Introduction
The field of pediatric oncology has witnessed stunning success over the
years with remarkable improvement in outcomes of various pediatric
cancers.1 Intensive chemotherapy is a key component of
the management of pediatric cancers, which is associated with a host of
treatment-related toxicity like bone marrow suppression, and
mucositis.2,3
Neutropenic enterocolitis (NEC) is a life-threatening gastrointestinal
oncological emergency observed in cancer patients during
chemotherapy.4 It has been synonymously termed
typhlitis, cecitis and ileo-caecal syndrome. The term typhlitis was
derived from the Greek word- Typhlon , meaning caecum, indicating
the most common region of bowel involved in NEC.5 It
was initially described in children with acute leukemia, however it has
been described in adults as well as in other solid malignancies and
non-neoplastic conditions like aplastic anemia, post hematopoietic stem
cell transplantation (HSCT) and retroviral
infection.6,7
The true incidence of neutropenic enterocolitis in Indian setup is
unknown. Though described as a triad of fever, neutropenia and pain
abdomen, all the features may not be seen in the same patient. Hence,
ultrasonography and CT abdomen have been used to supplement the
diagnosis. Most retrospective analyses report incidence of NEC from
1.7% to 16.2%.8-14 However, there is scant
literature regarding the incidence of neutropenic enterocolitis in
developing nations.
Biomarkers like serum citrulline, faecal and serum calprotectin,
intestinal fatty acid binding protein, matrix metalloprotease 2,3 and 9
and interleukins IL-1 and IL-6 have been evaluated as biomarkers for
chemotherapy and radiotherapy related mucositis with variable
results.15-18 However, none of them have been
evaluated in NEC. Calprotectin, a 36 kDa calcium binding protein and
major constituent of neutrophil granules, forms an attractive biomarker
for NEC.
Microbiome refers to the summation of all the microorganisms residing in
and on the body. It is highly complex in composition and diversity. The
understanding of microbiome and role in health and disease is still
evolving. Any dysregulation in the interaction, quantity or quality of
microbiota is termed as dysbiosis. Qualitative alteration may take the
form of loss of alpha diversity (degree of microbial species diversity
within a single anatomical site) or beta diversity (degree of microbial
diversity in the same site between two individuals or
groups).19
Gut dysbiosis has been well described in diseases like inflammatory
bowel disease (IBD), irritable bowel syndrome and Clostridiodes
difficle infection. However, its role in pediatric oncology has not
been adequately explored. Gut dysbiosis has been proposed to influence
various aspects of cancer therapeutics- therapeutic effect, toxicity
including mucositis, HSCT, and even long-term effects like obesity and
neurocognitive functions.20-22 Conversely, gut
dysbiosis has been noted in relation to cancer chemotherapy,
radiotherapy, immunotherapy and antimicrobials- both prophylactic and
therapeutic.
Gut dysbiosis has been postulated to play a key role in the pathogenesis
of gastrointestinal mucositis. Various mechanisms like modulation of
inflammatory and oxidative stress, production of protective short chain
fatty acids (SCFA), promotion of goblet cell function and epithelial
repair and promotion of local immunity have been
proposed.23 Gut dysbiosis in response to chemotherapy,
as noted in preclinical as well as human studies, includes decrease in
Shannon index, a marker of alpha diversity, and alteration in the
relative abundance of various species. Decrease in the abundance ofFirmicutes including Lactobacilli and increase inBacteroides 24-26 has been noted in few studies,
whereas the converse has been observed in others.27,28
With the above gaps in knowledge, a prospective observational study was
planned to study the incidence, clinical and laboratory features,
outcome and its determinants in pediatric patients with NEC. It also
aimed at exploring gut dysbiosis in patients with neutropenic
enterocolitis and the utility of biomarker- fecal calprotectin.