Discussion
The incidence of neutropenic enterocolitis in the current study was
7.4%. Fever and pain abdomen were the most common symptoms. However,
diarrhoea, haematochezia and mucositis were observed at a higher
frequency than in other studies (Table 1).
All the patients had neutropenia, severity and duration of which
correlated with various outcome parameters. Significant hypoproteinaemia
and hypoalbuminemia observed in 60% and 78% of children respectively
can be explained by the loss of serum proteins and albumin through the
inflamed gastrointestinal mucosa. Similar findings were noted by User et
al14 and Moran et al30, where
hypoalbuminemia was observed in 50% and 46% respectively.
No definite risk factors for neutropenic enterocolitis could be
identified in the current study. Clostridiodes difficileinfection, found as a risk factor by El-Matary et
al10, was not isolated in any patient. Anthracyclines,
etoposide and cytarabine based chemotherapy were administered in half of
children with neutropenic enterocolitis; however, this association was
not found to be statistically significant. The degree of gut dysbiosis
was higher in children with NEC, with significantly higher isolation
rates of Bacteroides species, nonsignificant higher isolation ofClostridium species and lower growth of Lactobacillusspecies. Though this doesn’t establish the causality of gut dysbiosis,
underlying dysbiosis could predispose a susceptible individual to
neutropenic enterocolitis, and a ‘healthy flora’ may be protective for
development of mucositis and neutropenic enterocolitis.
On etiological evaluation, blood culture positivity rate was 17%,
majority being contributed by Klebsiella pneumoniae. Fungal
cultures and CMV PCR were non-contributory. Other series have reported
culture positivity rates of 8-25%; majority of isolates being gram
negative bacilli.8,31,32,33 Stenotrophomonas
maltophila , isolated in one patient, has been rarely implicated in the
causation of neutropenic enterocolitis34.
The current study found only the presence of free fluid to be an
independent adverse prognostic factor predicting mortality. However,
factors like female gender, younger age, duration and severity of
neutropenia and bowel wall dilatation and thickening were associated
with other parameters like longer duration of hospital stay and bowel
rest. Notably, isolation of Bacteroides and lack ofLactobacillus were associated with longer requirement of bowel
rest, thus suggesting a possible role of gut dysbiosis in pathogenesis
of neutropenic enterocolitis. Cartoni et al35 found
higher mortality in patients with bowel wall thickening >
10 mm (60% vrs 4.3%). McCarville et al8 also found a
similar association with bowel wall thickening and duration of
neutropenia. User et al14 found that the presence of
hypoalbuminemia, hypokalemia and metabolic acidosis were associated with
poor outcome, which was not found in the current study.
Faecal calprotectin was elevated in patients with NEC as compared to
patients without NEC and healthy controls. Stringer et al found a
similar elevation of faecal calprotectin in patients with chemotherapy
related diarrhoea, though the degree of elevation was significantly
less.28 Wedlake et al found a significant rise in
faecal calprotectin after pelvic radiotherapy.17However, van Vliet et al found faecal calprotectin to be below
detectable range in a majority of patients with chemotherapy related
mucositis and diarrhoea.18
Though prognostic value of fecal calprotectin couldn’t be demonstrated,
it appears to have diagnostic value. Using a cut off value of 75 µg/g,
faecal calprotectin as a diagnostic tool yielded a sensitivity of 65%
and specificity of 63% with AUC of 0.74.
Various studies have uniformly noted a decrease in alpha diversity as
measured by Shannon Index as a marker of gut dysbiosis. They also
reported decrease in isolation of Lactobacillus andBifidobacterium . However, there are conflicting reports onBacteroides and other Firmicutes as markers for dysbiosis
of faecal microbiota. van Vliet et al, Huang et al and Stringer et al
report a decrease in Bacteroides species as a marker of gut dysbiosis,
whereas Rajagopala et al36, Montassier et
al24 and Zwielehner et al25 reported
increase in Bacteroides and decrease in Firmicutes . This
difference in patterns of gut dysbiosis may be explained by racial,
geographical and dietary differences and difference in age. In the
current study, increase in Bacteroides and reduction inLactobacilli were noted in children with NEC. (Table 6)
The relative abundance of each flora did not have significant impact on
mortality, this might have been contributed by the small sample size in
the non survivors. However, isolation of Bacteroides and absence
of Lactobacilli did have an impact on requirement of prolonged
bowel rest; isolation of Bacteroides increased the requirement of
bowel rest by 2.2 days and presence of Lactobacilli tended to
decrease the requirement of intravenous alimentation by 2.4 days. This
observation supports the hypothesis and mechanism of role of gut
microbiota as proposed by van Vliet et al23. This
gives basis for further studies on gut microbiota in the field of
pediatric oncology and role of interventions like prebiotics and
probiotics to target gut dysbiosis.
Conflict of interests: None