Nutrition and Growth in Chronic Disease

Editor(s): Corina Hartman, Raanan Shamir .

Nutrition and Growth in Chronic Disease

Corina Hartman and Raanan Shamir

Environmental, behavioral (nutrition and physical activity), and disease-related factors can prevent attainment of full genetic potential for growth. Undernutrition is most often the cause of growth faltering and poor skeletal development. Disease-related factors, such as malabsorption, inflammation, and immobility also have profound effects. These effects are illustrated in selected abstracts in this chapter discussing dis- eases such as inflammatory bowel disease (IBD), cystic fibrosis (CF), celiac disease (CD), and children with food allergies. This overview of health and disease effects on growth and skeletal development provides insights into the plasticity of human growth and    its sensitivity to the overall health or diseases.

Inflammatory  Bowel Disease

Growth improvement with adalimumab treatment in children with moderately to severely active Crohn’s  disease

TD Walters, WA Faubion, AM Griffiths, RN Baldassano, J Escher, FM Ruemmele, JS Hyams, A Lazar, S Eichner, B Huang,  Y Li and RB Thakkar

Background

The IMAgINE 1 trial investigated the efficacy and safety of adalimumab (ADA), a fully human monoclonal antibody against tumor necrosis factor (TNF)-α, for induction and maintenance of remission in children with moderately to severely active Crohn’s disease (CrD). The present study reported the effect of ADA on height velocity in pediatric patients with impaired baseline linear growth, participants in the IMAgINE 1 trial.

Methods

IMAgINE 1 was a 52-week, phase 3, multicenter, randomized, double-blind trial that assessed the efficacy and safety of 2 induction doses (160/80 vs. 80/40 mg) and 2 maintenance dose regimens (40 vs. 20 mg) of ADA in 6- to 17-year-old patients with moderately to severely active CrD. The children reported in this analysis were a subset of patients from the IMAgINE 1 trial, considered to have growth potential, that is, females with a bone age <13 years and males with a bone age <14 years.

Results

The IMAgINE 1 trial enrolled 100 patients, majority of whom (73/100, 73%) had linear growth impairment at baseline (height velocity z-score <–1.0). During the 52 weeks of ADA therapy, linear growth normalized in patients who initially had significant impairment at baseline. The median height velocity z-score improved from -3.25 at baseline to –0.34 by 26 weeks, and further improved to +0.21 by 52 weeks. By week 26 and also at week 52, there was no significant difference in linear growth rate between the group with initial impairment compared with those with normal linear growth at baseline.
Patients who received high-dose ADA had greater median height velocity z-scores compared with patients who received low-dose ADA at both 26 and 52 weeks. The median height velocity z-score at 52 weeks was +0.67 for the high-dose and –0.42 for the low-dose ADA group.
Patients receiving ADA without dose escalation had greater median height velocity z-scores com- pared with patients who required dose escalation to weekly ADA. The median height velocity at 52 weeks was +1.71 in patients without dose escalation and –1.36 in patients whose dose escalated (p < 0.007). Patients with baseline growth impairment, who were responders to ADA induction therapy, achieved a significant growth improvement by week 26 but nonsignificant although numerical different at week 52 compared with non-responders at week 4. The median height velocity z-score at 26 weeks was +0.09 vs. –2.92, p = 0.023 and +0.68 vs. –1.78, p = 0.160 at 52 weeks, in responders vs. non-responders. Week 4 response status was a significant predictor of linear growth normalization at week 26 (OR 9.28 [95% CI 1.39–62.10]; p < 0.022). ADA trough levels at week 4 after induction therapy were also a significant predictor of growth normalization (OR 1.13 [95% CI 1.01–1.27]; p < 0.033). ROC curve analysis suggested that an ADA trough concentration of 10.9 mg/mL was the best cutoff for growth normalization in this patient population (area under the ROC curve, 0.605). At week 52, male patients were significantly more likely to exhibit normalization in height velocity than female patients (OR 4.04 [95% CI 1.12–14.50]; p < 0.032).
Patients treated with ADA with linear growth impairment at baseline who achieved and maintained durable remission throughout the study (defined by pediatric Crohn’s disease activity index [PCDAI] <10 at >80% of visits after week 4) were significantly more likely to exhibit a normal growth rate at week 52 than patients without durable remission (p < 0.023). Disease severity and corticosteroids use prior to trial had no impact on growth velocity during ADA treatment.

Conclusion

ADA therapy significantly improved linear growth rate in pediatric patients with baseline growth retardation enrolled in the IMAgINE 1 trial. Restoration of normal growth was significantly associated with clinical remission and was especially profound in week 4 responders and in patients with higher ADA blood levels.

Comments 

CrD is a progressive inflammatory disorder of the gastrointestinal tract. About 15% to 25% of IBD cases occur in children and adolescents. Growth, nutritional problems, and delayed pubertal development are common complications in pediatric CrD. Restoration of linear growth and achievement of the full growth potential are as important as maintaining disease remission and quality of life. Growth failure in children with CrD is multifactorial and involves chronic inflammation, undernutrition, corticosteroid therapy, and insulin-like growth factor-1 (IGF-1) growth hormone axis dysfunction [1]. Among the therapeutic strategies used in children and adolescents with CrD, some were also shown to improve growth, that is, nutritional interventions such as exclusive enteral nutrition used for induction of remission, surgery in patients with limited disease, and anti-TNF-α treatment. Data from clinical trials have shown that anti TNF-α therapy can improve height velocity in children with CrD. Furthermore, early treatment with anti TNF-α (less than 3 months after diagnosis) starting before or in early puberty leads to greater improvement in height and height velocity with Infliximab (IFX; a chimeric anti-TNF-α antibody) [2].
ADA, a fully human monoclonal antibody, is approved for use in children aged 6–17 years with moderately to severely active CrD (United States and Europe). The results of this study showed that ADA was an effective treatment for inducing and maintaining clinical response and remission in children, who had failed conventional therapies or previous anti TNF-α therapy. Children with moderately to severely active CrD who completed the IMAgINE 1 trial through week 52 and who had responded to treatment entered the open-label extension IMAgINE 2 study.
Children with no linear growth impairment at baseline maintained their growth velocity over time. In patients with growth retardation at baseline, linear growth normalized during the 52 weeks of ADA therapy. Indeed, by week 26, there was no significant difference in linear growth rate between the groups with initial growth impairment compared with those with normal linear growth at baseline. This growth rate was maintained at week 52. The growth velocity rate was higher in patients on high-dose ADA, in patients who were responders to ADA induction therapy at 4 weeks and ADA naïve patients. ADA trough levels at week 4 after induction therapy were a significant predictor of growth normalization and ADA trough concentration of 10.9 mg/mL was the best cutoff for growth normalization in this patient population. Male patients were significantly more likely to exhibit normalization in height velocity than female patients at 52 weeks. Growth velocity during ADA treatment was not influenced by disease severity but patients with linear growth impairment who achieved and maintained durable remission throughout the study were significantly more likely to exhibit a normal growth rate at week 52 than patients without durable remission.
It can be concluded that full growth potential in children and adolescents with CrD is achievable today in the era of biologic therapy. Timely use of biologic therapy, keeping the disease under control, and maintaining good nutritional status may improve the chances of children and adolescents with significant growth retardation to achieve their growth potential and predicted height as adults. 

Changes in hepcidin and hemoglobin after anti-TNF-alpha therapy in children and adolescents with Crohn’s disease

MA Atkinson, MB Leonard, R Herskovitz, RN Baldassano and MR Denburg

Background 

The IMAgINE 1 trial investigated the efficacy and safety of adalimumab (ADA), a fully human monoclonal antibody against tumor necrosis factor (TNF)-α, for induction and main- tenance of remission in children with moderately to severely active Crohn’s disease (CrD). The present study reported the effect of ADA on height velocity in pediatric patients with impaired baseline linear growth, participants in the IMAgINE 1 trial.

Methods

IMAgINE 1 was a 52-week, phase 3, multicenter, randomized, double-blind trial that assessed the efficacy and safety of 2 induction doses (160/80 vs. 80/40 mg) and 2 maintenance dose regimens (40 vs. 20 mg) of ADA in 6- to 17-year-old patients with moderately to severely active CrD. The children reported in this analysis were a subset of patients from the IMAgINE 1 trial, considered to have growth potential, that is, females with a bone age <13 years and males with a bone age <14 years.

Results

The IMAgINE 1 trial enrolled 100 patients, majority of whom (73/100, 73%) had linear growth impairment at baseline (height velocity z-score <–1.0). During the 52 weeks of ADA therapy, linear growth normalized in patients who initially had significant impairment at baseline. The median height velocity z-score improved from -3.25 at baseline to –0.34 by 26 weeks, and further improved to +0.21 by 52 weeks. By week 26 and also at week 52, there was no significant difference in linear growth rate between the group with initial impairment compared with those with normal linear growth at baseline.
Patients who received high-dose ADA had greater median height velocity z-scores compared with patients who received low-dose ADA at both 26 and 52 weeks. The median height velocity z-score at 52 weeks was +0.67 for the high-dose and –0.42 for the low-dose ADA group.
Patients receiving ADA without dose escalation had greater median height velocity z-scores compared with patients who required dose escalation to weekly ADA. The median height velocity at 52 weeks was +1.71 in patients without dose escalation and –1.36 in patients whose dose escalated (p < 0.007). Patients with baseline growth impairment, who were responders to ADA induction therapy, achieved a significant growth improvement by week 26 but nonsignificant although numerical different at week 52 compared with non-responders at week 4. The median height velocity z-score at 26 weeks was +0.09 vs. –2.92, p = 0.023 and +0.68 vs. –1.78, p = 0.160 at 52 weeks, in responders vs. non-responders. Week 4 response status was a significant predictor of linear growth normalization at week 26 (OR 9.28 [95% CI 1.39–62.10]; p < 0.022). ADA trough levels at week 4 after induction therapy were also a significant predictor of growth normalization (OR 1.13 [95% CI 1.01–1.27]; p < 0.033). ROC curve analysis suggested that an ADA trough concentration of 10.9 mg/mL was the best cutoff for growth normalization in this patient population (area under the ROC curve, 0.605). At week 52, male patients were significantly more likely to exhibit normalization in height velocity than female patients (OR 4.04 [95% CI 1.12–14.50]; p < 0.032).
Patients treated with ADA with linear growth impairment at baseline who achieved and maintained durable remission throughout the study (defined by pediatric Crohn’s disease activity index [PCDAI] <10 at >80% of visits after week 4) were significantly more likely to exhibit a normal growth rate at week 52 than patients without durable remission (p < 0.023). Disease severity and corticosteroids use prior to trial had no impact on growth velocity during ADA treatment.

Conclusion

ADA therapy significantly improved linear growth rate in pediatric patients with baseline growth retardation enrolled in the IMAgINE 1 trial. Restoration of normal growth was significantly associated with clinical remission and was especially profound in week 4 responders and in patients with higher ADA blood levels.

Comments

CrD is a progressive inflammatory disorder of the gastrointestinal tract. About 15% to 25% of IBD cases occur in children and adolescents. Growth, nutritional problems, and delayed pubertal development are common complications in pediatric CrD. Restoration of linear growth and achievement of the full growth potential are as important as maintaining disease remission and quality of life. Growth failure in children with CrD is multifactorial and involves chronic inflammation, undernutrition, corticosteroid therapy, and insulin-like growth factor-1 (IGF-1) growth hormone axis dysfunction [1]. Among the therapeutic strategies used in children and adolescents with CrD, some were also shown to improve growth, that is, nutritional interventions such as exclusive enteral nutrition used for induction of remission, surgery in patients with limited disease, and anti-TNF-α treatment. Data from clinical trials have shown that anti TNF-α therapy can improve height velocity in children with CrD. Furthermore, early treatment with anti TNF-α (less than 3 months after diagnosis) starting before or in early puberty leads to greater improvement in height and height velocity with Infliximab (IFX; a chimeric anti-TNF-α antibody) [2].
ADA, a fully human monoclonal antibody, is approved for use in children aged 6–17 years with moderately to severely active CrD (United States and Europe). The results of this study showed that ADA was an effective treatment for inducing and maintaining clinical response and remission in children, who had failed conventional therapies or previous anti TNF-α therapy. Children with moderately to severely active CrD who completed the IMAgINE 1 trial through week 52 and who had responded to treatment entered the open-label extension IMAgINE 2 study.
Children with no linear growth impairment at baseline maintained their growth velocity over time. In patients with growth retardation at baseline, linear growth normalized during the 52 weeks of ADA therapy. Indeed, by week 26, there was no significant difference in linear growth rate between the groups with initial growth impairment compared with those with normal linear growth at baseline. This growth rate was maintained at week 52. The growth velocity rate was higher in patients on high-dose ADA, in patients who were responders to ADA induction therapy at 4 weeks and ADA naïve patients. ADA trough levels at week 4 after induction therapy were a significant predictor of growth normalization and ADA trough concentration of 10.9 mg/mL was the best cutoff for growth normalization in this patient population. Male patients were significantly more likely to exhibit normalization in height velocity than female patients at 52 weeks. Growth velocity during ADA treatment was not influenced by disease severity but patients with linear growth impairment who achieved and maintained durable remission throughout the study were significantly more likely to exhibit a normal growth rate at week 52 than patients without durable remission.
It can be concluded that full growth potential in children and adolescents with CrD is achievable today in the era of biologic therapy. Timely use of biologic therapy, keeping the disease under control, and maintaining good nutritional status may improve the chances of children and adolescents with significant growth retardation to achieve their growth potential and predicted height as adults.

Changes in hepcidin and hemoglobin after anti-TNF-alpha therapy in children and adolescents with Crohn’s disease

MA Atkinson, MB Leonard, R Herskovitz, RN Baldassano and MR Denburg

Background

Anemia is the most common nutritional deficiency in patients with IBD. The pathophysiology of anemia involves poor intake but also defective absorption, gastrointestinal blood loss, and chronic inflammation. The main key mediator of anemia of chronic inflammation is the iron- regulatory protein, hepcidin. The present study investigated prospectively, the serum hepcidin levels in children and adolescents with CrD at baseline and 10 weeks after anti-TNF-therapy.

Methods

Serum hepcidin-25 and hemoglobin (Hb) were measured in 40 children and adolescents with CrD at baseline and 10 weeks after initiation of anti-TNF therapy. Measures of disease activity, inflammatory markers, and cytokines were obtained in all subjects. Anemia was defined by World Health Organization (WHO) criteria (Hb <11.5 g/dL in children aged 2–11 years, Hb <12 g/dL in females aged >12 years, Hb <13 g/dL in males 12–18 years, and <13.5 g/dL in males >18 years). 

Results

The mean Hb was 10.6 ± 1.2 g/dL and 95% of subjects were anemic at baseline. Only serum C-reactive protein (CRP) was positively correlated with hepcidin concentrations at baseline (r = 0.34, p = 0.03). After anti-TNF therapy, at 10 weeks, median (interquartile range [IQR]) hepcidin concentrations decreased significantly (27.9 [16.2–52.9] vs. 23.2 [11.1–37.7] ng/mL, p = 0.01). Mean ± SD Hb also increased significantly (10.6 ± 1.2 to 10.9 ± 1.1 g/dL, p = 0.02), and the increase was sustained at 12 months, although 90% of participants continued to meet anemia criteria at 10 weeks. Disease activity and markers of inflammation also decreased and albumin levels increased. Higher TNF-α, interleukin (IL)-6, ESR, and CRP were associated with higher hepcidin concentrations (p = 0.04, p = 0.03, p = 0.003, and p < 0.001, respectively). Increased levels of disease activity, as evaluated by PCDAI were also associated with higher hepcidin.

Conclusions

In children with CrD, anti-TNF therapy was associated with decreased levels of hepcidin and increased Hb 10 weeks after induction, suggesting that the anti-inflammatory actions of TNF-α blockade may extend to suppression of the specific stimuli for hepcidin production. This further supports a link between hepcidin, abnormal iron homeostasis, inflammatory cytokines, and CrD activity. Improvement in anemia may be a secondary benefit for children who receive this therapy.

Comments

Anemia is the most common nutritional complication of IBD. The prevalence of anemia is reported to be as high as 77% in children and 42% in adolescents, compared to 40% in adults [3]. Anemia is associated with impaired growth, poor quality of life due to increased fatigue, and decrease in cognitive function. The etiology of anemia in IBD is multifactorial due in part to inflammation, chronic blood loss, and poor iron/micro-nutrient intake. Iron supplementation by enteral and/ or intravenous (IV) route is the mainstay of therapy for iron deficiency anemia but inflammation-mediated impaired iron trafficking often results in resistance to these treatments. There is now consensus that anemia of chronic inflammation is at large a consequence of altered iron metabolism facilitated by inflammatory mediators. Immune mediators, such as IL-6 and possibly other cytokines involved in host defense, lead to hepcidin-induced hypoferremia, resulting in iron sequestration within the reticuloendothelial system and decreased iron availability for erythropoiesis [4]. Hepcidin is the principal regulator of iron homeostasis, including dietary iron absorption, iron recycling by macrophages, and the release of iron from hepatic stores. Hepcidin expression is induced by circulating iron and tissue iron stores, as well as inflammatory cytokines and suppressed by hypoxia, iron deficiency, and ineffective erythropoiesis. Hepcidin binding to its receptor causes internalization and degradation of ferroportin (the sole iron exporter), resulting in down-regulation of dietary iron absorption by intestinal enterocytes and inhibition of stored iron release from reticuloendothelial cells, preventing the utilization of absorbed or stored iron for erythropoiesis in the bone marrow.
Therapeutic monoclonal antibodies against IL-6 receptor (tocilizumab), IL-6 (siltux- imab), and TNFα (golimumab or IFX) were shown to decrease hepcidin and improve anemia [5].
Prior studies have shown that compared to healthy controls, serum levels of hepcidin were elevated in adults with CrD and were positively correlated with disease activity and serum concentrations CRP and IL-6 and negatively correlated with Hb levels [6]. The decrease in hepcidin levels, in this study, associated with a concurrent marked decrease in cytokines, inflammatory markers, and CrD activity, suggests that the anti-inflammatory actions of TNF-α blockade may extend to the suppression of specific stimuli for hepcidin production, in addition to a small increase in Hb. These findings suggest that stimuli for hepcidin transcription are relieved after anti-TNF induction, supporting a link between hepcidin, abnormal iron homeostasis, inflammatory cytokines, and CrD activity. Although treatment of the underlying disease remains at the center of therapy for inflammatory diseases, recent advances in molecular understanding of the hepcidin-ferroportin axis are stimulating the development of new targeted therapies.

Correction of iron deficiency anemia with intravenous iron sucrose in children with inflammatory bowel disease

I Danko and M Weidkamp

Aims

Iron deficiency anemia (IDA) is common in children with IBD. Oral iron supplementation has serious limitations including poor adherence, adverse effects, and iron malabsorption related to bowel inflammation. The objective of this study was to evaluate the feasibility and efficacy of periodic IV iron treatments for correction of IDA in children with IBD.

Methods

This prospective study was conducted in 24 children with IBD treated with IFX, 21/24 with CrD. Participants received 3 mg/kg (maximum 200 mg) IV iron sucrose (IS) after each IFX treatments if they were iron deficient according to the following criteria:
1 Ferritin <30 ng/mL or transferrin saturation (TSAT) <20% with normal CRP, or
2 Ferritin <100 ng/mL and TSAT <20% with elevated CRP.
They continued to receive IV IS with each IFX treatment until 2 consecutive laboratories showed no evidence of iron deficiency. Disease activity (PCDAI or pediatric ulcerative colitis index), hematology, and iron indices obtained during the study were compared with historical data from the same patients.

Results

The participants received a total of 138 IS infusions. The mean (±SD) number of infusions was 5.6 (±3.7) with a range of 2–18 per individual patient. The frequency of IS infusions ranged from 0.5 to 2.7 bimonthly. The mean ferritin (±SE) rose from 21.9 (±3.2) to 48.8 (±6.3) ng/mL (p = 0.0004), TSAT (±SE) from 13.2 (±1.8) to 23.6 (±2.6)%, (p = 0.0009), and Hb (±SE) from 11.4 (±0.3) to 12.7 (±0.3) g/dL, (p = 0.006). The proportion of patients with normal mean ferritin, TSAT, and Hb rose from 33 to 75% (p = 0.002), 21–63% (p = 0.006), and 25–79% (p = 0.0002), respec- tively. One patient with ulcerative colitis (pancolitis) was a nonresponder and 6 other patients, 4 with CrD and 2 with ulcerative colitis were relatively poor responders with an increase in mean Hb of <0.5 g/dL. All poor responders had a normal mean post-IS CRP, and, except 2 patients all had mean disease activity <10. No adverse reactions were reported.

Conclusions

The study shows that incorporation of IV IS into routine management of IDA in children with IBD is feasible, safe, and effective. This approach overcomes the 2 major obstacles that impede successful management of IDA in these patients, namely non-adherence with oral iron supplements and poor iron absorption associated with chronic inflammation.

Comments 

The anemia of patients with IBD is at many times the result of a combination of dysregulated iron trafficking due to chronic inflammation and iron deficiency. The decision to whether supplemental iron is needed in a patient with IBD and anemia should be preceded by careful evaluation of iron status, including information on Hb, mean corpuscular volume, serum ferritin, and TSAT. In addition, inflammatory markers such as CRP must be taken into consideration. Interpretation of iron stores based on serum ferritin may be misleading since ferritin, as an acute-phase reactant, may be normal or elevated even in the presence of iron deficiency. For this reason, ferritin levels, up to 100 μg/L, may still be consistent with iron deficiency, in the presence of elevated inflammatory markers. The treatment with oral iron has significant limitations in IBD, being less efficient than the IV route. In addition, unabsorbed iron may harm intestinal mucosa and worsen IBD symptoms by aggravating intestinal inflammation. Oral iron supplementation may also affect microbiota and increases fecal calprotectin [6]. Taking into account these possible effects, the recently published European Crohn’s and Colitis Organisa- tion (ECCO) guidelines state that the IV route should be preferred in the patients with IBD [7]. IV preparations have the advantage of bypassing intestinal absorption and compliance problems as iron replacement can be achieved with few doses of the newer high-dose preparations.There are a number of different IV iron formulations: high and low molecular weight iron dextran, IS, ferric gluconate, ferric carboxymaltose and ferumoxytol. As IV iron preparations have different physicochemical properties, the administration requires different dosages: more frequent lower individual doses are needed for IS or gluconate, whereas more stable preparations (e.g., iron dextran or ferric carboxymaltose) can be given as large single IV doses [8]. Concerns regarding the safety of IV iron preparations refer particularly to high molecular weight dextran formulations, which have an increased risk of anaphylaxis resulting from anti-dextran antibodies. Newer IV iron drugs such as IS and ferric carboxymaltose have been studied in few children with IBD and appear to have good safety profiles, high efficacy, and improved compliance as fewer IV doses are needed to correct iron deficiency (carboxymaltose) [9]. This study  is the first prospective study that reported the efficacy of an IV iron preparation in the treatment of IDA in children with IBD. Further studies using the new high-dose iron preparations are awaited.

Cystic Fibrosis

Effects of diagnosis by newborn screening for cystic fibrosis on weight and length in the first year of life

DH Leung, SL Heltshe, D Borowitz, D Gelfond, M Kloster,  JE Heubi, M Stalvey and BW Ramsey; for the Baby Observational and Nutrition Study (BONUS) Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network

Aims

To examine the growth (weight gain and linear growth) status in the first year of life in infants with CF diagnosed by newborn screening (NBS) for CF. Furthermore, the study explored concur- rent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements.

Methods

The study evaluated infants prospectively enrolled in the Baby Observational and Nutrition Study (BONUS), a prospective multicenter study of infants with CF. Study visits coincided with guideline-recommended CF clinic visits (monthly until 6 months and at 8, 10, and 12 months of age) and included anthropometry, diet records, fecal elastase levels, respiratory tract cultures, and chest radiography (according to CF Foundation care guidelines). Clinical data, dietary intake, hematology, biochemistry, and serum vitamin levels (A, D, and E) were collected at enrollment and at 6 and 12 months.

Results

The BONUS cohort consisted of 231 infants with CF, 215 (93.1%) completed follow-up through 12 months of age.

Weight

Birth weights of BONUS infants were statistically lower than those of WHO healthy newborns (mean z-score, –0.15; 95% CI –0.27 to –0.04), with a median birth weight of 3.2 (range 2.5– 4.4) kg. By 12 months of age, BONUS infants demonstrated increased weight gain, and weight for age was not different from that of WHO healthy infants (mean z-score, –0.04; 95% CI –0.17 to 0.09) and better than the 1994–1995 CF birth cohort.

Length

Birth lengths of BONUS infants were higher than those of WHO healthy newborns (mean z-score, 0.44; 95% CI 0.26–0.62), with a median birth length of 50.8 (range 40.1–57.3) cm. How- ever, length for age in BONUS infants was lower than that in WHO healthy infants at 3, 6, and  12 months of age (12-month mean z-score, –0.56; 95% CI –0.70 to –0.42). Length was improved compared with the historic cohort at 6 months (z-score increase, 1.06; 95% CI 0.82–1.30) and at 12 months (z score increase, 0.63; 95% CI 0.41–0.86).

Feeding

The median caloric intake in the first year was 107 kcal/kg/day (range 86–133 kcal/kg/day).
Exclusively breastfed infants weighed more than formula-fed infants or those fed a combination at 3 months of age (mean z-score difference, 0.54; 95% CI 0.22–0.87) but not at 6 or 12 months. Feeding type was not associated with infant length at any time point.
Using cumulative anthropometrics through the first year, participants were categorized into low-weight and low-length groups. Among the 222 BONUS infants with follow-up beyond 6 months, 30 (13.6%) had low-weight; 53 (23.9%) low-length; and 24 (10.8%) had both. Low-weight infants consumed significantly more calories than did normal-weight infants at 6 months (153 vs. 101 kcal/ kg/day). Low-length infants also consumed significantly more calories (131 vs. 100 kcal/kg/day). 

Associations between growth and clinical features

Weight and length z-scores of infants from the BONUS cohort were affected by the class of disease mutations, presence of pancreatic insufficiency (PI), meconium ileus, gender, presence of Pseudomonas aeruginosa colonization of respiratory tract and wheezing.

Conclusions

Although z-score for weight for age lagged behind WHO normative values at birth and during the first 6 months of age, BONUS infants’ z-score for weight increased to those of WHO healthy infants by 12 months. Correction in weight gain was a striking improvement compared with a 1994–1995 historic cohort, before universal NBS for CF in the United States. In contrast to weight improvement, most infants showed persistent delay in linear growth at 1 year. The study showed that NBS for CF in the United States has likely contributed to the correction of malnutrition and improved suboptimal growth in infants with CF.

Differences in outcomes between early and late diagnosis of cystic fibrosis in the newborn screening era

MJ Coffey, V Whitaker, N Gentin, R Junek, C Shalhoub, S Nightingale, J Hilton, V Wiley, B Wilcken, KJ Gaskin, and CY Ooi

Aims

The study aimed to evaluate and compare the clinical outcomes of patients with CF who had a late diagnosis of CF (LD-CF) despite neonatal screening (NBS), and determined whether their outcomes differ from children diagnosed with CF after a positive NBS and early diagnosis of CF (NBS-CF) during the same time period.

Methods

This retrospective study included all cases with LD-CF identified through the Australian CF Data Registry. As a comparator, each subject with LD-CF was matched 1:2 with patients with NBS- CF for age, sex, exocrine pancreatic status identified through Wisconsin NBS. LD-CF was defined as an individual who fulfilled the criteria for CF and was either (1) NBS negative (LD-NBS-negative) or (2) NBS positive (LD-NBS-positive), but discharged after a sweat test chloride (SC) <60 mmol/L.

Results

A total of 45 LD-CF cases were identified and included along with 90 matched NBS-CF controls. Of the LD-CF cases, 39 were LD-NBS-negative and 6 were LD-NBS positive (2 with a SC<30 mmol/L and 4 with a SC 30–60 mmol/L).
Pancreatic function status was known in 37 of the patients with LD-CF (82%), and of those, 27 (73%) were PI and 10 (27%) were pancreatic sufficient (PS). At the time of diagnosis, 38 patients with LD-CF (84%) and 90 patients with NBS-CF (100%) had manifestations of CF recorded.
The LD-CF cohort presented with significantly more respiratory (66 vs. 4%; p < 0.0001), gastrointestinal (24 vs. 6%; p = 0.005), and failure to-thrive manifestations (29 vs. 3%; p < 0.0001) when compared with NBS-CF controls at the time of diagnosis. The median number of hospital admissions per year for CF-related respiratory illness was significantly higher for patients with LD-CF compared with patients with NBS-CF (0.49 [0.2–1.1] vs. 0.2 [0–0.5] respectively; p = 0.0004).
The mean (SD) height z-score was significantly lower for patients with LD-CF compared with NBS- CF (–0.65 [0.22] vs. –0.03 [0.15]; p = 0.02). No difference between the LD-CF and NBS-CF cohorts in regard to mean (SD) z-score for weight (–0.48 [0.21] vs. 0.01 [0.14], p = 9.06) or body mass index (BMI; –0.11 [0.17] vs. –0.03 [0.12], p = 0.7) were evident.
The mean (SD) lung function variables were significantly worse for LD-CF compared with NBS-CF, including forced vital capacity (FVC) (2.1 [0.10] vs. 2.5 L [0.06], p = 0.003), forced expiratory volume/1 second (FEV1) (1.7 [0.08] vs. 2.0 L [0.06], p = 0.003), and FEV1% (0.88 [0.03] vs. 0.97 [0.02],p = 0.007).
Microbiology data showed a significantly higher rate of isolation of P. aeruginosa over the duration of follow-up in the LD-CF cohort compared with the NBS-CF cohort (82 vs. 69%, p = 0.03).

Conclusions

In this study, children diagnosed lately with CF, most with a false negative NBS result, had significantly worse health at the time of diagnosis, including more respiratory, gastrointestinal, and failure-to-thrive manifestations. Compared with matched controls, children with CF diagnosed earlier by NBS, children with LD-CF had poorer length growth, worse respiratory outcomes including poorer lung function, higher rates of chronic P. aeruginosa colonization, and increased frequency of hospitalization for CF-related respiratory illness at follow-up.

Comments


CF is a complex and greatly variable monogenic disease caused by mutations in the    CF transmembrane conductance regulator (CFTR) gene on chromosome 7. Airways, pancreas, male genital system, intestine, liver, bone, and kidney are involved. The lack of CFTR or its impaired function causes fat malabsorption and chronic pulmonary in- fections leading to progressive lung damage. Previously considered lethal in infancy and childhood, the landscape of CF has changed dramatically in the  last  decade, thanks to the incorporation of new technologies for the diagnosis and treatment of  the disease.
Diagnosis based on clinical grounds is usually straightforward in patients with typical manifestations, but occasionally it may be delayed for months. Universal NBS for CF has been implemented in all 50 states in the United States since 2010 and in many countries with a high prevalence of CF around the world [10]. CF NBS programs are based on blood immunoreactive trypsinogen (IRT) measurement in the first days of  life followed by, in infants with raised IRT by various combinations of genetic analysis, measurement of pancreatitis-associated protein, and IRT retesting by 1 month of age.

NBS protocols were shown to reduce the therapeutic burden, hospitalization rates, and morbidity associated with CF and are even more significant, especially now in the era of CFTR-targeted therapies for early diagnosis and rescue therapy before irreversible organ damage occurs.
Early diagnosis affords the opportunity to improve long-term outcomes through close monitoring and appropriate interventions beginning before severe nutritional deficits or irreversible airway damage have occurred. As CFTR modulator therapies that treat the basic genetic defect in CF became available across a broad range of ages and CFTR genotypes, initiation of these therapies in infancy holds the promise of changing the disease outcome. However, despite identification of CF in the youngest patients and emphasis on early nutritional supplementation and prompt implementation of pan- creatic enzyme replacement therapy (PERT), growth in children with CF continues to lag significantly behind that of healthy children. The good news brought to us by the study by Leung et al. as described on page 92 above, is that, though z-scores for weight for age lagged behind WHO normative values at birth and during the first 6 months of age, BONUS infant z-scores for weight increased compared to those of WHO healthy infants by 12 months. Correction in weight gain represents a striking improvement compared with a 1994–1995 historic cohort, before universal NBS for CF in the United States. Although significant progress was noted in weight gain of infants with CF, a subgroup of infants remained underweight despite increased caloric intake, PERT, and addition of H2 blockers to improve enzyme efficacy. Lung colonization with P. aerugi- nosa and wheezing were associated with the highest risk for low weight or length, even in this very young and relatively healthy population.
In contrast to the weight improvement, linear growth showed persistent delay at 1 year in most BONUS infants. Stunting was not seen in infants with PS. Since pancreatic phenotype is more strongly associated with genotype, patients with PS tend to have milder CFTR mutations (classes IV and V). Although the difference in linear growth between PS and PI children could be attributable to changes in absorption of critical micronutrients, poor growth may ultimately be a consequence of more severe CFTR dysfunction.
An additional finding in the BONUS cohort children was the detection of lower serum IGF-1 levels compared to the values reported in healthy infants. Infants with low length had even lower serum IGF-1 and IGF binding protein 3 levels than the rest of the BONUS cohort. The mechanism behind reduced IGF-1 levels in infants with CF is unknown, but several studies have suggested a direct link between IGF-1 and CFTR dysfunction besides the effect of chronic inflammatory state on IGF-1/GH axis [11]. However, even in the current era of universal NBS, some individuals are diagnosed late, either because they were born before implementation of NBS or in regions in which NBS was not offered, or because of a false-negative NBS. The present study compared the outcome of children with CF who had a LD-CF despite NBS, with children diagnosed after a positive NBS (NBS-CF). The patients with false-negative NBS result and late diagnosis were more stunted and had worse respiratory outcomes including poorer lung function, higher rates of chronic P. aeruginosa colonization, and increased frequency of hospitalization for CF-related respiratory illness at follow-up. In conclusion, as NBS for CF has become universally adopted in the United States and internationally, studies on the early course of disease have become more prevalent. Despite catch-up weight following NBS, linear growth impairment occurs during the first year, even among newborn-screened infants, suggesting that earlier and more aggressive nutritional therapy may be necessary to achieve normal growth. Furthermore, it is clear that lung disease is present in the first months of life, and the ability to change the early course of lung disease in CF has been limited so far. Recent studies have shown that CFTR modulators that are targeted toward specific CFTR mutations can improve the CFTR function, with resulting improvements in weight and lung function in adults and older children with CF. These new drug therapies may be able to prevent the onset of lung disease and other complications of CF if started early in life; however, safety and efficacy studies in younger children are still to be completed.

Differences between WHO and CDC early growth measurements in the assessment of cystic fibrosis clinical outcomes

D Usatin, EH Yen, C McDonald, F Asfour, J Pohl and J Robson

Aims

The study specifically addressed the question whether reaching weight for length (WFL) ≥50th percentile at age 2 years on World Health Organization (WHO) growth standards alone correlates with the same clinical outcomes displayed by those reaching WFL ≥50th percentile on both WHO and Centers for Disease Control and Prevention (CDC) measures.

Methods

The study included data from the Cystic Fibrosis Foundation Patient Registry (CFFPR) of children born between 1990 and 1994, diagnosed with CF prior to age 2 years, and followed prospectively. Weight and length taken at the participants’ 2-year-old visit were used to calculate WFL. WFL percentiles were calculated using previously published CDC and WHO algorithms.
Based on the WFL percentiles at the age of 2, the children diagnosed with CF before the age of 2 years were separated into 3 groups: patients <50th percentile on both WHO and CDC measures, patients achieving ≥50th percentile on the WHO, but not the CDC, and patients achieving ≥50th percentile on both growth charts.
FEV1 predicted percentage (FEV1pp) and lung transplant-free survival data were tracked annu- ally from early childhood into adulthood. Additional data collected at 18 years were BMI and number of days hospitalized with pulmonary exacerbations in the previous year.

Results

According to the CFFPR 3014/5333, CF patients born between 1990 and 1994 were diag- nosed with CF before age 2 years.
CF patients who achieved WFL ≥50th percentile on both WHO and CDC measures at age 2 years also had the highest FEV1pp at 18 years, compared to those who achieved WFL ≥50th percentile on the WHO measure alone (p = 0.041).
Patients in the categories of WFL <50th percentile on both WHO and CDC or WFL ≥50th percentile on the WHO alone had similar FEV1pp at age 18, both significantly worse than those WFL ≥50th percentile on both the WHO and CDC curves at age 2 years.
Breaking WHO and CDC WFL percentiles at age 2 years into 4 categories: WFL <10th, 10–25th, 25–50th, and ≥50th percentile, showed a stepwise increase in FEV1pp across increasing WFL percentile groupings, for both the WHO and CDC measures.
Lung transplant-free survival at age 18 years was highest among patients who achieved the ≥50th percentile WFL on both WHO and CDC curves by age 2 years. Similarly, in the adjusted Cox model, lung transplant/mortality risk was lowest in patients who reached WFL ≥50th percentile on both WHO and CDC measures at age 2 years. Patients with WFL <50th percentile at age 2 years on the WHO and CDC curves had significantly lower BMI at age 18 years than those who achieved ≥50th percentile WFL on both WHO and CDC curves (p < 0.001).

Conclusions

This study showed that early growth status is a major predictor of clinical outcomes, including lung function and overall survival, into adulthood. Setting a goal of attaining WFL ≥50th percentile by age 2 years on the CDC curve, not only on WHO curve using intensive treatment with nutritional supplementation, medical therapies and behavioral interventions improve the possibility of reaching these goals.

Comments

In 2015, Machogu et al. [11] published data on pulmonary function outcome at 6 years in 1,155 children with CF from the CFFPR according to their weight for age (WFA) or WFL percentiles at the age of 2 years, evaluated either using WHO or CDC growth charts. The results were straightforward: children with WFL on 50th percentile on WHO charts, who were bellow 50th percentile according to CDC chart, had a lower FEV1 at the age of 6 years compared to children at or above the 50th percentile on both charts. The authors of this study looked further on and reported the pulmonary function and overall survival at age 18 years related to growth data evaluated using WHO or CDC growth charts at 2 years age. Lung function and transplant-free survival at age 18 years was highest among patients who achieved the ≥50th percentile WFL on both WHO and CDC curves by age 2 years.
Use of the WHO standards to measure children from 12 months to 2 years routinely yields higher WFL percentiles compared to the CDC curves in children with CF. WFL measurements using WHO standards at age 2 may generate a false sense of security among providers and families with respect to achievement of early growth goals. This discrepancy has important implications for children diagnosed with CF, as several studies have shown a strong association between early growth and CF clinical out- comes throughout childhood and as shown in this study with long-term survival. Until the ideal/best WHO BMI percentile will be established/validated with long-term outcomes, health providers for CF children should still set up their nutritional goals above ≥50th percentile for WFL/ BMI on CDC growth charts.

Macronutrient intake in preschoolers with cystic fibrosis and the relationship between macronutrients and growth

SS Filigno, SM Robson, RD Szczesniak, LA Chamberlin, MA Baker, SM Sullivan, J Kroner and SW Powers

Aims

The study investigated the baseline dietary intake of preschoolers, including percentage of children with CF reaching recommended caloric intake and the distribution of macronutrient intake overall and by meal. The relationship of macronutrient intake to growth was also evaluated.

Methods

The study analyzed dietary data from a large multisite randomized clinical trial of pre- school-aged children with CF that examined the effectiveness of a behavioral and nutrition intervention compared to an education and control treatment (CONTROL) to improve intake and growth. Participant demographics were collected via a parent completed questionnaire. All anthropometric and dietary measures were taken at baseline and post-treatment (6 months). Dietary in- take of each child was assessed using a 7-day dietary record completed by parents. Given there were no significant differences between behavioral and nutrition intervention and CONTROL groups on dietary intake prior to treatment, intake for both treatment groups was collapsed to examine descriptive statistics regarding the overall dietary intake for the entire sample.

Results

The study included 75 children aged 2–6 years diagnosed with CF and PI. The mean (±SD) age was 3.8 (±1.3) and baseline weight for age z-score was –0.41 (±0.80) and height for age (HAZ) was –0.51 (±0.81). BMI was less than the 50th percentile in 44% of children.
Compared to the average recommended daily allowances (RDA), the energy intake achieved at baseline was 109.5% (±25.8), with only 45% of all children meeting the 110% minimum RDA recommendation. Only 53% of children were meeting the minimum recommendation of 35% daily energy from fat. Of the 44% of children defined at nutritional risk (<50th BMI percentile), 55% were not meeting the 110% minimum RDA. Children meeting the optimal nutritional status (≥50th BMI percentile) were consuming an average of 94 kcal/kg/day, within the ≥90–110 kcal/kg/day recommendation to sustain growth.
Regarding the relationship between macronutrients and growth, change in percent energy from protein was a significant predictor of change in HAZ from baseline to post-treatment, F(1125) = 12.93, p < 0.001. Change in percent energy from fat or carbohydrates did not significantly impact change in HAZ or weight for age z-score.

Conclusions

The results of this study showed that many preschool children were not meeting nutrition and growth recommendations for children with CF. Increasing intake of macronutrients with a great impact on energy intake and growth should be a primary nutritional target. Interventions to increase nutrition intake should include tracking and monitoring of macronutrients in addition to total energy and thorough growth monitoring.

Comments

According to CFF nutrition consensus and guidelines, children and adolescents with CF are expected to experience typical growth when appropriate nutrition and PERT are provided [13, 14]. Close attention to nutrition and growth is integral to the care of patients with CF and should be assessed at every visit. Nutritional status by all parameters (wasting, stunting, body composition) has been shown to affect lung function and survival in patients with CF in many studies before and this year too [15]. Despite close monitoring and appropriate anticipatory guidance, BMI greater than the 50th percentile can be difficult to attain and maintain. The nutritional status in children with CF has been improving over time, however, on average BMI percentile decreases with advancing age.
Nutritional care of patients with CF should address several aspects including: provision of appropriate amount of calories, PERT, and fat-soluble vitamin supplementation. Achieving the recommended caloric intake of 110–200% of the RDA of kcal/kg with at least 35–40% of daily energy derived from fat in children with CF is sometimes difficult. This study reported the nutritional data of a contemporary sample of preschoolers receiving standard of care at several accredited CF Centers in the US.
The reported data is not encouraging as more than half (55%) of the preschoolers were not meeting the minimum 110% RDA for energy recommendation, and 44% of children had BMIs <50th percentile. The average daily percent energy from fat consumed for the entire sample was just at the minimum recommendation of 35%, and only 53% of the children were meeting this recommendation. Children were within the acceptable macronutrient distribution range for carbohydrates and protein.
The increased focus on improving the nutritional status in patients with CF over the last years has contributed to more children receiving proactive assessment and intervention. An approach to feeding education during the preschool years involves systematic monitoring, goal setting, and timely feedback about nutrition intake that can help parents of children with CF to engage in feeding practices with the goal of achieving optimal nutrition outcomes. A variety of options are available for the management of suboptimal nutritional status, including oral supplementation (vitamin and mineral supplementation and calorie-dense liquids), behavioral treatment, pharmacotherapy (including appetite stimulants and CFTR modulators), and enteral nutrition. Awareness of clinical staff about the overall nutritional status of their patient population and timely nutritional support when clinical indices fall below standards should be the standard of care.

Celiac Disease

Celiac disease is associated with reduced bone mineral density and increased FRAX scores in the US National Health and Nutrition Examination survey

E Kamycheva, T Goto and CA Jr Camargo

Aims

National Health and Nutrition Examination Survey (NHANES) is a unique program of studies designed to assess the health and nutritional status of US adults and children. The survey combines interviews and physical examinations of about 5,000 persons per year. Based on the most recent nationally representative NHANES datasets from cycles 2009–2010 to 2013–2014, the study investigated whether CD is associated with decreased bone mineral density (BMD) and is an independent risk factor of osteoporotic fractures in the US population.

Methods

The NHANES data included questionnaire data (diet and behavior), tissue transglutaminase IgA (tTG IgA) and anthropometry. CD was defined by positive (>10.0 U/mL) or weakly positive (4.0–10.0 U/mL) tTG IgA ELISA test. BMD of hip and spine was measured by dual energy X-ray absorptiometry (DXA). DXA scans were performed on eligible survey participants 8 years and older during the 2009–2010 cycle and only on participants aged ≥40 years during 2013–2014 NHANES cycle. Fracture risk assessment tool (FRAX) score (10-year risk for hip fracture and major osteoporotic fractures, hip, clinical spine, wrist, and humerus) was calculated for participants aged ≥40 years.

Results

NHANES, 2009–2010 included 6,712 individuals, 1,466 children 6–18 years old. Using the linear regression model with multiple adjustments (for serum 25-hydroxyvitamin D [25(OH)D], vitamin D-containing supplements, calcium-containing supplements, and smoking status), BMD z-scores for hip were found to be significantly lower for children with CD (Δ z-score –0.59, p = 0.02). BMD z-scores for spine were also significantly lower in children with CD (Δ z-score –0.46, p < 0.001) as compared to children without CD. In adults aged ≥18 years, only men with CD tend- ed to have lower BMD in hip by 0.06 g/cm2 (p = 0.08); they also demonstrated lower BMD in spine by 0.11 g/cm2 (p < 0.001), as compared to men without CD.
NHANES, 2013–2014 included 2,993 adults 40 years and older. In the linear regression model (ad- justed for BMI, serum calcium, intake of milk, and smoking status), men with CD had 0.14 g/cm2 lower BMD for hip (p = 0.02) and 0.11 g/cm2 lower BMD for spine (p = 0.005), as compared to their counterparts without CD. Moreover, men with CD had 2.25 % higher FRAX hip fracture score (p = 0.006) and 2.43% higher FRAX major fracture score (p = 0.05), as compared to men without CD. By contrast, there was no difference in BMD or FRAX scores among women with and without CD. Conclusions: This nationally representative database of the US population reports a significant association between CD/ CD autoimmunity and reduced BMD in both children and male adults. Furthermore, in men aged ≥40 years, CD/CD autoimmunity was significantly associated with higher FRAX fracture score and, thus, appears to be an independent risk factor for osteoporotic fractures in this group.
However, the study’ findings only pertain to subjects with CD autoimmunity. The presence of CD was not validated by either duodenal biopsies or patient’s medical records. Thus, subjects with known CD adherent to gluten-free diet (GFD) were not included in the CD group. Nevertheless, assuming that subjects included in the CD group could have undiagnosed CD, or are diagnosed but not adhering to GFD, the results are of major clinical importance: (1) to promote active screening and diagnosis for CD and (2) adherence to GFD in patients already diagnosed with CD.

Reduced bone mineral density in children with screening-detected celiac disease

S Björck, C Brundin, M Karlsson and D Agardh

Aims

The aim of this study was to evaluate if BMD is affected in children with asymptomatic, screening detected CD either with or without GFD.

Methods

The study evaluated children participating in the Celiac Disease Prediction in Skåne (CiPiS) study, a prospective population-based cohort study aimed to identify CD by repeated screening using tTG IgA in HLA genotyped children. At the age of 9 years, children participating in the CiPiS were invited for measurement of BMD and bone-related metabolites.

The study investigated 3 cohorts selected from the CiPiS study:

  • 1 Children diagnosed with CD at 3 years age, 56/3,435, based on positive tTG IgA blood test and intestinal biopsy who were on GFD at the time of investigation
  • 2 Children diagnosed with CD at 9 years age, 72/4,077, by and additional tTG IgA screening, before initiation of GFD
  • 3 A control group matched for gender, HLA-DQ, and birth year for every child with CD was selected from the tTG IgA negative children at follow-up screening.

All participants were investigated by anthropometry, a questionnaire related to lifestyle factors, BMD, and a blood sample for evaluation of different parameters related to bone mineral metabolism.

Results

Lifestyle parameters were not different between the 3 study groups with the exception of GFD in the cohort diagnosed with CD at the age of 3 years. 

BMD

Compared to controls, the 9 year old children with screening-detected CD had lower total body and spine BMD at diagnosis. Children diagnosed with CD at 3 years, and on GFD had no dif- ferent BMD when compared to controls.

25(OH) Vitamin D3 and PTH

25(OH)D3 levels were lower and PTH levels were higher in untreated newly diagnosed CD children, compared to controls. Children with CD on GFD did not differ from control in levels of 25(OH)D3 and PTH.

Systemic cytokines

In children newly diagnosed with CD, systemic levels of the cytokines IL-1β, IL-6, IL-8, IL-10, IL12p70, IL-13, and TNFα were increased in spite of levels of IL-15 were decreased compared to matched controls. Children on GFD did not differ from controls in any measured systemic cytokine.

Conclusions

Asymptomatic children 9 years old with screening-detected CD had lower total body and spine BMD already at diagnosis, whereas children with CD on GFD had BMD similar to healthy controls. This strengthens the conclusion that children with CD diagnosed by population-based screening, may benefit from an early diagnosis to institute treatment to restore bone health.

At-risk screened children with Celiac disease are comparable in disease severity and dietary adherence to those found because of clinical suspicion: a large cohort study

L Kivelä, K Kaukinen, H Huhtala, ML Lähdeaho, M Mäk and K Kurppa

Aims

The study aimed to identify clinical, serologic, and histological features and follow-up results in a high-risk group of children diagnosed with CD by screening and compare it with those identi- fied based on clinical suspicion, and thus evaluate the potential benefits and detriments of CD screening.

Methods

The study analyzed the data collected from the research database at Tampere Center for Child Health Research, University of Tampere and the Department of Pediatrics, Tampere University Hospital, which contains medical information on children diagnosed with CD from the late 1960s to present. The information included patients’ clinical characteristics, CD serology, laboratory parameters, severity of histologic damage, and follow-up data regarding adherence and clinical and serologic response to GFD. From 2012 onward, most patients included in the database were participants in a prospective study enrolment. Only children diagnosed from the year 2000 onward were included. Altogether, 504 children with CD proven by biopsy were included in the final study cohort.

Results

Of the children included in the analysis, 145 (28.8%) were detected by screening and 359 (71.2%) based on symptoms (gastrointestinal in 68.0% and extra-intestinal in 32.0%). However, 51.8% of the screening-detected children reported symptoms at diagnosis, usually less severe than in patients diagnosed clinically, but otherwise the groups did not differ in the distribution of symptoms. Anemia (7.1 vs. 22.9%, p < 0.001), poor growth (15.7 vs 36.9%, p < 0.001) were more prevalent in clinically based diagnosed children. Hb (126 vs. 124 g/L, p = 0.008) and albumin (41.0 vs. 38.0 g/L, p = 0.016) were lower in clinically detected patients. There were no differences in serology or histology between the groups. Screening-detected children had better dietary adherence (91.2 vs. 83.2%, p = 0.047). The groups showed equal clinical response (97.5 vs. 96.2%, p = 0.766) to GFD. Conclusions: More than half of the screening-detected patients with CD had symptoms unrecognized at diagnosis. The severity of histologic damage, antibody levels, dietary adherence, and response to treatment in screening-detected cases was comparable with those detected on a clinical basis. The results of the study show that even apparently asymptomatic patients may have well ad- vanced serologic and histologic disease and therefore a subsequent risk of long-term complications.

Comments

CD is an autoimmune enteropathy that develops in genetically predisposed individuals, upon ingestion of gluten, the major storage protein in wheat, barley, and rye.
The common presentation of CD has shifted from the historically classic symptoms of malabsorption (chronic diarrhea, weight loss, and failure to thrive) in childhood to non-classic symptoms, which can be present in childhood or adulthood. The more common, non-classical symptoms include iron deficiency, bloating, constipation, chronic fatigue, headache, abdominal pain, and osteoporosis.
CD can affect the bone health of children in several ways and present with a variety of signs and symptoms including bone pain, rickets, tetany, osteomalacia, osteopenia, osteoporosis, fractures associated with minimal trauma, or growth failure with or without symptoms of malabsorption. With the exception of osteopenia or osteoporosis identified by DXA, other manifestations are rarely the presenting signs and symptoms of CD in children [17].
Most reports of low BMD are from symptomatic patients diagnosed with CD. Timely diagnosis and initiation of a GFD rapidly restores bone mass to normal levels in children and adolescents [18]. Instruction on age-appropriate intake of calcium, vitamin D, and the need for exercise to promote bone health should be provided during nutritional counseling at the time of diagnosis.
Albeit screening-detected children have similar degree of mucosal damage than those diagnosed based on clinical suspicion, whether screening-detected children have reduced BMD as a consequence of an unrecognized disease already present at diagnosis has not been shown. The study of Sara Björck investigated for the presence of low BMD in asymptomatic children prospectively identified in a population-based screening compared to matched controls diagnosed with CD 6 years before and on GFD and children without CD. The study found that children with screening-detected CD had lower total body and spine BMD already at 9 years of age whereas children with already screening-detected CD on GFD since early age had a BMD similar to healthy controls. The study adds to the arguments that children detected in population-based screening, may benefit from an early diagnosis to institute GFD to restore bone health.
The NHANES-based study of Kamycheva described in this chapter on page 99, investigated the association between CD autoimmunity (positive serology) and BMD (children and men ≥18 years) and increased risk of fractures in men ≥40 years. In this study, CD was defined as positive tTG IgA test, a test with sensitivity of 93% and specificity of more than 98%. The study identified a significant association between CD autoimmunity and reduced BMD in both children and adults. Furthermore, in men aged ≥40 years, CD autoimmunity was significantly associated with FRAX hip fracture score and borderline significantly associated with FRAX major fracture score and, thus, appears to be an independent risk factor for osteoporotic fractures in men. This study, there- fore, suggests that not only asymptomatic children with CD, but also children and adults with positive celiac serology/ autoimmunity are at risk of poor bone status and osteoporotic-related fractures in adulthood.
CD fulfils several WHO criteria for population screening, although the benefits of this approach remain controversial, in particular, because it is unclear whether asymptomatic screening-detected patients will adhere to the demanding and restrictive GFD and whether clinical outcome of these patients is similar to those detected due to malabsorptive symptoms. Although untreated CD predisposes to severe complications in symptomatic patients, it is not known whether this is also true to screening- detected individuals with possible less severe histologic damage. The previous 2 studies showed that low bone mass have been detected even in otherwise asymptomatic children with CD, and even in individuals with positive celiac autoimmunity, and this situation may remain permanent if left untreated.
This study investigated the clinical, serologic, histologic features and follow-up results in children with CD diagnosed during screening in a risk group and those identified based on clinical suspicion. The authors reported a high prevalence of unrecognized gastrointestinal symptoms as well as anemia and poor growth. Furthermore, the severity of histologic damage, antibody levels, dietary adherence, and response to treatment in screening-detected cases was comparable with those detected on a clinical basis.
The results of this study and the previous ones suggest that based on the high percentage of unrecognized clinical symptoms and excellent response, adherence to the GFD active screening for CD is highly recommended. Alternatively, a low-threshold case finding among at-risk children should be adopted, but it is important to realize that even apparently asymptomatic patients may have well advanced serologic and histologic disease and a subsequent risk of long-term complications.

Early growth in children with celiac disease: a cohort study

CR Kahrs, MC Magnus, H Stigum, KEA Lundin and K Størdal

Aims

The study investigated growth during the first 2 years of life in children later diagnosed with CD compared with children without CD.

Methods

The Norwegian Mother and Child Cohort Study is a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. The children evaluated in the present study were born from 1999 to 2009. The children’s weight and length at birth and at 3, 6, 8, 12, 15–18, and 24 months were used for the present study. CD was identified through combined data from the questionnaires administered to parents and the Norwegian Patient Register.

Results

The study enrolled 58,235 cohort controls and 440 children with CD. The mean age at the end of follow-up was 8.6 years (range 4.6–14.2).

Height

The longitudinal analysis for the period 0–12 months yielded a non-significant reduction in height z-score for children with CD, whereas the period 0–24 months yielded a significant reduction (–0.07 SD scores (SDS) per year, 95% CI –0.13 to –0.01), as compared with children without CD.

Weight

The longitudinal analysis from 0 to 12 months yielded no significant differences for weight among children with CD versus controls at the end of follow-up, with similar non-significant differences from 0 to 24 months of age (–0.01 SDS, 95% CI –0.08 to –0.05).

Conclusions

Children later diagnosed with CD were shorter as early as 12 months of age compared with those without diagnosis at the end of follow-up. The differences in absolute numbers were small at 12 months but increased in the second year of life even when excluding children with symptoms from before 2 years of age. As symptoms started at a mean of 4 years, the study suggests that growth impairment occur early and commonly in children with CD.

Comments

Recent studies have reported a decrease in the prevalence of failure to thrive and short stature as presenting manifestation of CD, to 26 and 11% respectively. Growth failure has been reported to be present 1 (boys) and even 2 (girls) years prior to the diagnosis of CD. Several studies have shown that the institution of GFD in children with newly diagnosed CD leads to rapid symptoms’ disappearance and catch-up of body weight (mostly within the first year after withdrawal of the gluten from the diet) whereas height catches up somewhat more gradually, sometimes up to 2–3 years or even more.
The study of Kahrs CR reported that growth faltering occurred even in the first 2 years of life, long before the symptoms or diagnosis of CD was done. There was no knowledge of CD serology at that time in these children, but it is possible that GH-IGF-1 axis disturbance was present at that time, even before CD serology seroconversion, at the earliest stages of mucosal changes. Prospective studies in children at genetic risk, including thorough investigation of the GH-IGF1 axis will be able to provide new data   on the earliest CD-induced systemic changes of growth axis.


Food Allergy

 

The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies

R Meyer, C De Koker, R Dziubak, H Godwin, G Dominguez-Ortega, A Chebar Lozinsky, AK Skrapac, Y Gholmie, K Reeve and N Shah


Background

Non-IgE mediated food allergies include food protein induced gastrointestinal allergies such as proctocolitis, enterocolitis, eosinophilic gastrointestinal disorders, food protein induced enterocolitis syndrome, and enteropathy. Previous studies have indicated growth faltering in children with IgE-mediated allergy, but limited data is available on those with delayed type allergies. The study reported the impact on growth before and after the start of elimination diets in children with food protein induced non-IgE mediated gastrointestinal allergies.

Methods

This prospective, observational study was performed at the Gastroenterology Depart- ment, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK and en- rolled children aged 4 weeks to 16 years without non-allergic comorbidities who were required to follow an elimination diet for the diagnosis of suspected non-IgE mediated gastrointestinal food allergies. Growth data were recorded as z-scores for weight-for-age (Wtage), Htage, and weight- for-height (WtHt) for children ≤5 years of age and BMI for children >5 years. Dietary intake was recorded for a minimum of 4 weeks after initiating the elimination diet.

Results

The study reported the data from 130 children, median age 23.3 months (IQR 9.4–69.2). Hydrolyzed formula (HF) was given to 10.8% children, 17.2% avoided one food, 30.2% 2 foods, 15.5% 3 foods, and 37.1% eliminated ≥4 foods. Almost all children (94.8%) in this study eliminated CM from their diet, 74% also avoided soya with 45.7 and 44.8% avoiding eggs and wheat, respectively. The most frequent combination (30.2%) of eliminated foods was CM, soya, eggs and wheat (with or without other foods).

Anthropometry

The mean Wtage, Htage, WtHt (<5 years of age), and BMI z-scores (>5 years of age) for children after a minimum of 4 weeks elimination was 0.044, –0.186, 0.296, and 0.042. Elev- en out of 130 children (9%) were stunted and 2/90 (2.2%) children <5 years of age were wasted (z- score less than –2), and 2/40 (5%) >5 years had a BMI less than –2 z-score. Conversely, 2/90 (2.2%) and 4/40 (10%) children <5 and >5 years of age, respectively, were overweight with a WtHt or BMI z-score >2.

Food intake

Diaries from 110 children were included in the data analysis as some infants were be- ing breastfed. Compared to UK Dietary Reference Values, 68.2 and 50.0% of children met their requirements for energy and protein, respectively. About 21.8% did not achieve their EAR for energy versus only 2.7% not achieving requirements for protein, in fact, 47.3% exceeded the protein requirements for their age.

Association between growth parameters and nutritional intake

There was a statistically significant improvement in Wtage after the 4-week elimination diet. The elimination diet itself (i.e., CM, soya, egg, wheat) and the number of foods eliminated did not have a positive impact on growth over a 4-week period. However, vitamin and/or mineral supplements and hypoallergenic formulas were positively associated with WtHt and Wtage.

Conclusions

Nutritional management of children with non-IgE mediated gastrointestinal food allergies, significantly impacts growth. In this study, patients had improved growth parameters (weight) following dietary elimination. This positive impact was associated with energy and protein intake, the use of HF and vitamin and/or mineral supplementation, irrespective of the type of elimination diet and the numbers of foods eliminated. Whether these findings are unique to children with this type of allergy and stable over a longer period of diet elimination should be studied further.

Iodine status and growth in 0- to 2-year-old infants with cow’s milk protein allergy

RA Thomassen, JA Kvammen, MB Eskerud, PB Júlíusson, C Henriksen, and J Rugtveit 

Background

Iodine is an essential trace element necessary for the production of thyroid hormones, and adequate levels of thyroid hormones are needed for normal growth and neurological development of the brain and central nervous system in infancy and childhood. Several case reports have found goiter and signs of goiter due to low iodine intake in children restricting cow’s milk protein (CMP) in their diet. The aim of the present study was to investigate iodine intake and status and growth in CMP allergic (CMPA) children and identify factors affecting iodine status and growth. Methods: This observational cross-sectional study included 57 infants less than 2 years of age with CMPA. Two spot urine samples were collected and analyzed for iodine, together with a 3-day food record and a food frequency questionnaire. Urine iodine concentrations were compared with the WHO cut-off values for iodine deficiency (median urinary iodine concentration [MUIC] of >100 mg/L is considered as adequate in children younger than 2 years). SDS of weight, length, and head circumference at birth and at study inclusion were recorded.

Results

The median age was 9 months and the median time on CMP-free diet before enrolment was 17 weeks. Almost all children (98%) had gastrointestinal symptoms, 46% had eczema or skin symptoms, more than one third had failure to thrive and one third had food refusal. Feeding difficulties were reported in 70% of the children. More than half (57%) were breastfed at the time of enrolment; 24% mainly breastfed and 33% partially. An HA was used by 69%. MUIC was 159 μg/L (<25–457 μg/L) and the prevalence of MUIC <100 μg/L was 31%. The mainly breastfed children had significantly higher prevalence of iodine deficiency: 58% had a MUIC <100 μg/L compared with 12 and 32% in the partially breastfed and the weaned. The total iodine intake and percentage of RDI for iodine (excluding breast milk) was significantly higher in the partially breastfed and weaned children compared to the mainly breastfed children. The dietary factors positively associated with iodine excretion were enriched baby cereals and meeting the dietary requirement for iodine. Stunting was present in 5%. Underweight and wasting in 11% and were associated with food refusal and poor appetite, but not with iodine status.

Conclusions

The present study suggests that children with CMPA have a high prevalence of iodine deficiency and slightly lower growth deficit than the reference population; however, the 2 condi- tions were not related. The mainly breastfed infants were at higher risk of iodine deficiency com- pared to weaned infants on HF or consuming enriched baby cereals. The children with feeding difficulties had increased risk of malnutrition.

Comments 

Food allergies are commonly diagnosed in children, and recent statistics show an increasing worldwide prevalence of reported food allergies. Food allergies affect approximately 8% of children and 5% of adults [19]. Allergen avoidance is the mainstay  of treatment for food allergy; however, many of the most common food allergens are integral parts of the typical Western diet and contain macronutrients and micronutrients that are essential for normal growth and development. Even with close supervision, growth in children with food allergy can lag. Although several studies have assessed the relationship of food allergy, nutrition, and growth in smaller groups of children, population-wide studies investigating these issues are limited [20]. Cow’s milk allergy (CMA) represents the most common food allergy during childhood, affecting 2–3% of children. A strict elimination diet removing cow’s milk, dairy products, and their traces remains the main treatment plan until allergy resolution.
One of the largest studies that examined growth status in children with food allergies included 6,189 children aged 2–17 years from NHANES 2007–2008 and 2009–2010. Overall, 6.3% (95% CI 5.5–7.3) of children reported a food allergy, with the most com- mon trigger identified as milk (1.8%; 95% CI 1.3–2.3), followed by peanut (1.2%; 95% CI 0.9–1.6) and egg (0.6%; 95% CI 0.4–0.8). In multivariate analyses, mean weight, height, and BMI percentiles were significantly lower in those with milk allergy but not in other groups of children with food allergy. Children with milk allergy also had decreased triceps skin folds, a measurement of adiposity (mean difference, 1.8 mm; 95% CI 0.55–3.05 mm; p = 5.006). Adjustment for dietary intake of total calories, protein, fat, calcium, and vitamin D did not change the findings of decreased growth measurements in children with milk allergy or adiposity measurements [21]. What the NHANES study reinforces is that in a non-IgE mediated gastrointestinal allergy population on an elimination diet, a significant number of children with this allergy will be stunted, irrespective of dietary advice including a suitable hydrolyzed formula and vitamin and mineral  supplementation.
The study of Meyer et al., described above in page 104, investigated the change in weight and height after a minimum of 4 weeks elimination diet (for 94.8% cow’s milk elimination) in 110 children aged 23.3 months (IQR 9.4–69.2) with non-IgE mediated milk allergy. The study showed improvement in WtHt and Wtage on the elimination diet, unrelated to the elimination diet itself (i.e. CM, soya, egg, wheat) and the number of foods eliminated. In this study, stunting was present in 9% of children, but only a very small number of children were wasted (2.2 and 5%). As there was on average a minimum of 4 weeks between the start of the elimination diet and the follow-up measurements, the time was insufficient for significant linear growth to occur. The study shows that individualized dietary advice may help children with non-IgE mediated gastrointestinal food allergies on elimination diet maintain and even improve the weight. Whether height could also be improved in these children should be investigated over longer period times.
The study of iodine status in infants with CMPA and children on CMP free diets reported a poor iodine status in infants on exclusive breast milk compared to infants on combined breast milk and formula or formula only. However, the iodine status in the CMPA infants in the current study was a cross-sectional one without a control group and was not inferior compared with healthy infants in other iodine sufficient countries and the data on iodine status of healthy infants in Norway are lacking. Moreover, despite the slightly lower mean weight SDS and length SDS for the study population, there was no correlation between growth and iodine deficiency in this cohort.
Since breastfed infants are highly dependent on the content of iodine in breast milk, which in turn is dependent on the breastfeeding mothers’ iodine status, breastfeeding mothers should be monitored and dietary advice on iodine sources and supplements should be offered. The relationship between growth and iodine status in infants on exclusive breastfeeding should be further investigated.
The effect of food allergies and food avoidance on children’s health should include not only comprehensive dietary advice and follow-up to ensure appropriate macro- and micronutrients’ intake and normal growth pattern but also timely achievement of appropriate feeding skills and behavior.

Attention  Deficit/Hyperactivity Disorder

Association of stimulant medication use with bone mass in children and adolescents  with  attention-deficit/hyperactivity disorder

AJ Feuer, A Thai, RT Demmer and M Vogiatzi

Background and aims

Animal studies suggest that sympathetic nervous system activation leads to decreased bone mass. Stimulant medications used to treat attention-deficit/hyperactivity disorder (ADHD) have been shown to decrease growth velocity in pediatric patients, but their effect on bone mass is not clear. Since amphetamines increase sympathetic tone, it is possible that they also affect bone remodeling. Because bone mass accrual takes place during childhood and adolescence, assessment of stimulant medications’ effects on bone density in growing children is of critical importance. The present study investigated the association between stimulant use and bone mass in children and adolescents.

Methods

This cross-sectional analysis used data collected from January 1, 2005, to December 31, 2010, from the NHANES database. NHANES is a series of cross-sectional, nationally representative health and nutrition surveys of the US population. All children, adolescents, and young adults aged 8–20 years with DXA, anthropometric, demographic, and prescription medication data were eligible for participation. Stimulant users were defined as participants who reported use of amphetamine, methylphenidate, lisdexamfetamine dimesylate, dextroamphetamine sulfate, or levoamphetamine. Nonusers were defined as participants who did not report the use of those medications. Of the 6,489 respondents included in the multivariable linear regression analysis, 159 were stimulant users and 6,330 were nonusers. Bone mineral content (BMC) and BMD were measured using DXA scans of the left hip and lumbar spine. Demographic variables included age, sex, and race or ethnicity, anthropometry (height, weight, BMI z-scores, smoking status, physical activity, and so- cioeconomic status as well as serum levels of 25(OH)D were related to BMD and BMC measurements.

Results

The study included 6,489 NHANES participants with a mean (±SD) age of 13.6 (±3.6) years. There were 159 individuals who reported stimulant use.
Male users had significantly lower BMIs, BMI z scores, weight, and weight z scores than nonusers, whereas female stimulant users had significantly lower weight and BMI. Male and female users had significantly shorter heights than nonusers. The poverty income ratio and physical activity level were similar in both groups. Serum 25(OH)D concentrations were significantly higher among stimulant users versus nonusers.
Stimulant use was still associated with lower bone mass after adjustment for covariates. The mean lumbar spine BMC was significantly lower in stimulant users versus nonusers (12.76 g; 95% CI 12.28–13.27 vs. 13.38 g; 95% CI 13.26–13.51 g; p = 0.02), as was the mean lumbar spine BMD (0.90g/cm2; 95% CI 0.87–0.94 vs. 0.94 g/cm2; 95% CI 0.94–0.94 g/cm2; p = 0.03) and mean femoral neck BMC (4.34 g; 95% CI 4.13–4.57 vs. 4.59 g; 95% CI 4.56–4.62 g; p = 0.03). The mean BMD of the femoral neck (0.88 g/cm2; 95% CI 0.84–0.91 vs. 0.91 g/cm2; 95% CI 0.90–0.91 g/cm2; p = 0.08) and total femur (0.94 g/cm2; 95% CI 0.90–0.99 vs. 0.99 g/cm2; 95% CI 0.98–0.99 g/cm2; p = 0.05) were also lower in stimulant users versus nonusers. Participants treated with stimulants for 3 months or longer had significantly lower lumbar spine BMD (0.89 g/cm2; 95% CI 0.85–0.93 vs. 0.94 g/cm2; 95% CI 0.94–0.94 g/cm2; p = 0.02) and BMC (12.71 g; 95% CI 12.14–13.32 vs. 13.38 g; 95% CI 13.25–13.51 g; p = 0.03) and femoral neck BMD (0.87 g/cm2; 95% CI 0.74–0.83 vs. 0.91 g/cm2; 95% CI 0.83–0.84 g/cm2; p = 0.048) than nonusers.

Conclusions

The use of stimulants in children and adolescents was associated with lower DXA measurements of the lumbar spine and femur compared with nonusers. Reduction in bone mass during the critical period of bone accrual in adolescence and early adulthood can lead to permanent reduction in bone density and increase the risk of fractures. The study findings support the need for future prospective studies to examine the effects of stimulant use on bone mass in children.

Comments

ADHD is one of the commonly diagnosed childhood neurodevelopmental disorders, affecting around 3–4% of children and adolescents [23]. ADHD is characterized by age-inappropriate symptoms of inattention, hyperactivity, and impulsivity. Stimulant medications such as methylphenidate and dexamphetamine are the first-line phar- macological treatment of ADHD. The short-term evidence base efficacy of stimulants is well established. However, its long-term benefits are still unclear. While serious ad- verse events are very rare, common adverse effects include sleep disturbances, loss of appetite, and reduced growth.
Amphetamines are classified as indirect sympathomimetic agents that activate peripheral β-adrenergic receptors. During normal bone remodeling, norepinephrine suppresses bone formation and stimulates bone resorption, an effect that is mediated by the β2-adrenergic receptors expressed by osteoblasts. Because amphetamines in- crease β-adrenergic signaling, they may exert detrimental effects on the growing skeleton. Mice with β-adrenergic receptor knockout display a high bone mass phenotype. Furthermore, mice and adults with β-adrenergic blocking have higher BMD, suggesting that β-adrenergic signaling may also affect bone remodeling and bone mass in humans [24].
The effects of stimulants on bone have not been well studied. Using the NHANES extensive data, the present study shows that use of stimulants in children and adolescents was associated with significantly lower mean lumbar spine BMD and BMC and lower femoral neck BMC and total femur BMD. Noteworthy, BMD and BMC results were adjusted according to height and BMI z-scores which are important variables in the interpretation of DXA results in children. Since childhood and adolescence are critical periods of bone accrual, the lower bone mass in stimulant users is likely to be of clinical importance as longitudinal tracking of DXA measurements indicates that skeletal status during childhood is a strong predictor of peak bone mass in young adulthood [25]. Furthermore, a 5% to 10% reduction in peak BMD (equivalent to a reduction of BMD from 0.5 to 1 SD) can substantially increase the incidence of future fractures. As the prevalence of ADHD increases and the rate of ADHD diagnoses rise, the prescriptions for stimulants dispensed for these children are also in rise. As with other long-term concerns regarding the use of stimulants, including their possible effects on cardiovascular health and the risk of inducing other psychiatric problems, the skeletal effect and future risk for fracture should be further investigated [26].

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