During the study period 38 cases of EG (male 16, female 22) were
recorded. Demographic and clinical characteristics of the patients are
presented in table 1.

Figure 1 shows the age distribution of patients, according to gender.
Sexteen out of 38 (42.1\%) patients were in the age 0-3 years, 13 of
them (13/16, 81.2\%) were females, 5 were infant, 17/38 patients
(44.7\%) were above the age of 10.

Hematological disease was present in 35/38 (92.1\%) patients (table 1).
Five out of 38 (13.1\%) patients were under treatment for relapsed
disease (4/29 for acute leukemia, 1 for Ewing sarcoma).

The infection occurred after an average time of 5.4 months (median 4.8
months, range 0.07-21.8 months) from the diagnosis of the underlying
disease or the relapse. Sixteen out of 38 (42.1\%) patients were in the
induction phase of treatment, 8 in the consolidation phase, 8 in the
re-induction phase, 1 patient in the maintenance phase, 2 in the salvage
treatment, 2 patients had received allogeneic stem cell transplantation,
1 patient had underwent surgery for treatment of relapsed Ewing sarcoma.

Thirty-seven out of 38 (97.3\%) patients had severe neutropenia lasting
more than 7 days, with neutrophil count \textless{} 0.1 x
10\textsuperscript{9}/L in 35 patients (92.1\%), 27/38 (71\%) patients
had received prolonged corticosteroid treatment at the moment of EG.
Nine out of 38 (23.7\%) patients had iatrogenic diabetes.

\textbf{Diagnosis.} The diagnosis of EG was documented by positive
culture of wound swab in 34/38 patients, associated with positive blood
culture in 18 patients; by positive blood culture in 4. In total 22/38
(57.9\%) patients had bacteremia.

The isolated bacteria was \emph{Pseudomonas aeruginosa} in 34
cases,\emph{Stenotrophomonas maltophilia} in 3 and \emph{Escherichia
coli} in 1. In 10 patients a co-infection, with presence of more than
one bacteria in the same culture, was documented: 3 \emph{Staphylococcus
epidermidis,} 1 \emph{Staphylococcus haemoliticus,}
1\emph{Corynebacterium striatum,} 1 \emph{Enterococcus faecalis,}
1\emph{Enterococcus faecium,} 1 \emph{Enterococcus faecium}
+\emph{Bacteroides fragilis,} 1 \emph{Enterobacter cloacae,} 1 multidrug
resistant \emph{Klebsiella pneumoniae.}

The EG involved the perineal region in 19/38 (50\%) patients, other
sites of EG are presented in table 2.

In 22/38 (57.9\%) patients of our series the EG was associated with
bacteremia, in 14 cases as single lesion, in 8 cases involving multiple
sites in the body. Among the 16 patients without bacteremia, the
infection was disseminated in 3/16 (18.7\%), localized in 13/16
(81.3\%).

In total, in 13/38 (34.2\%) cases the EG presented as no-bacteriemic
single cutaneous lesion.

The different age of presentation as regard to bacteriemic and non
bacteriemic forms are presented in table 3. No different age
distribution appeared between the bacteriemic and no-bacteriemic group
(average age 8.5 years vs 6.8 yrs respectively, \emph{ns} ); however the
group of children with bacteriemic EG and disseminated presentation were
apparently older (11.4 yrs) compared to the other groups (table 3).

Sixteen out of 38 (42.1\%) patients were receiving antimicrobial
prophylaxis or empiric antibacterial treatment, according to local
practices, based on amoxicillin/clavulanate in 5 patients, cotrimoxazole
in 2, meropenem in 2, ciprofloxacin in 2, ceftriaxone in 2, ceftazidime
in 1, clindamicin in 1, ampicillin in 1.

\textbf{Treatment and outcome.} Treatment was based on antibacterial
drugs in all children, started after a median of 1.1 days, with a
latency of 0 days in 21 patients, 1-3 days in 13 patients,
\textgreater{} 3 days in 3. The therapy was delivered for a median time
of 20.5 days (range 9-270 days). Eleven patients received monotherapy
with anti-Gram negative agent (piperacillin/tazobactam in 5, meropenem
in 4, ciprofloxacin and ceftazidime in 1 each), 27 children received
combined antimicrobal treatment, with 2 drugs in 22 patients
(ceftazidime or cefepime and amikacin in 13, meropenem or imipenem and
amikacin in 4, meropenem and ciprofloxacin in 2), [?]3 drugs in 5 cases.
Second line antibiotic treatment was needed in 6/11 patients in which a
monotherapy approach had been attempted, and in 5/22 children treated
with two drug-combined therapy. In 12/37 (32.4\%) tested patients the
antimicrobal susceptibility revealed MDR bacteria (table 4), 9 of them
had received antimicrobal prophylaxis. Ten out of 12 (83.3\%) patients
with MDR infection presented a bacteremic form of EG (83.3\% in the MDR
group vs 46.1\% in the non-MDR group, \emph{p=0.0403} ). The lenght of
treatment did not differ between cases with MDR bacteria and non-MDR
(average 30.6 days vs 27.2 days, \emph{ns} ).

Surgical treatment, namely debridement of the necrotic tissue, was
performed in 24/38 (63.1\%) patients, 18/24 (75\%) of these patients had
the EG involving more sites in the body and/or bacteriemic disease. In
addition five patients underwent Vacuum therapy and 4 patients were
treated with hyperbaric chamber. In 5 patients the intervention of
plastic surgery with skin graft was needed.

In all patients the recovery from the infection was documented,
unfortunately in 5 patients the EG recurred. Nine out of 38 patients,
after healing of the lesions, showed deep scars, with muscle atrophy in
2 cases.

The median follow up time was 38.3 months (range 2.9-121.9 months).

Four out of 38 (10.5\% mortality rate) patients died, one due to relapse
of the EG with KPC co-infection, two due to progression of the
underlying disease, the last one died later on due to transplant related
mortality after allogeneic stem cell transplantation (SCT). Death
occurred after 4, 4.5, 13 and 10 months, respectively. Three out of 4
deaths occurred in the bacteremic infections, with a mortality rate of
13.6\% (3/22) in this group. The mortality rate in the non-bacteremic EG
was 6.2\% (1/16).

\textbf{DISCUSSION}

This study reports on a series of 38 cases of EG in children with
hematological disease and cancer. EG is reported mainly in
immunocompromised and cancer patients, nevertheless, even in patients
with malignancies, this complication is described only as case reports
or small case series. An extensive review described a total of 162 cases
of EG in immunocompromised and immunocompetent patients of any age,
among whom there are several case reports and case series, the largest
being of 17 patients\textsuperscript{1}. Our study represents the most
extensive series of EG in the hematology and oncology setting, not only
pediatric. Based on the wider number of patients in our study, we aimed
at outlining the characteristics of presentation of EG in children with
malignancies, in order to point out the clinical profile of patients at
risk, to early recognize the EG and to treat it properly.

As expected, children in our population were affected mostly (92.1\%) by
hematological malignancies, since 34/38 patients had acute leukemia and
1 patient severe aplastic anemia (SAA), confirming the role of the
underlying disease as risk factor for the infectious disease. In fact,
the treatment of acute leukemia is associated with deep alteration of
innate and adoptive immunity. Almost all patients in our series had
severe neutropenia (97.3\%) and the majority was on corticosteroid
treatment (71\%) at the moment of infection, while 9/38 (23.7\%)
children had iatrogenic diabetes.

Neutropenia has been reported as the most frequent risk factor for EG in
different reports\textsuperscript{1,3,4}, while corticosteroid treatment
is known to play a role abrogating host defenses against
bacterias\textsuperscript{18-19}. In addition, hyperglicemia influences
the risk of infection in hematologic malignancies\textsuperscript{20}.

All these risk factors are known to have detrimental effect on the host
immune response due to suppression of phagocyte-mediated killing,
humoral immune and T-lymphocyte responses\textsuperscript{21}. The skin
and gut dysbiosis, the mucositis and epithelial damage, consequence of
the disease treatment, represent an open window for the access and
spreading of pathogens\textsuperscript{4,6}. Moreover the endothelial
damage likely due to chemotherapy\textsuperscript{22} might be a
facilitating risk factor for the development of EG, which starts
typically with microvessel lesion and necrotizing vasculitis caused by
bacteria, leading to perivascular invasion and ischemic necrosis of the
surrounding tissue. EG is a septic vasculitis in which microorganisms
may be demonstrated within the vessel wall and may occlude the vessels
lumina\textsuperscript{23}. The microscopic lesion justify the clinical
picture of a cutaneous erithematous papula rapidly evolving into the
typical destruent and large necrotic lesion (supplemental figure S1).

EG has been described as localized lesion or as bacteremic form often
with septicemic dissemination, involving different sites in the
body\textsuperscript{5}. In accordance to data reported in the
literature\textsuperscript{1}, the majority of patients (57.9\%) in our
series presented the EG associated with bacteremia, while about in one
third (34.2\%) of cases the EG presented as single cutaneous lesion
without bacteremia.

According to most case reports, the primary involved site was the
perineal region (50\% of primary site), and this did not differ among
patients with or without bacteremia. However we observed also less
typical sites of EG such as central venous catheter (CVC) exit, the site
of bone marrow puncture at the posterior iliac crest, the periombelical
area, the scapula, providing that any area of the body might be
involved. As a result, the occurrence of EG in hidden skin sites hampers
the early diagnosis. We therefore suggest an accurate inspection of the
skin in patients at risk of EG, in order to recognize the initial lesion
as early as possible (supplemental figures S1, S2, S4).

Apparently no prevalent age-distribution could be documented in our
series, since almost any age is represented, from very young children to
older ones. However, a more accurate analysis of the age of presentation
suggests some considerations (figure 1): first we confirmed the
susceptibility of older children to infectious complications in the
pediatric hematological setting as previously
reported\textsuperscript{24-27}, in fact near half of children were
older than 10 years. In addition, our data demonstrated that over 50\%
of patients were around the age of 5 or younger and, in particular,
42.1\% of patients were in the age 0-3 years and five patients were
infants. Moreover in the age group 0-3 years over 80\% were females.
Thus in our sample younger female children might be at higher risk for
this peculiar infection. The occurrence of EG in very young children and
newborns is also described in some case reports\textsuperscript{11-13,
28}.

As generally reported for infectious complications in hematological
malignancies\textsuperscript{29}, more than 40\% of EG were documented
in the induction phase of treatment. This is detrimental for the outcome
of the malignancy, considering the subsequent delay in the delivery of
chemotherapy due to such a devastating skin lesion.

Confirming the epidemiology traditionally reported, \emph{P.
aeruginosa}was identified in the majority of patients (89.5\%). \emph{S.
maltophilia} , and \emph{E. Coli,} also described as etiologic agent of
EG\textsuperscript{1}, were cultured in the remaining cases. In 10
patients a co-infection was documented, which influenced negatively the
outcome in 1 case.

The distribution of resistance to antibiotics of the gram negative
bacteria identified, revealed 31.6\% of prevalence of MDR bacteria,
comparable to the prevalence of 30\% reported in a previous AIEOP survey
on \emph{P. aeuginosa} bacteremias in the same setting of
patients\textsuperscript{30}. These data are also corroborated by the
recent report of the European Antimicrobial Resistance Surveillance
Network (EARS-Net)\textsuperscript{31}, in particular as regard to
piperacillina-tazobactam, the antibiotic to whom 1/3 of isolates were
resistant in our series.

The subset of 12 patients infected by MDR bacteria, as expected, showed
characteristics of more aggressive clinical presentation and outcome,
with a significantly different distribution of bacteremia.

The start of targeted antibiotic treatment was prompt in the majority of
patients. This is an important key in the treatment of
EG\textsuperscript{32}, in keeping with the recommendations of
international guidelines\textsuperscript{33} to overcome the rapid
growth of the lesion. The necrosis of the tissue in the outcome of EG is
a problem of utmost importance, since delays the recovery from the
infection and might challenge the quality of life of this setting of
patients, even after healing of the lesion, due to the occurrence of
deep scarring (supplemental figures S2, S3, S5, S6).

In order to remove the infected necrotic tissue and to ameliorate and
the healing of the wound, in our experience a surgical debridement has
been considered in most cases, especially for larger lesions with
extensive necrosis and more aggressive disease, confirming a described
approach\textsuperscript{34,35}.

The vacuum therapy, reported in some cases to promote faster healing of
the wound bed\textsuperscript{36}, has been also applied in 5 patients,
and in 3 cases prevented the occurrence of deep scars. The treatment
with hyperbaric chamber has been also attempted in 4 cases, with
successful result in 2.

In those patients with extensive tissue loss, different techniques for
wound healing, such as negative-pressure therapy, hyperbaric chamber and
dermal substitutes implant, might have a role.

The mortality rate for EG reported in the literature ranges from 8-15\%
in non-bacteremic infections to 20-77\% in bacteremic
EG\textsuperscript{5-6}. In our experience we documented lower fatality
rate, probably due to the prompt start of targeted therapy in almost all
patients. However in some cases the delay in the delivery of proper
anticancer treatment probably hampered the control of the underlying
disease.

\textbf{CONCLUSIONS.}

EG is an infectious complication described in pediatric patients under
treatment for hematological malignancies and cancers, especially during
severe neutropenia. Very young and older children seemed to be at higher
risk of EG. Prompt recognition of early lesion is of utmost importance.
Timely start of proper treatment approach warrants the recovery,
although scarring sequelae might occure.

\textbf{DISCLOSURES}

\textbf{Conflicts of interest:} ~The authors have no conflicts of
interest to disclose. \textbf{Ethics approval:} Data processing was in
accordance with Italian law for patient confidentiality and good
clinical practice. The study was conducted according to Italian policy
for retrospective studies and in accordance with local Ethical Committee
judgment. All the procedures used were in accordance with the ethical
standards of the Declaration of Helsinki (1964) and its later amendments
or comparable ethical standards.

\textbf{Availability of Data:} The data that support the findings of
this study are available on request from the corresponding author. The
data are not publicly available due to privacy or ethical restrictions.

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\textbf{LEGEND LIST}

\textbf{Figure 1}

Distribution of \emph{n=} 38 patients with echtyma gangrenosum according
to different age groups and gender.

\textbf{Supplemental Figure S1}

A cutaneous erithematous papula (A) rapidly evolving (B) into the
typical destruent and large necrotic lesions (C,D)

\textbf{Supplemental Figure S2}

Picture of ecthyma gangrenosum. The early erythematous lesion (A), the
papula (B), the resulting scarring skin lesion (C)

\textbf{Supplemental Figure S3}

Localized ecthyma gangrenosum: a small papula (A) evolving in eschar
(B), the clean lesion (C), the resulting scar (D)

\textbf{Supplemental Figure S4}

Echtyma gangrenosum: a bluish (A) and a reddish (B) papula

\textbf{Supplemental Figure S5}

The eschar (A) and the scar (B) resulting from the same ecthyma
gangrenosum lesion

\textbf{Supplemental Figure S6}

A case of muscle atrophy after healing of large ecthyma gangrenosum
localization

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/471303/articles/562850-ecthyma-gangrenosum-in-children-with-cancer-diagnosis-at-a-glance-a-retrospective-study-form-the-infection-working-group-of-italian-pediatric-hematology-oncology-association}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/471303/articles/562850-ecthyma-gangrenosum-in-children-with-cancer-diagnosis-at-a-glance-a-retrospective-study-form-the-infection-working-group-of-italian-pediatric-hematology-oncology-association}

\textbf{Hosted file}

\verb`Table 3.docx`  available at \url{https://authorea.com/users/471303/articles/562850-ecthyma-gangrenosum-in-children-with-cancer-diagnosis-at-a-glance-a-retrospective-study-form-the-infection-working-group-of-italian-pediatric-hematology-oncology-association}

\textbf{Hosted file}

\verb`Table 4.docx`  available at \url{https://authorea.com/users/471303/articles/562850-ecthyma-gangrenosum-in-children-with-cancer-diagnosis-at-a-glance-a-retrospective-study-form-the-infection-working-group-of-italian-pediatric-hematology-oncology-association}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/figure-1/figure-1}

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