Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg.

BACKGROUND: Intractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AIMS: To provide an overview on etiology and management of ID patients in Italy in the last 12 years. METHODS: The members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. RESULTS: 69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). CONCLUSION: ID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

Teduglutide in pediatric intestinal failure: A position statement of the Italian society of pediatric gastroenterology, hepatology and nutrition (SIGENP).

In recent years, the spectrum of possible treatments for Intestinal Failure (IF)-Short Bowel Syndrome (SBS) has been enriched by the implementation of GLP-2 analogues. In Italy, teduglutide (Ted), an analogue of GLP-2, was approved in January 2021 by the Italian Regulatory Agency for Drugs (AIFA) for IF-SBS patients ≥1 year old. According to the Agency indications, Ted can now be prescribed by regional reference centers, with costs fully charged to the National Health Service. Following pediatric-use approval in our country and in light of scarce evidence in childhood, the pediatric network for IF of the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) planned to share management methods of Ted in pediatric IF. The main purpose was to identify the best candidates from a cost-effective perspective. Thus, focusing on available literature and on expert opinions, the present position statement provides consensus-based recommendations on the use of Ted for pediatric gastroenterologists and nutritionists treating children with SBS.

Italian pediatric nutrition survey.

INTRODUCTION: the prevalence of malnutrition in children and its impact on clinical outcomes is underrecognized by clinicians in Italy as well as worldwide. A novel definition of pediatric malnutrition has been recently proposed by a working group of the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), based on the correlation between illness and the use of zscores of anthropometric measurements. AIM: to investigate the prevalence of malnutrition and related nutritional support among hospitalized children in Italy, in a nationwide survey performed in a single day (16/4/2015). METHODS: an open access website (http://nday.biomedia.net) was used to collected data from 73 hospitals and 101 wards in 14 Italian regions (1994 patients). Anonymous information was collected on hospitals' characteristics, patient's anthropometry, admission diagnosis, presence of chronic diseases and use of nutritional support: oral nutritional supplements (ONS), enteral nutrition (EN) or parenteral nutrition (PN). Z-scores of anthropometric measurements, calculated with Epi Info 7.1.5, defined nutritional status: wasting was identified by BMI or Weight-for-Length z-score (<-1 mild, <-2 moderate, <-3 severe), stunting by Height-for-Age Z-score <-2. WHO 2006 and CDC 2000 growth charts were used respectively for children younger and older than 2 years old. RESULTS: 1790 complete records were obtained for hospitalized patients aged 0-20 years, with median age 6.16 (0.1-20 years and 53.3% males). 52.9% were aged 0-6 years and 58.8% of children suffered from chronic diseases. Wasting was detected in 28.7% of the total sample with higher occurrence observed in age ranges 0-6 and 14-20 years, while 17.3% of patients showed stunting; surprisingly almost 27% of them were aged 0-2. A ranking of the admission diagnosis with the highest rate of malnutrition was complied. The prevalence of wasting was significantly (p < 0.005) higher amongst children with chronic diseases (34.1% vs. 27.1%); stunting prevalence tripled in patients with chronic disease (24.5% vs. 8.3%). Only 23.5% of malnourished children (17%, 25.6% and 36.7%, respectively mild, moderate and severe malnutrition) received nutritional support: 11.7% received oral nutrition supplements (ONS, modular or complete), 11.5% enteral nutrition (EN, 6.4% via nasogastric tube, 5.1% via gastrostomy) and 6.8 % received parenteral nutrition (PN); in some patients a combination of two. Nutritional support is more commonly used among stunting patients, 39.5% of children under treatment. CONCLUSION: Malnutrition of any grade was observed in nearly 1/3 and stunting in 17% of the reported hospitalized children, and it is likely to be underrecognized as the nutritional support reached only a small part of the malnourished children.

Ultrasound scanning in infants with biliary atresia: the different implications of biliary tract features and liver echostructure.

OBJECTIVE: To evaluate ultrasonographic features of the liver and biliary tree, including the presence of the triangular cord, in infants with biliary atresia and to analyze the correspondence between hepatic echostructure and histological aspects of the liver. MATERIALS AND METHODS: 35 consecutive infants (19 males) with documented diagnosis of biliary atresia were included. Ultrasonography evaluation, performed at a mean age of 63.1 ± 34.9 days, was focused on the extrahepatic bile ducts, characteristics of the gallbladder and liver, and the presence of the triangular cord. Liver biopsies were examined with particular regard to the presence and severity of fibrosis. RESULTS: On ultrasound, the gallbladder was not seen in 11 (31 %) cases, while in the remaining 24 patients the gallbladder was regular in 6 patients and irregular in 18 cases. The triangular cord was identified in 9 (26 %) of 35 patients. In 21 patients the liver echostructure appeared normal, while in 14 infants the liver parenchyma was more echogenic and coarse than normal. Liver biopsy showed signs of cirrhosis or fibrosis in all cases, including patients with a normal hepatic echostructure. CONCLUSION: Although the triangular cord was visualized in one-fourth of the infants with biliary atresia, abnormalities of the gallbladder on ultrasound (absence or abnormalities of length/shape) were detected in 83 % of the patients. Therefore, ultrasound evaluation of the liver and biliary tree plays an important role in suspecting biliary atresia. On the other hand, a low correspondence between liver echostructure aspects and the presence and severity of fibrosis at liver biopsy was identified. Therefore, severe liver disease in infants with biliary atresia cannot be excluded only on the basis of ultrasound findings.

Home enteral nutrition in children: a 14-year multicenter survey.

BACKGROUND/OBJECTIVES: The practice of home enteral nutrition (HEN) represents a relevant aspect of the clinical management of both malnourished children and well-nourished children unable to be fed using an oral diet. The aim of this study was to estimate in an Italian paediatric population over a 14-year period (1996-2009), the clinical relevance and results over time of HEN activity. SUBJECTS/METHODS: HEN-computerized database and medical/dietetic charts were evaluated for patients aged at start of HEN <18 years and HEN duration >1 month. RESULTS: During the study period, we recorded 757 HEN programs. HEN began at a median age of 2 years for a median duration of 8.1 months. The complication rate was 14.8%. In the second period of the survey (2003-2009), the main changes concerned the underlying diseases requiring HEN, choice of formula feeding and access route. In 2009, the estimated overall prevalence of HEN was 3.47 and the incidence 2.45 per 100 000 inhabitants from 0 to 18 years of age. CONCLUSIONS: The epidemiological data of this study demonstrate that HEN concerns a growing number of Italian children and families. Some aspects of HEN clinical management should be modified to reach the recommended standards.

Requesting iodine supplementation in children on parenteral nutrition.

BACKGROUND & AIMS: Iodine supplementation of parenterally fed infants recommended by ESPGHAN is 1 microg/kg/day. To assess nutritional and thyroid status of children on parenteral nutrition (PN) through urinary iodine concentration (UIC). PATIENTS AND METHODS: Children (1-17 yrs), undergoing PN and receiving an iodine supply of 1 microg/kg/day, were enrolled from 2000 to 2007. RESULTS: We observed 15 children (10 males, mean age 76.53+/-60.4 months) on PN from 14 to 84 weeks (mean 38.5+/-21.4). Ten were on TPN and five on PPN; nine had short bowel syndrome (SBS) and six had other intestinal diseases requiring PN. Iodine supply in TPN ranged between 1 and 1.6 microg/kg/day (mean 1.1+/-0.3 microg/kg/day), while in PPN it ranged from 2.3 to 2.8 microg/kg/day (mean 2.6+/-0.7 microg/kg/day). We found an inverse correlation between duration of PN in months and UIC (P=0.05). Four weeks after PN onset, UIC<100 microg/L was found in all SBS patients and 3/6 non-SBS patients (P<0.05). After 12 weeks, 8/15 (53%) patients had UIC<50 microg/L, but thyroxine, TSH and thyroid volume remained unchanged. CONCLUSIONS: A PN iodine supply of 1 microg/kg/day may be suboptimal. Higher supplies should be evaluated in controlled trials.

Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children?

OBJECTIVES: To assess the features of fat redistribution, detected by clinical and ultrasound (US) methods, and the presence of metabolic disorders in HIV-infected children undergoing antiretroviral therapy. To evaluate if serum levels of resistin, a hormone produced only by visceral adipose tissue, are a marker of fat redistribution in these patients. DESIGN AND METHODS: Forty-five consecutive symptomatic HIV-infected children were considered for inclusion in the study. Patients were enrolled if treated for at least 6 months with antiretroviral therapy with or without protease inhibitor (PI) and if compliant to the study protocol. Patients were evaluated for: anthropometric measures, fat redistribution by clinical and US methods, serum lipids, parameters of insulin resistance by homeostasis model assessment for insulin resistance, serum resistin levels by an enzyme-linked immunosorbent assay. RESULTS: Eighteen children fulfilled the inclusion criteria and were enrolled in the study. Twelve (66%) children had clinical and/or US evidence of fat redistribution; 9 (75%) of them were on PI therapy; only 3 of 6 children without fat redistribution were on PI therapy (p<0.05). Serum lipids and insulin resistance parameters did not differ between children with or without fat redistribution. There was a highly significant linear correlation between visceral fat detected by US and circulating resistin levels (r=0.87; p<0.0001). CONCLUSIONS: Fat redistribution occurred in most HIV-infected children undergoing PI therapy. Because serum resistin levels reflect the amount of visceral fat, they could be considered a sensitive marker of fat redistribution in HIV-infected children.

Update on coeliac disease and type 1 diabetes mellitus in childhood.

The increased prevalence of coeliac disease (CD) among children with type 1 diabetes mellitus (DM1) implies that there is more than a simple association. A link between the gut immune system and DM1 has been suggested both in animal models and in humans. We review the literature on the epidemiology and genetic and clinical aspects shared by these two diseases and speculate on the role of gluten on the possible relationship between CD and DM1, on the basis of recent animal and human studies. The data suggest a failure in oral tolerance mechanisms in DM1 other than that in CD. It remains to be understood why only a small proportion of patients with DM1 proceed to the production of coeliac-associated antibodies and to overt enteropathy.

Management of diabetes in childhood: are children small adults?

Diabetes in childhood is the most common chronic disease and generally fits the type 1 category, even though other forms of non-autoimmune diabetes are now emerging in this age. At variance with adults, children and adolescents undergo physiological process, which may frequently require adjustments of clinical management of diabetes. Moreover, the hormonal and psychological changes during puberty may be crucial in conditioning management. Furthermore, common illnesses frequently affecting children may also destabilise metabolic control. Consequently, education in children is the cornerstone of treatment. This review focuses on the several and peculiar aspects of practical management of diabetes in paediatric age, which require professional figures such as paediatricians, nurses, dieticians, psychologists, social assistants originally trained in paediatric area, able to deal with the age-related medical, educational, nutritional and behavioural issues of diabetes.

Adrenocortical tumor in a boy: final height is not impaired despite a severe advancement of bone age.

The long-term sequelae on the growth pattern in successfully resected virilizing adrenal tumors (ACT) have not been clearly defined. We report on 10 years follow-up of a boy with virilizing ACT until the attainment of final height. This is the first clinical description in a boy with a marked advancement of bone age, indicating that despite advanced physical and skeletal maturity the prognosis on growth is good, provided that regression of virilization is obtained.

Ritonavir combination therapy restores intestinal function in children with advanced HIV disease.

OBJECTIVES: To investigate the intestinal absorptive processes in children with HIV infection before and after treatment with combination therapy that includes ritonavir. To test the hypothesis that combination therapy improves intestinal function. DESIGN: Intestinal function tests were performed in 10 children with advanced HIV disease at the enrollment and after 3 and 6 months of therapy with ritonavir combined with two HIV reverse transcriptase inhibitors. HIV viral load and CD4 cell counts were also determined; body weight was monitored. METHODS: The D-xylose absorption test, the steatocrit and the determination of fecal alpha1-antitrypsin concentration were used to evaluate carbohydrate and fat absorption, as well as fecal protein loss. Serum iron levels were measured to indirectly evaluate iron absorption. HIV-1 RNA-polymerase chain reaction (PCR) and immunofluorescence imaging were used to evaluate virologic and immunologic responses. RESULTS: In all, 9 children had carbohydrate malabsorption, 3 steatorrhea, 2 protein loss, and 7 iron deficiency. Most tests produced normal results after 3 months of therapy, and all abnormalities were abolished 6 months after institution of combination therapy. Mean results of each of four absorption tests were significantly changed on combination therapy. Viral load was progressively reduced and CD4 count was increased, with an inverse relationship. An evident shift of body weight pattern toward catch-up growth was observed in all children. CONCLUSIONS: Ritonavir combination therapy results in prompt and sustained restoration of intestinal function, which is associated with reduction in viral load, increase in CD4 counts, and gain in body weight.

Severe and protracted diarrhea: results of the 3-year SIGEP multicenter survey. Working Group of the Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP).

BACKGROUND: The spectrum of severe and protracted diarrhea (SPD), previously defined as intractable diarrhea, has changed during the past several decades. Despite recent advances in determining the cause of SPD and in treatment, this syndrome still represents a challenge and is becoming a major problem affecting health care resources. This study was conducted to characterize the epidemiology, spectrum of causes, and the outcome of SPD in Italy in recent years. METHODS: All the SPD cases seen at the major centers of pediatric gastroenterology in Italy during a 3-year period (1993-1996) were recruited in this multicenter, prospective survey. RESULTS: Thirty-two children (26 boys and 6 girls; median age at the onset of SPD, 40 days) were enrolled in this study by 9 of 26 participating centers. Twelve were newly diagnosed cases, with an estimated SPD incidence rate in Italy of 0.64 to 0.92 x 10(-5) infants per year. The most common causes were autoimmune enteropathy (n = 8) and ultrastructural abnormalities of the enterocyte (n = 7), whereas food intolerance and postenteritis syndrome were less frequent (3 and 2 cases, respectively). Two children with autoimmune enteropathy fulfilled the criteria for the X-linked variant of this condition. At the end of the study period, 9 of 31 patients had recovered, 15 still had diarrhea, and 7 had died. CONCLUSIONS: Severe and protracted diarrhea is a rare but challenging problem in Italy. Because parenteral nutrition or intestinal transplantation are the only options in a subset of cases (e.g., ultrastructural abnormalities of the enterocyte), infants with SPD should be referred to specialized centers where advanced diagnostic and therapeutic facilities are available.

Adherence to antiretroviral therapy in HIV-infected children in Italy.

Adherence to antiretroviral therapy is a major problem in children with HIV infection, who depend on parents or foster parents for receiving drugs. During an ongoing investigation on intestinal function in children with symptomatic HIV infection who were treated with zidovudine, blood samples were obtained six hours after the administration of zidovudine as reported by the parents and, again, one and six hours after its administration in the hospital, and drug concentration was measured by radioimmunoassay. Both peak and steady state zidovudine levels were within the expected concentration ranges after administration in the hospital. In contrast, they were below the effective concentration in five of the 10 children that reportedly had received the drug at home by the parents. These data directly show poor compliance with antiretroviral therapy in children. Compliance with antiretroviral therapy should be carefully checked in children and strategies are needed to increase full and permanent adherence with antiretroviral therapy by people in charge to administer drugs to HIV-infected children.

Pancreatic dysfunction and its association with fat malabsorption in HIV infected children.

BACKGROUND: Nutrient malabsorption frequently occurs in HIV infected children, but very few studies have investigated exocrine pancreatic digestive capacity in these cases. AIMS: To investigate pancreatic function in HIV infected children and to determine whether faecal fat loss, a prominent feature of intestinal dysfunction, is associated with pancreatic dysfunction. PATIENTS: Forty seven children with HIV infection without apparent pancreatic disease and 45 sex and age matched healthy controls. METHODS: Pancreatic function was evaluated by measuring elastase 1 concentration and chymotrypsin activity in stools by ELISA and colorimetric methods, respectively. Intestinal function was evaluated by measuring fat and protein loss by the steatocrit method and by faecal alpha1 antitrypsin concentration. RESULTS: 14 (30%) had abnormal pancreatic function tests: seven had isolated elastase activity deficiency, three isolated chymotrypsin deficiency, and four pancreatic deficiencies in both enzymes. Patient enzyme values were significantly lower than those of controls. Low faecal pancreatic enzymes were not associated with symptoms. Twelve children had steatorrhoea and four had increased alpha1 antitrypsin. Steatorrhoea was significantly associated with reduced faecal pancreatic enzymes. There was a significant negative correlation between elastase 1 concentration and steatocrit. Children with pathological faecal elastase 1 or chymotrypsin values did not differ from the other HIV infected children with respect to nutritional and immunological status, stage of HIV disease, presence of opportunistic infections, or drug administration. CONCLUSIONS: Abnormal pancreatic function tests are a frequent feature of paediatric HIV infection; this condition is associated with steatorrhoea, which probably contributes to the disease.

Serum pancreatic enzymes in human immunodeficiency virus-infected children. A collaborative study of the Italian Society of Pediatric Gastroenterology and Hepatology.

BACKGROUND: Numerous studies have shown pancreatic disease in adult human immunodeficiency virus (HIV)-infected patients, but there are very few reports on pediatric patients. Our aim was to determine the prevalence of increased serum pancreatic enzyme levels and their relationship to clinical manifestations of acute pancreatitis in HIV-infected children. METHODS: Forty-seven consecutive, symptomatic HIV-infected children (24 male; median age, 7.3 years; range, 1-17 years) and 45 sex- and age-matched controls without gastroenterologic disease were enrolled. In all subjects serum total amylase, pancreatic amylase, and lipase were assayed with commercial kits. The following were recorded: disease progression (CDC class), nutritional status (weight Z-score), CD4 lymphocyte count, drug treatment during the previous 12 months, presence of opportunistic infections, clinical evidence of acute pancreatitis (increased serum pancreatic enzymes associated with vomiting, abdominal distention, and intolerance when eating). RESULTS: Ten of 47 HIV patients had increased serum total amylase values; however fewer patients had increased specific pancreatic enzymes: 6 of 47 for pancreatic amylase (range, 1.8- to 19.8-fold normal limit) and 7 of 47 for lipase (range, 1.4- to 4-fold normal limit). Values were normal in all controls. Two HIV patients with increased total amylase had clinically evident parotid inflammation. None of the patients with increased serum pancreatic amylase and/or lipase had clinical symptoms of acute pancreatitis. Regression analysis showed no correlation between increased serum pancreatic enzyme levels and disease progression (CDC class), immunologic status (CD4 count), nutritional status, drug administration, or opportunistic infections. CONCLUSIONS: Fifteen per cent of HIV-infected children had biochemical evidence of pancreatic involvement; however, this condition was unrelated to clinical signs of pancreatitis. Neither drug administration nor opportunistic infections seem to determine the increased serum pancreatic enzyme levels.

In vivo and in vitro efficacy of octreotide for treatment of enteric cryptosporidiosis.

Previous evidence suggested a role of enterotoxin in the pathophysiology of cryptosporidiosis. If so, antisecretory drugs should be effective in reducing diarrhea. We evaluated the in vivo and in vitro efficacy of octreotide, which possesses antisecretory effects, for cryptosporidial diarrhea. Two children with severe cryptosporidial diarrhea were treated with octreotide. The volume modifications and chemical composition of stools were determined. Fecal supernatant was added to Caco-2 cell monolayers mounted in Ussing chambers with or without serosal octreotide and electrical parameters were monitored. Octreotide was effective in reducing the stool volume and fecal Na+ concentration. Fecal supernatant induced an enterotoxin-like increase in transepithelial potential difference. Octreotide induced a dose-dependent decrease in basal potential difference, consistent with an absorptive effect. In cells pretreated with octreotide, fecal supernatant induced an increase in the potential difference, whose magnitude and duration were significantly reduced compared to untreated cells. These results provide in vivo and in vitro evidence for the secretory nature of cryptosporidial diarrhea and for the efficacy of octreotide through a direct interaction with the enterocyte.

Oral bacterial therapy reduces the duration of symptoms and of viral excretion in children with mild diarrhea.

BACKGROUND: Oral administration of live Lactobacillus casei strain GG is associated with the reduction of duration of diarrhea in children admitted to the hospital because of diarrhea. The purposes of this work were to investigate the clinical efficacy of oral administration of Lactobacillus in children with mild diarrhea who were observed as outpatients, and to see whether Lactobacillus GG can reduce the duration of rotavirus excretion. METHODS: Duration of diarrhea was recorded in 100 children seen by family pediatricians and randomly assigned to receive oral rehydration or oral rehydration followed by the administration of lyophilized Lactobacillus casei, strain GG. Rotavirus was looked for in the stools of all children and in those in whom results were positive, stools were examined again 6 days after the onset of diarrhea. RESULTS: In 61 children results were positive for rotavirus and in 39 results were negative. Duration of diarrhea was reduced from 6 to 3 days in children receiving Lactobacillus GG, with a similar pattern in rotavirus-positive and -negative children. Six days after the onset of diarrhea, stools in only 4 out of 31 children that received Lactobacillus GG were positive for rotavirus compared with positive findings in 25 out of 30 control subjects. CONCLUSIONS: Oral administration of Lactobacillus GG is effective in rotavirus-positive and rotavirus-negative ambulatory children with diarrhea. Furthermore, it reduces the duration of rotavirus excretion.