Increased Resting Energy Expenditure is Associated with Failure to Thrive in Infants with Severe Combined Immunodeciency

Mary A. Barron, MSc, RD, Melanie Makhija, MSc, MD, Lorrie E. M. Hagen, RD, Paul Pencharz, MD, PhD, Eyal Grunebaum, MD, and Chaim M. Roifman, MD Objectives To measure resting energy expenditure (REE) and determine whether increased REE (hypermetabolism) is associated with failure to thrive (FTT) in patients with severe combined immunodeciency (SCID) at diagnosis. Study design REE was measured in 26 patients with SCID in a single transplant center. Predicted REE was determined with World Health Organization standards. Measured REE >110% of predicted REE was classied as hypermetabolism. Other data collected included FTT status, infections, genotype, phenotype, and the feeding methods used. Results Fifteen of 26 patients (57.7%) had FTT, and 18 of 26 patients (69.2%) were hypermetabolic. Hypermetabolism occured in 14 of 15 patients (93%) with FTT, and only 4 of 11 patients (36%) without FTT had hypermetabolism (P = .003). There was a signicant difference between the measured REE (71.75 16.6 kcal/kg) and the predicted REE (52.85 2.8 kcal/kg; P < .0001). Eleven of 17 patients (65%) required nasogastric feeding, parenteral nutrition, or both to meet their energy needs. Conclusions Hypermetabolism is common in patients with SCID and may contribute to the development of FTT. The hypermetabolism in these patients may necessitate intensive nutrition support. (J Pediatr 2011;159:628-32).
evere combined immunodeciency (SCID) is a group of rare inherited diseases that present in early childhood with severe dysfunction of T and B lymphocytes.1 Patients with SCID often sustain persistent systemic infections, including pneumonia and chronic diarrhea, and inammation manifesting as Omenn syndrome.1 Failure to thrive (FTT) has been observed at diagnosis of SCID in 54% to 88% of patients.2,3 In the pediatric population, FTT is caused by inadequate energy intake, malabsorption, or increased energy needs. In patients with SCID, oropharyngeal candida and chronic gastrointestinal tract infections have been associated with poor oral feeding and malabsorption, respectively, which may lead to FTT. Improved oral intake and treatment of infections restores weight gain in some but not all patients with SCID. This suggests another cause of FTT in SCID, which may be hypermetabolism. Additionally, systemic infections and inammation may increase REE in SCID as it does in human immunodeciency virus and juvenile rheumatoid arthritis.4,5 However, patients with SCID often display fatigue and lethargy, which might decrease energy requirements.6 Predicted REE can be estimated from published data7; however, poor agreement between predicted REE and measured REE has been shown in children with chronic diseases,8,9 emphasizing the need to measure the REE in patients with SCID. We report for the rst time measured REE in a large group of patients with SCID and the association of hypermetabolism with the FTT seen in these patients. We also describe the feeding methods used to achieve the energy needs of patients with hypermetabolism and SCID.

Methods
All patients in whom SCID was diagnosed in a 13-year period from 1993 to 2006 who had indirect calorimetry (IC) performed shortly after diagnosis and before receiving a bone marrow transplant (BMT) at The Hospital for Sick Children (SickKids), were included in the study. Patients were excluded when they were treated for prolonged periods at other institutions before transfer to SickKids. Any patient From the Division of Immunology and Allergy, The who refused IC and any patient admitted directly to the pediatric or neonatal inCanadian Centre for Primary Immunodeciency, The tensive care units and subsequently undergoing transplantation in the intensive Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeciency, The Hospital for Sick Children, care unit were excluded. Also, any patient in whom SCID was diagnosed who did Toronto, Ontario, Canada (M.B., M.M., L.H., E.G., C.R.);
BMT FTT SickKids IC LAF NG PN REE SCID Bone marrow transplant Failure to thrive The Hospital for Sick Children Indirect calorimetry Laminar air ow Nasogastric Parenteral nutrition Resting energy expenditure Severe combined immunodeciency
Departments of Clinical Dietetics (M.B., L.H.) and Paediatrics (M.M., P.P., E.G., C.R.), Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Physiology and Experimental Medicine Program, Research Institute and Department of Agricultural Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada (P.P.); and University of Toronto, Toronto, Ontario, Canada (P.P., E.G., C.R.) Supported by the Canadian Centre for Primary Immunodeciency and the Jeffrey Modell Foundation. C.R. is the holder of the Donald and Audrey Campbell Chair of Immunology. The authors declare no conicts of interest.
0022-3476/$ - see front matter. Copyright 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.03.041

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Vol. 159, No. 4  October 2011 not receive a BMT was excluded. The study was approved by the Research Ethics Board at SickKids. Other information collected retrospectively from the patients medical charts and dietitians records included the clinical features at presentation, SCID genotype and phenotype, weight and length at diagnosis, weight and length history, presence of FTT, microbiology for respiratory isolates, and stool culture results at diagnosis. Nutritional data including the feeding routes used to reach the patients energy needs was also collected. All patient weights and lengths were plotted by age and sex on Tanner-Whitehouse growth charts, which were the standard curves used at SickKids at the time of the study. Data for patients with cartilage hair hypoplasia were plotted on an achondroplasia growth curve.10 FTT was dened as previously described by Zenel as either (1) both height and weight less than the third percentile or (2) weight that has crossed two or more percentiles downward compared with the height percentile.11 Additionally, any patients with documented FTT, as dened as aforementioned, with growth stunting were also deemed to have FTT. This method for dening FTT is used for patients #24 months of age, therefore we excluded any patient who was >24 months of age at diagnosis.11 IC was performed with the Deltatrac II Metabolic Monitor (Sensor Medics Co, Yorba Linda, California). REE was measured with indirect open-circuit calorimetry in the method previously described by Green et al.12 All patients were placed in laminar air ow (LAF) isolation on admission to the immunology/BMT unit, and the metabolic cart was calibrated to the air ow in each room before data collection. Calorimetry measurements were obtained by a trained research nurse on patients in the fasted state. Patients were afebrile and not receiving supplemental oxygen at the time of the measurements. All calorimetry measurements were performed after admission and before conditioning for BMT. A normal metabolic rate was dened as a measured REE within 90% to 110% of the predicted REE for age and sex. Hypermetabolism was dened as a measured REE >110% of the predicted REE for age, weight, and sex, as suggested by the standard normative data published by the World Health Organization7 on the basis of the Schoeld equations.13 Results are expressed as means plus or minus SD. Statistical tests, including descriptive statistics, c2, Fisher exact, paired t test, Bland and Altman analysis, Pearson correlation, and logistic regression, were performed with Excel (Microsoft Inc, Redmond, Washington) and SAS softwares (SAS Institutes Inc, Cary, North Carolina). extensively treated at other centers, one patient whose guardians refused IC, and one patient for whom the IC results were unavailable. Four patients were >24 months at diagnosis and therefore were excluded. Of the 26 study patients, there were 20 male patients (77%) and 6 female patients (23%). Most patients were >3 months of age at diagnosis (mean, 4.7 months; SD, 3.1 months; range, 0 to 10 months), and SCID was diagnosed in 4 patients at birth on the basis of family history. Patient data is outlined in the Table. Failure to Thrive and Hypermetabolism Fifteen of 26 patients (58%) met the criteria for FTT; 9 of 15 patients (60%) had a descrepancy of two or more percentiles between their weight and height; 5 of 15 patients (33%) had both weight and height less than the third percentile, and 1 patient (7%) presented to HSC with growth stunting and documented FTT. Eighteen of 26 patients (69%) in the study were hypermetabolic. There was a signicant difference between the mean measured REE (71.75 16.6 kcal/kg/day) compared with the mean predicted REE (52.85 2.8 kcal/ kg/day), a difference of 18.9 16.7 kcal/kg/day (P < .0001, paired t test). The predicted REE was unable to accurately estimate measured REE (r = 0.03, Pearson correlation; Figure 1; available at www.jpeds.com). With the Bland and Altman analysis, a poor agreement between the measured REE and the predicted equations was shown (Figure 2; available at www.jpeds.com). The measured REE ranged from 66% to 196% of the predicted REE (mean, 136%; SD, 32.5). Measured REE was reduced in two patients, within reference range in 6 patients, and increased in 18 patients. We found that there was a signicantly positive association between FTT and hypermetabolism. Fourteen of 15 patients (93%) with FTT had hypermetabolism, compared with only 4 of 11 patients (36%) without FTT who had hypermetabolism (P = .003, Fisher exact test). The odds of hypermetabolism in FTT in this study was 24.5x times (95% CI, 2.3 to 262.5; P = .0019, c2). One of 4 patients in whom SCID was diagnosed at birth had hypermetabolism, and none of them had FTT. Hypermetabolism was signicantly more common in infants 3 to 12 months old, in 17 of 20 patients (85%) compared with 1 of 6 patients <3 months of age (P = .005, Fisher exact). The most common genetic mutation was IL2Rg, and hypermetabolism occurred in 7 of 9 (78%) of these patients (Table). Nutrition The mean weight of our patients was 6.27 kg (SD, 1.8 kg; range, 3.45 to 13.00 kg). Nutrition data was available for 17 of 18 patients who were hypermetabolic. For the 17 patients to meet their energy needs, it took a mean of 25 days (range, 0 to 82 days) by using a variety of nutrition support modalities. Six of 17 patients (35%) met their needs via the oral route with increased energy infant formula; 9 of 17 patients (53%) needed parenteral nutrition (PN); 4 of 17 patients (24%) needed nasogastric (NG) feeding, and 2 of the 4
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Results
Of the 38 patients in whom SCID was diagnosed and who underwent transplantation at SickKids in the 13-year period, 26 met the study criteria. Excluded were 3 patients who underwent transplantation in the intensive care unit, 3 patients

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Table. Patient features

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Vol. 159, No. 4 Clostridium difcile (1), and mixed isolates (4; Clostridium difcile and adenovirus, Clostridium difcile and rotavirus, Escherichia coli and rotavirus, and Staphylococcus aureus and polio virus). Diarrhea was signicantly more likely in patients with FTT than in patients without FTT (P = .03, Fisher exact). The odds of diarrhea in our patients with FTT as compared with patients who did not have FTT was 7.8 times (95% CI, 1.2 to 52.4; P = .02, c2). Pneumonia Fifteen of 26 patients (57.7%) had pneumonia, and 13 of 15 patients had positive respiratory culture results. The respiratory isolates were Pneumocystis jirovecii (6), Moraxella catarrhalis (2), parainuenza 3 (2), and respiratory syncytial virus (1). Multiple isolates were found in two patients by using bronchoalveolar lavage (Mycoplasma pneumoniae and coagulase-negative Staphylococcus, and Streptococcus viridans and coagulase-negative Staphylococcus). Every patient with Pneumocystis jirovecii had hypermetabolism and FTT (6/6). There was a non-signicant association between pneumonia and FTT (P = .10, Fisher exact). The odds of pneumonia in patients with FTT was 4.8 times (95% CI, 0.9 to 25.8; P = .06, c2). Infection Twenty-three of 26 patients (88.4%) had any type of infection (respiratory, positive stool culture results with diarrhea, urinary tract infection, otitis media, and/or thrush), and 18 of the 23 patients (78.2%) had FTT. Of the 3 patients without any infection, none had FTT. There is a signicant association between infection and FTT (P = .02, Fisher exact). The OR could not be calculated with this sample. We performed logistic regression to determine the probability of FTT by using the measured REE expressed as a percentage of the predicted REE. The regression was adjusted for diarrhea and pneumonia individually and then for both (Figure 3). There is an increased probability of FTT when hypermetabolism is present, independent of diarrhea and pneumonia. When diarrhea is present, the probability of FTT is further increased, independent of pneumonia. With an elevated measured REE (125% predicted REE), the probability of FTT is >75% when diarrhea is also present.

FTT Hypermetabolic n = 26 (%) n = 15 (%) n = 18 (%) Age range <3 months $3-12 months Immunotype T+ SCID T- SCID Genetic defect IL2Rg ADA deciency Omenn Syndrome IL7 Ra RMRP CD3d RAG2 deciency Not determined Nutrition FTT Hypermetabolic Presenting features Diarrhea Pneumonia Oral/esophageal candidiasis Fever Any infection 6 (23.1) 20 (76.9) 6 (23.1) 20 (76.9) 9 (34.6) 4 (15.4) 3 (11.5) 2 (7.7) 2 (7.7) 2 (7.7) 1 (3.9) 3 (11.5) 15 (57.7) 18 (69.2) 18 (69.2) 15 (57.7) 10 (38.4) 9 (34.6) 23 (88.4) 0 15 (100) 5 (33.3) 10 (66.6) 6 (40) 3 (20) 1 (6.7) 1 (6.7) 1 (6.7) 0 0 3 (20) 1 (5.5) 17 (94.5) 5 (27.8) 13 (72.2) 7 (38.9) 3 (16.7) 1 (5.5) 1 (5.5) 2 (11.1) 0 1 (5.5) 3 (16.7)

patients who were NG fed also required PN. All patients with normal metabolic rates were fed via the oral route; none required NG feeding or PN. Diarrhea Eighteen of 26 patients (69.2%) had diarrhea, and 14 of 18 patients had positive stool isolates for viruses. One patient did not have diarrhea clinically, but had positive stool isolates. Of these 15 patients, the cultures were rotavirus (5), torovirus (3), adenovirus (1), norwalk-like virus (1),
1

Probabili of failure to thrive ity o

0.8

0.6

0.4

0.2

Discussion
60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 Measured REE as percent predicted REE

Figure 3. Probability of FIT relative to measured REE. A logistic regression analysis of the probability to have FTT relative to the measured REE expressed as a percentage of the predicted REE in patients with SCID that had: pneumonia (- -A- -), diarrhea ($$$-$$$), pneumonia and diarrhea (:), or no diarrhea or pneumonia (-$$-).
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In this study, we measured REE at diagnosis with the goal of using this quantitative measurement tool to improve the nutritional status of infants with SCID before transplantation. This was done because several studies have shown that significantly reduced weight and poor nutrition, before BMT, negatively affect outcome.14-16 We show that patients with SCID with the most signicant weight loss also had the highest metabolic rates (181%, 182%, and 196% predicted REE). These results demonstrate that unlike infants with human immunodeciency virus
Barron et al

October 2011 infections,6,17-19 patients with SCID fail to adapt to weight loss, which likely adds to the malnourished state in this condition. Most patients in our study who had FTT were also hypermetabolic. Patients in our study who received a diagnosis between 3 to 12 months of age were more likely to be hypermetabolic than patients who received a diagnosis at birth. Of the 4 infants who received a diagnosis at birth, only 1 patient had an increase in their REE. The REE measurement occurred at 49 days of age, which may have been enough time to grow viridans streptococcus and coagulasenegative staphylococcus from respiratory isolates and to become positive for torovirus in the stool. The patient did not have FTT at birth or when the REE was measured, but without LAF isolation, prophylactic antibiotics, and appropriate calorie input, the FTT might have been developed. Twelve of the 18 patients (67%) who had diarrhea at diagnosis also had hypermetabolism and FTT. These patients required more energy per day, but likely had malabsorption of fat and other components of the infant formula they were consuming. The simple method of changing to an elemental or semi-elemental formula for these infants would not necessarily result in weight gain because the daily energy needs of 67% of the infants with diarrhea was still far greater than the normal daily requirements. It is likely that diarrhea from chronic gastrointestinal infections and the increased metabolic rate contributed to the development of FTT, as suggested by the regression analysis. When the measured REE was at 100% predicted REE (normal metabolic rate) with no diarrhea and no pneumonia, there was zero probability of FTT. In the presence of diarrhea, with or without pneumonia, the probability of FTT increased to >75% when the measured REE was at 125% predicted REE. At a very high measured REE, $150% predicted REE, there is almost a 100% risk of FTT when diarrhea is present, independent of pneumonia. Only one-third of patients in our study with hypermetabolism were able to meet their increased metabolic needs via the oral route alone. To achieve their increased energy needs orally, the infant formula was concentrated to provide more energy per milliliter (0.8 to 1.0 kcal/mL) than standard infant formula (0.67 kcal/mL). To provide sufcient energy to meet the increased metabolic demand, the remaining two-third of the patients with hypermetabolism required more invasive modes of nutrition support including NG tube feeding and PN via central venous access in the pre-transplant period. The measured REE was helpful to determine the energy needs of these malnourished infants with SCID in the pre-BMT period. The objective measured REE was particularly important considering the poor agreement we found between the predictive equations and the measured REE, unlike infants and children with human immunodeciency virus.18 It is important to have an accurate estimate of the daily energy requirement to provide optimal nutrition while using minimally invasive measures to achieve this goal. In the cases of extreme hypermetabolism, as shown in our study, all 3 modes of nu-

ORIGINAL ARTICLES
trition support (oral, NG, and PN) were needed simultaneously to provide sufcient energy. We conclude that hypermetabolism may be responsible at least in part for the FTT seen in patients with SCID at diagnosis. Measuring REE proved useful in planning adequate energy goals for this patient population. Whether improvement of the nutritional status in patients with SCID before BMT results in decreased morbidity and mortality postBMT remains to be studied. n
The authors would like to thank all the families who participated in the study, Brenda Reid, immunology advanced practice nurse, and all the nurses in the immunology/BMT isolation unit who provided outstanding care to our patients.
Submitted for publication Dec 7, 2010; last revision received Feb 16, 2011; accepted Mar 21, 2011. Reprint requests: Chaim M. Roifman, MD, 555 University Ave, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada. E-mail: chaim.roifman@ sickkids.ca

References
1. Notarangelo LD. Primary immunodeciencies. J Allergy Clin Immunol 2010;125:S182-94. 2. Hague RA, Rassam S, Morgan G, Cant AJ. Early diagnosis of severe combined immunodeciency syndrome. Arch Dis Child 1994;70: 260-3. 3. Yee A, De Ravin SS, Elliott E, Ziegler JB. Severe combined immunodeciency: a national surveillance study. Pediatr Allergy Immunol 2008;19: 298-302. 4. Sharpstone DR, Ross HM, Gazzard BG. The metabolic response to opportunistic infections in AIDS. AIDS 1996;10:1529-33. 5. Knops N, Wulffraat N, Lodder S, Houwen R, de Meer K. Resting energy expenditure and nutritional status in children with juvenile rheumatoid arthritis. J Rheumatol 1999;26:2039-43. 6. Macallan DC, Noble C, Baldwin C, Jebb SA, Prentice AM, Coward WA, et al. Energy expenditure and wasting in human immunodeciency virus infection. N Engl J Med 1995;333:83-8. 7. FAO/WHO/UNU. Energy and protein requirements. Report of a joint FAO/WHO/UNU Expert Consultation. World Health Organ Tech Rep Ser 1985;724:1-206. 8. Shakur Y, Richards H, Pencharz PB. Is it necessary to measure resting energy expenditure in clinical practice in children? J Pediatr 2008;152: 437-9. 9. Sentongo TA, Tershakovec AM, Mascarenhas MR, Watson MH, Stallings VA. Resting energy expenditure and prediction equations in young children with failure to thrive. J Pediatr 2000; 136:345-50. 10. Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall JG. Standard growth curves for Achondroplasia. J Pediatr 1978;93:435-8. 11. Zenel JA, Jr. Failure to thrive: a general pediatricians perspective. Pediatr Rev 1997;18:371-8. 12. Green GJ, Weitzman SS, Pencharz PB. Resting energy expenditure in children newly diagnosed with stage IV neuroblastoma. Pediatr Res 2008;63:332-6. 13. Schoeld WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 1985;39:5-41. 14. Bulley S, Gassas A, Dupuis LL, Aplenc R, Beyene J, Greenberg ML, et al. Inferior outcomes for overweight children undergoing allogeneic stem cell transplantation. Br J Haematol 2008;140:214-7. 15. Dickson TM, Kusnierz-Glaz CR, Blume KG, Negrin RS, Hu WW, Shizuru JA, et al. Impact of admission body weight and chemotherapy dose adjustment on the outcome of autologous bone marrow transplantation. Biol Blood Marrow Transplant 1999;5:299-305. 631

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18. Alfaro MP, Seigel RM, Baker RC, Heubi JE. Resting energy expenditure and body composition in pediatric HIV infection. Pediatr AIDS HIV Infect 1995;6:276-80. 19. Arpadi SM, Cuff PA, Kotler DP, Wang J, Bamji M, Lange M, et al. Growth velocity, fat-free mass and energy intake are inversely related to viral load in HIV-infected children. J Nutr 2000;130:2498-502.

16. Lange BJ, Gerbing RB, Feusner J, Skolnik J, Sacks N, Smith FO, et al. Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 2005;293:203-11. 17. Schwenk A, Hffer-Belitz E, Jung B, Kremer G, Brger B, Salzberger B, o u et al. Resting energy expenditure, weight loss, and altered body composition in HIV infection. Nutrition 1996;12:595-601.

50 Years Ago in THE JOURNAL OF PEDIATRICS Achalasia in Children as a Cause of Recurrent Pulmonary Disease
Schultz EH. J Pediatr 1961;59:522-8.

ifty years ago, Schultz reported the association between achalasia and recurrent pulmonary disease. Although there have been major advances in the understanding of its pathophysiology and diagnosis in the last 50 years, the clinical presentation remains the same, and the treatment options he described continue to be the mainstay of therapy, but they have become more sophisticated.1,2 The hallmark of achalasia consists in a lack of esophageal peristalsis and incomplete relaxation of the lower esophageal sphincter, which result from a lack of postganglionic neurons that release nitric oxide and vasoactive intestinal polypeptide,2 and not because of parasympathetic dysfunction as proposed by Schultz. Today the diagnosis is made with esophageal manometry, not radiologic studies.1,2 The advent of high-resolution manometry, which is easier to perform and provides a better assessment of esophageal function, is a major recent technical advancement.2 Like 50 years ago, we still do not have a specic therapy. The treatment continues to be non-specic and aims to relieve the functional obstruction.1,2 As was described then, the two main treatment modalities include esophageal pneumatic dilatation and surgical esophagomyotomy.1,2 The technique for pneumatic dilatation has not changed, but there has been improvement in the balloons used, making it safer. The long-term response rate to dilatation has been described as 50%, although at times multiple dilatations are needed.1,2 With the advent of minimally invasive surgery, esophagomyotomy now results in shorter patient hospital stays, reduced morbidity, a quick return to activities, and a 90% long-term success rate.2 Treated patients continue to have long-term dysphagia and gastroesophageal reux.2 Therefore, although future years will certainly see improvement in the treatment and diagnosis, the prognosis of patients with achalasia will continue to be the same until we have a specic treatment. Samuel Nurko, MD Center for Motility and Functional Gastrointestinal Disorders Childrens Hospital Boston, Massachusetts
10.1016/j.jpeds.2011.05.049

References
1. Hussain SZ, Thomas R, Tolia V. A review of achalasia in 33 children. Dig Dis Sci 2002;47:2538-43. 2. Rosen R, Nurko S. The Esophagus: motor disorders. In: Walker A, et al., eds. Pediatric gastrointestinal disease. 4th ed. Philadelphia: Decker; 2004. p. 424-62.

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ORIGINAL ARTICLES

Figure 1. Pearson correlation of measured REE and predicted REE. Measured resting energy expenditure (MREE) expressed as kcal/kg/day compared with the predicted resting energy expenditure (PREE) expressed as kcal/kg/day in 26 patients with SCID at diagnosis. REE was measured with indirect open-circuit calorimetry, and predicted REE was calculated by using the patients age, weight, sex, World Health Organization data and Schoeld equations (r = 0.03; P = .8).

Figure 2. Bland and Altman analysis of measured REE and predicted REE. The mean of the measured resting energy expenditure (MREE) and predicted resting energy expenditure (PREE) was compared with the difference in the two measurements. Top line and diamond points represent the upper 95th percentile condence limit for the mean difference between measured REE and predicted REE. Bottom line and square points represent the lower 95th percentile condence limit for the mean difference between measured REE and predicted REE. The middle line with triangle points represent the difference between the measured REE and predicted REE. Increased Resting Energy Expenditure is Associated with Failure to Thrive in Infants with Severe Combined Immunodeciency
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