PEDIATRIC CLINICS AMSTERDAM Idiopathic toe-walking

Enterocolitis in oncology patients remains an important complication withpoor insight in microbial, pathological and inflammatory aspects.Pediatric oncology patients admitted with neutropenic fever, who develop-ed abdominal pain and diarrhea, were monitored with rectal biopsies,cultures, and inflammatory markers.Twenty-five patients were included (mean age 7.1 years). Eight patients(32%) needed intensive care treatment, 3 (12%) patients died. Gram-positivebacteraemia was diagnosed in 4 patients (16%). Most patients had negativeblood and stool cultures. Predictors of a severe clinical course of the ente-rocolitis were an increased serum IL-8 (>1000 pg/mL) and an increasedserum CRP (>150 mg/L), both measured on the first day of clinical illness.Relative risks for admission to ICU were 11.3 (95% CI 1.6 to 77.9) for elevatedIL-8 and 6.4 (95% CI 0.92 to 45.1) for increased CRP. Rectal biopsies andpathology could not predict outcome (p=0.22). IL-8 analysis at the onset ofenterocolitis symptoms can identify high-risk patients, which might beused clinically to design future intervention trials. IntroductionNeutropenic enterocolitis represents a complex spectrum of inflammatoryprocesses of the colon seen in immunocompromised hosts after intensivechemotherapy for malignancies. It ranges from pseudo-membranous colitiscaused by Clostridium difficile to typhlitis. The clinical picture ranges frommild infection to severe transmural colitis with a high mortality-rate(50-100%). The pathogenesis of this disorder is thought to be due to amultifactorial disruption of the mucosal barrier, in which the bacterialflora, neutropenia and cytotoxic therapy play a role. Prognostic inflamma-tory markers in neutropenic enterocolitis have not been defined to date. Inneutropenic enterocolitis both toxic and ischemic bowel injury may playan important role. The response of the inflammatory cascade to pathogensattacking the gastro-intestinal mucosa involves mainly the cytokines IL-6,IL-8, IL-10 and TNFα. The role of these cytokines may be important in thepathophysiology of the inflammatory responses in neutropenic enterocoli-tis in children.Therefore a prospective single unit study was started to identify the inci-dence of enterocolitis in a paediatric oncology unit, to gain insight in thepathogenetic mechanisms, and to identify clinical and inflammatoryprognostic markers.MethodsEntry criteria were neutropenic pediatric oncology patients who had abdo-minal pain, diarrhea and fever for more than 24 hours. Neutropenia wasdefined as <500/μL absolute neutrophils. Diarrhoea was defined as havingat least grade 2 diarrhoea (4-6 times in 24 hours correlating to the CTC toxi-city criteria). Fever was defined as a temperature >38.5°C.All types of malignancies were included. On the first day of the study thefollowing were performed; 1) history and clinical checklist 2) physicalexamination 3) stool cultures 4) rectal biopsy 5) blood investigations and6) serum levels of inflammatory markers.On day 3 and day 7 above investigations were repeated. The rectal biopsywas repeated if findings on day 1 were abnormal. The next course ofchemotherapy started when all abnormal findings had normalized.The study was performed in a single pediatric oncology unit. Approvalfrom the medical ethics committee was obtained. Informed consent wasobtained from the parents and from the child if >12 years of age. StatisticsTo examine the prognostic value of elevated inflammatory markers weused both cut-offs mentioned in the literature (for IL-8 above 1000 pg/mL,CRP above 150 mg/L) and optimal cut-offs from the data were calculatedusing the Youden index (sensitivity + specificity -1) as criterion. To estima-te the predictive value of increased inflammatory parameters we calcula-ted relative risks with 95% confidence intervals (CI). All reported p-valuesare two-sided. ResultsOver a 3-year-period (November 1998 until January 2002), 452 new patientswith oncological disorders were admitted to the unit. Of these 25 patientsfulfilled the entry criteria of the study and were included, 15 were maleand 10 were female. The diagnoses at presentation showed 11 haemato-logical disorders (ALL/ANLL), 4 B-cell lymphoma’s, 9 solid tumours and1 haemophagocytic syndrome. The mean age at diagnosis was 7.1 years(range 1.0-17.1 years). Enterocolitis presented in most cases within the first3 months after diagnosis and the start of chemotherapy.The vast majority of patients had signs of mucositis (92%), 40% of patientshad less than 48 hours of fever and 60% had fever >48 hours. The stoolpattern was recorded as “watery and frequent” in 60% of patients and in28% of patients “bloody diarrhoea” was recorded. The abdominal pain wasclassified as “cramps” in 72% of patients, and 24% of patients had conti-nuous pain. Histological examination of the rectal biopsies resulted in “nochanges” in 12 patients (48%), “infiltrate only” without pseudomembranesin 9 patients (36%), “pseudomembranes” in 3 patients (12%) and 1 patienthad “ulcerative changes” with fibrin exudates (4%). Only 2 patients hadC. difficile in the stool culture and 1 of these patients had a positive bloodculture with C. difficile (the same strain was found in the blood-culture as inthe stool-culture). In 3 patients C. difficile toxin stool tests were positive.Of the 25 patients, 8 were admitted to the ICU due to cardiovascularSeverity of enterocolitis predicted by IL-8in pediatric oncology patients M.D. van de Wetering MD, H.N. Caron MD PhD, M. Biezeveld MD, J.A.J.M. Taminiau MD PhD, F.J. ten Kate MD PhD, L. Spanjaard MD PhDand T.W. Kuijpers MD PhD.What’s new in pediatrics 1 Department of Pediatrics, Emma Children's Hospital AMC, Amsterdam2 Department of Pathology, AMC, Amsterdam3 Department of Medical Microbiology, AMC, Amsterdam. PEDIATRICCLINICSAMSTERDAM-PAGE9symptoms for which inotropic support was indicated. Ofthese patients five did not have a proven bacteraemia.Three died following the enterocolitis episode.To identify possible factors predictive of the clinicalcourse we used admittance to ICU with need for inotro-pic support during the enterocolitis episode as our pri-mary endpoint. Of the evaluated inflammatory serum markers CRP andIL-8 showed a significant difference between the 2groups (Fig. 1 and 2). Using a cut-off value of 1000 pg/mL6 out of 7 patients were found to have a high IL-8 in theICU group compared to 2 out of 16 patients in the non-ICU group. The risk of ICU admittance was 11.3 times(95 % CI 1.6-77.9) higher in the elevated IL-8 group thanin the non-ICU group. All 3 patients who died had IL-8>1000 pg/mL (table 1). DiscussionThe main aim of the study was to identify patients like-ly to develop a severe enterocolitis. The clinical symp-toms diarrhea, abdominal pain and mucositis showed nosignificant difference between the ICU and the non-ICUgroup. The rectal biopsy findings did not contribute totreatment decisions, it was shown that the findings ofpseudomembranes on rectal biopsy correlated fully withC. difficile toxin positivity or culture positivity. Routinelaboratory investigations could not distinguish thesevere cases from the less severe cases.The inflammatory parameters in the present studyshowed that CRP and IL-8 were of prognostic value. Theextent and course of serum concentrations of IL-8 andIL-6 in the patients with colitis symptoms were signifi-cantly different from those seen in septic conditions innon-neutropenic children. In non-neutropenic patientsconcentrations of IL-8 are at least 10-100 fold higher. IL-8 used at a cut-off point of 1000 pg/mL, was found to bea strong prognostic factor. Although the chemotacticactivity towards neutrophils is the most important func-tion of IL-8, we know that in these patients neutrophilsare missing and also absent in the extravascular tissues.Taken together, these data indicate that IL-8 in neutrope-nic patients is less likely derived from enterocytes andmyeloid cells, but from tissue cells such as endothelialcells, and fibroblasts. The chronic low flow and hypo-xia prone situation is not impossible as a contributingfactor for endothelial cell-induced IL-8 generation. Wehypothesize that the IL-8 increase seen in our patientsreflects the extent of damage of the intestinal wall, andcould therefore predict the severity of the disease. Forthe daily clinical practice, we would strongly advise toinitiate early aggressive supportive care in neutropenicpatients with abdominal cramps and diarrhea in whomIL-8 levels are elevated. Full article: European Journal of Cancer. Vol 40 (4),2004: 571-578Chapter 4 of thesis: Prediction and prevention ofinfectious complications in children with cancerby M.D. van de WeteringCRPconcentration(mg/L) PatientsICUNon-ICU1000