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 patients1. 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 reports1,3,4, while corticosteroid treatment
is known to play a role abrogating host defenses against
bacterias18-19. In addition, hyperglicemia influences
the risk of infection in hematologic malignancies20.
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 responses21. 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 pathogens4,6. Moreover the endothelial
damage likely due to chemotherapy22 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
lumina23. 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
body5. In accordance to data reported in the
literature1, 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
reported24-27, 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 reports11-13,
28.
As generally reported for infectious complications in hematological
malignancies29, 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, P. aeruginosawas identified in the majority of patients (89.5%). S.
maltophilia , and E. Coli, also described as etiologic agent of
EG1, 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 P. aeuginosa bacteremias in the same setting of
patients30. These data are also corroborated by the
recent report of the European Antimicrobial Resistance Surveillance
Network (EARS-Net)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
EG32, in keeping with the recommendations of
international guidelines33 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
approach34,35.
The vacuum therapy, reported in some cases to promote faster healing of
the wound bed36, 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
EG5-6. 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.