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.