Nutritional challenges in children with primary immunodeficiencies undergoing hematopoietic stem cell transplant

Journal Pre-proof Nutritional Challenges in Children with Primary Immunodeficiencies Undergoing Hematopoietic Stem Cell Transplant Boutaina Zemrani, Jason K. Yap, Ben Van Dort, Victoria Evans, Jodie Bartle, Danielle Shandley, Joanne Smart, Julie E. Bines, Theresa Cole PII:

S0261-5614(19)33201-7

DOI:

https://doi.org/10.1016/j.clnu.2019.12.015

Reference:

YCLNU 4111

To appear in:

Clinical Nutrition

Received Date: 4 September 2019 Revised Date:

8 November 2019

Accepted Date: 10 December 2019

Please cite this article as: Zemrani B, Yap JK, Van Dort B, Evans V, Bartle J, Shandley D, Smart J, Bines JE, Cole T, Nutritional Challenges in Children with Primary Immunodeficiencies Undergoing Hematopoietic Stem Cell Transplant Clinical Nutrition, https://doi.org/10.1016/j.clnu.2019.12.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

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Nutritional Challenges in Children with Primary Immunodeficiencies

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Undergoing Hematopoietic Stem Cell Transplant

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Boutaina Zemrani a,b,*, Jason K Yap a, Ben Van Dort c, Victoria Evans a, Jodie Bartle d, Danielle Shandley d, Joanne Smart c, Julie E Bines a, Theresa Cole c

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Clinical Nutrition Unit, Department of Gastroenterology and Clinical Nutrition, The Royal Children’s Hospital, Melbourne, Australia

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b

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c

Department of Allergy and Immunology, The Royal Children’s Hospital, Melbourne, Australia

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d

Clinical Nutrition Unit, Lausanne University Hospital (CHUV), Lausanne, Switzerland

Department of Nutrition and Food Services, The Royal Children’s Hospital, Melbourne, Australia

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Corresponding Author:

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Boutaina Zemrani 1, Clinical Nutrition unit, Department of Gastroenterology and Clinical

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Nutrition, The Royal Children’s Hospital, Melbourne, 50 Flemington road, Parkville, VIC

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3052, Australia.

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Email : [email protected], phone : +61 93457032

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1

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Switzerland. Rue du Bugnon 46, 1005 Lausanne, Switzerland.

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Present address: Clinical Nutrition Unit, Lausanne University Hospital (CHUV), Lausanne,

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SUMMARY

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Nutritional profile and management of patients with primary immunodeficiencies

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(PID) undergoing hematopoietic stem cell transplant (HSCT) has not been described in the

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literature. We aim to report the nutritional challenges and practices peculiar to this population

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before and after HSCT and suggest clinical pathways for their management.

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We conducted a single-centre retrospective study. Inclusion criteria were children

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aged less than 20 years with a diagnosis of PID who have undergone HSCT at the Royal

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Children’s Hospital Melbourne since April 2014 with a minimal follow-up of 1 year. Nutritional

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parameters were collected in the pre-transplant period, at conditioning, and at 1, 3, 6 and 12

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months post-HSCT. Descriptive analysis were used.

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Between April 2014 and December 2018, 27 children received 31 HSCT. Before

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transplant, 33% had weight and/or height z-scores ≤ -2 standard deviation (SD). Forty

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percent required nutritional support before transplant: 33% had enteral nutrition (EN) while

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7% required long-term parenteral nutrition (PN) due to intestinal failure. After transplant,

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although most children were started on EN, 82% required PN with a mean duration of 67

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days. Mean time to full oral diet was 154 days. Pre-transplant mean weight and height z-

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scores were -0.57 and -0.88 respectively. After a decrease in anthropometric parameters the

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first 3 months post-transplant, progressive catch up was noticeable for weight (-0.27) with no

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catch up for height at 1 year (-0.93).

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Our work highlights the nutritional challenges and specificities of children with PID in

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the peri-transplant period. An approach to nutrition assessment and management in the pre-

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and post-transplant period is proposed.

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Keywords: Primary immunodeficiencies, Children, Transplant, Nutrition

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Abbreviations: HSCT, hematopoietic stem cell transplant; PID, immunodeficiencies; Treg, regulatory T cells; RCH, Royal Children’s Hospital.

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primary

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1. INTRODUCTION

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Primary immunodeficiencies (PID) are an umbrella term comprising a heterogenous group of

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nearly 400 disorders involving impairment of the adaptive and innate immune system[1].

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Allogeneic hematopoietic stem cell transplant (HSCT) is the only potentially curative option

62

for many PID that are otherwise lethal[2,3].

63

The phenotype of PID includes a broad spectrum of autoinflammatory, autoimmune, and

64

immunodeficient features where malnutrition is a frequent finding[4,5]. Malnutrition can be a

65

presenting symptom leading to diagnosis or can occur during follow up of PID. The

66

gastrointestinal (GI) tract is the largest immune organ and up to 50% of PID include GI

67

manifestations[2,5,6]. The nature and extent of GI and nutritional involvement are variable

68

according to the underlying disease, ranging from minor to severe symptoms including

69

intestinal failure requiring parenteral nutrition (PN). The GI immune system is mainly

70

regulated by T lymphocytes, specifically regulatory T cells (Treg) which play a critical role in

71

maintaining tolerance to non-pathogenic antigens such as dietary proteins[2,5].

72

Nutritional status prior to transplant can affect outcomes after HSCT[7-13]. Unlike other

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factors influencing transplant-related morbidity and mortality in PID, such as age, diagnosis

74

and comorbidities, malnutrition can be addressed.

75

Although nutrition management is a challenging task during HSCT, pediatric specific

76

guidelines do not exist. Moreover, nutrition studies conducted exclusively in HSCT recipients

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with PID are lacking. Limited HSCT studies on malignancies included a small number of

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children with non-malignant diseases[14-18] where PID were sometimes included[16,17].

79

Pediatric HSCT studies mainly assessed either EN feasibility[14,16,17,19] or short-term

80

outcomes related to EN versus PN use[15,18,20]. The heterogeneity of patient groups and

81

variability of parameters and outcomes used to measure the need and efficacy of EN or PN,

82

make it difficult to draw conclusions. PID are different from other diseases leading to HSCT

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due to the underlying immune GI involvement, pre-transplant therapies and comorbidities.

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Therefore, post-HSCT nutritional management may differ from non-PID patients.

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Our goal is to examine the nutritional profile of a cohort of patients with PID who underwent

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HSCT at a tertiary centre and develop suggestions for pre- and post-transplant nutritional

87

management based on our data and insights from the literature.

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2. MATERIALS AND METHODS

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Patient selection

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We conducted a retrospective chart review for all patients (<20 years) diagnosed with PID

91

who have undergone a HSCT at the Royal Children’s Hospital (RCH) in Melbourne from

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April 2014 onwards with a follow-up period of at least 1 year. Inpatient and outpatient

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records were reviewed for the collection of medical and nutritional data. This study was

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approved by the Human Research Ethics Committee of RCH (RCHM-2018-153782).

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Transplant procedure (described in a supplementary material)

96

Nutritional support

97

Oral intake was offered ad libitum using a low bacterial diet after transplant. Enteral nutrition

98

(EN) was started when a nasogastric tube (NGT) was inserted which occurred electively on

99

day -1 or day 0, if not needed before, to ensure energy requirements were met. EN was

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commenced continuously with isocaloric feeds (0.7 kcal/ml for infants and 1 kcal/ml for

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children >1 year), lactose-free and fibre-free. NGT dislodged before engraftment were not

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replaced until the patient had engrafted as per unit protocol. The rate of EN was titrated to

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energy needs and GI tolerance. When EN provided <50% of estimated energy requirements

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for 3 consecutive days, PN was commenced and EN was temporarily stopped or maintained

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according to tolerance. PN was cycled (administered over <24 hours/day) in stable patients.

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Children received standardized PN bags compounded by hospital pharmacy, comprising

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protein, glucose and micronutrients in accordance with PN recommendations[21]. Lipid

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emulsions used before 2015 were olive oil-based (olive oil 80%, soybean oil 20%). From

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2015, a composite 3rd generation lipid emulsion was used (fish oil 15%, olive oil 25%,

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soybean oil 30% and medium chain-triglycerides 30%). Lipid emulsions were not

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administered when triglyceride levels were >3-4mmol/L or in cases of fungal sepsis. PN was

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discontinued when oral or enteral intake exceeded 50-75% of requirements.

114

Until September 2017, energy requirements were calculated using Schofield equation[22] for

115

basal metabolic rate (BMR) corrected with a 1.4 factor, and Nutrient Reference Values[23]

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for children under 3 years of age. From October 2017, following an update in our nutrition

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protocol, only 100% of BMR was used during the first 30 days post-HSCT; a 1.2 to 1.4 factor

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was added after day 30. Protein requirements were calculated in accordance with PN

119

guidelines[21].

120

Data on the type, time of initiation, duration and indications of nutritional support received

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before and after transplant were collected.

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Nutritional assessment

123

Weight, height and weight-for-length (<2 years of age) or body mass index (BMI) (≥2 years

124

of age) z-scores were collected at the start of conditioning regimen, then at 1, 3, 6 and 12

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months post-transplant. Anthropometric measures of children with faltering growth were also

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recorded prior to nutritional rehabilitation. The results were plotted on World Health

127

Organization (WHO) growth charts for children <2 years of age and on Centers for Disease

128

Control growth charts for children ≥2 years of age. A normal nutritional status was defined as

129

a z-score between -2 and + 2 standard deviation (SD) as per WHO recommendations[24].

130

Laboratory data collected include serum albumin level at the start of conditioning and at

131

discharge and abnormal glucose (≤ 3 mmol/l or ≥ 10 mmol/l) and triglycerides levels (≥ 4

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mmol/l) during admission. Micronutrient assessment was investigated before and after

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transplant.

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Methods of Literature search

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A literature search was conducted in PubMed up to July 2019 using the following keywords:

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primary immunodeficiencies, hematopoietic stem cell transplant (or bone marrow transplant)

137

and nutrition. Given the scarcity of nutrition-related results, a second literature search was

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conducted using the keywords: hematopoietic stem cell transplant (or bone marrow

139

transplant), nutrition and children. Additional citations were hand-searched. Relevant papers

140

were selected to provide an overview of the topic.

141

Statistical analysis

142

Categorical variables were expressed by frequencies and percentages. Results regarding

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continuous variables were presented using the mean in case of normal distribution and the

144

median otherwise. Normality of the distribution was checked graphically.

145

146

3. RESULTS

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General patients’ characteristics

148

Between April 2014 and December 2018, 27 children with PID received an allogeneic HSCT

149

at RCH with a total of 31 transplants. Patients’ characteristics and transplant modalities are

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reported in table 1.

151 152 153 154

155 156

Table 1. General characteristics of patients and transplant data Characteristic Number of patients

Value 27

Gender, Male, n (%) Diagnosis CGD SCID WAS HLH CD40 ligand deficiency Stat 1 loss of function Shwachman-Diamond syndrome CTLA4 mutation Stat 3 gain of function XIAP deficiency Dock 8 deficiency Undefined combined immunodeficiency Age at diagnosis, years Mean (range) Median Age at first transplant, years Mean (range) Median < 1 year, n (%) Number of transplants, n (%) 1 2 3 Donor match status, n = 31, n (%) Matched related Matched unrelated Haploidentical Stem cell source, n= 31, n (%) Bone marrow Peripheral blood Umbilical cord

20 (74)

Conditioning regimen, n = 31, n (%) Treo, Flu +/- TT MAC Bu, Flu +/- TT RIC Bu, Flu +/- TT Flu, Mel +/-TT Flu, Mel, TBI GVHD prophylaxis, n = 31, n (%) Cyclosporine alone MMF alone Cyclosporine, MMF Cyclosporine, MMF, Cyclophosphamide MMF and tacrolimus Serotherapy Anti-thymocyte globulin Alemtuzumab Engraftment

6 (22) 4 (15) 3 (11) 3 (11) 2 (7) 2 (7) 2 (7) 1 (4) 1 (4) 1 (4) 1 (4) 1 (4) 2.7 (0-15.4) 1 6 (0.2-17.2) 4 6 (22) 31 (100%) 24 (89) 2 (7) 1 (4) 3 (10) 16 (52) 12 (38) 4 (13) 26 (84) 1 (3) 18 (58) 4 (13) 6 (20) 2 (6) 1 (3) 5 (16) 9 (29) 15 (49) 1 (3) 1 (3) 30 (97) 12/30 18/30

Neutrophil, day, median (range) Platelet, day, median (range) Mucositis, n (%)

11 (8-21) 18 (11-41) 24 (89)

Acute GVHD, n = 31, n (%) Grade II III-IV Localisation Gut Liver Skin Chronic GVHD, n = 31, n (%) Grade I-II Skin Veno- occlusive disease, n = 31, n (%)

7 (22)

4/7 1/7 5/7 2 (6) 2/2 2/2 4 (13)

Survival at 1 year, n (%) Survival at last follow-up, n (%) Follow up period, years, median (range)

24 (89) 24 (89) 2.5 (1- 4.2)

Length of pre-transplant hospital stay, days Mean (range) Median Length of post-transplant hospital stay, days Mean (range) Median Steroids exposure, n (%) Pre-transplant Post-transplant Pre- and post-transplant

6 (19) 1 (3)

35.7 (7-364) 10 73 (24-228) 43 21 (78) 4 (15) 6 (22) 11 (41)

157 158 159 160 161 162 163

Bu: Busulfan; CGD: chronic granulomatous disease; Flu: Fludarabin, HLH: hemophagocytic lymphohistiocytosis; IPEX: Immune dysregulation, polyendocrinopathy, enteropathy X-linked; Mel: Melphalan; SCID: severe combined immunodeficiency; MAC: myeloablative conditioning; MMF: Mycophenolate mofetil; RIC: reduced intensity conditioning; TBI: total body irradiation; TT: Thiotepa; Treo: Treosulfan; WAS: Wiskott-Aldrich; XIAP: X-linked inhibitor of apoptosis

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Pre-transplant

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The median age of PID diagnosis was 1 year, the median age at first transplant was 4 years.

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The optimal timing for transplant was determined by patient’s characteristics. Half of the

167

patients had a pre-transplant hospital stay >10 days, and 37% were inpatients >20 days

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before transplant, mainly due to infectious, autoimmune complications or need for inpatient

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nutritional rehabilitation. One patient requiring prolonged PN support due to intestinal failure

170

remained in hospital for 1 year prior to transplant.

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Main presenting symptoms and complications are shown in table 2. One third of patients had

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chronic or intermittent diarrhea, and a third had faltering growth, some without diarrhea.

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Table 3 summarizes the features of children with nutritional or GI symptoms. The

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predominant PID with GI and nutritional involvement were T-cell deficiencies, combined

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immunodeficiencies and phagocytic disorders.

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Table 2. Main presentations and complications in children with PID before and after HSCT Pre-HSCT, n = 27 • Systemic infections Bacterial Viral • Gastro-intestinal manifestations Chronic or intermittent diarrhea Faltering growth Intestinal failure requiring long-term parenteral nutrition Pancreatic insufficiency Hepatic manifestations (granulomas, infectious or auto-immune hepatitis, VODI) • Recurrent or fungal respiratory infections • Cutaneous symptoms (recurrent skin or soft tissue infections, eczema) • Neurological signs (ataxia, facial palsy, benign intracranial hypertension) • Other Post-HSCT, n = 31

178 179 180 181 182 183 184 185 186 187 188

CMV reactivation Other viral reactivations (Adenovirus, HHV6, EBV) Infectious enteritis (Adenovirus, Rotavirus, Norovirus, Clostridium diff.) Bacteraemia Fungal infections

n (%) 5 (19) 4 (15) 9 (33) 9 (33) 2 (7) 2 (7) 7 (26) 15 (56) 11 (41) 3 (11) 4 (15) n (%) 11 (35) 7 (23) 11 (35) 10 (32) 2 (6)

CMV: cytomegalovirus; EBV: Epstein Barr Virus; HHV6: human herpes virus 6; HSCT: Hematopoietic stem cell transplant; VODI: Hepatic veno-occlusive disease with immunodeficiency; PID: primary immunodeficiency

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Table 3. Characteristics of children with PID presenting with nutritional or gastrointestinal symptoms

Patient number

Diagnosis

Nutritional and Gastro-intestinal symptoms pre-transplant Intermittent diarrhea, abdominal pain Weight: 1.9 SD Height: 1.2 SD

Gastro-intestinal investigations

1

XIAP deficiency

2

Stat 3 gain of function

Severe chronic secretory diarrhea, Faltering growth Weight: -2 SD Height: -1.15 SD

Severe villous atrophy consistent with AI enteropathy, IF negative for anti-enterocyte antibodies, normal colon. Portal fibrosis and inflammation

Prolonged parenteral nutrition support

3

ShwachmanDiamond syndrome

Diarrhea, Faltering growth Weight: -2 SD Height: -1.16 SD

Low pancreatic elastase Normal GI histology Low FSV levels

EN, Pancreatic enzymes, FSV supplements

4

Stat 1 loss of function

Intermittent diarrhea Weight: 1.2 SD Height: -0.3 SD

Non-necrotizing granulomatous inflammation in ileum; normal colon

5

X-linked chronic granulomatous disease

Multiple small granulomas in small and large bowel

6

Severe combined immune deficiency, RAG type ShwachmanDiamond syndrome

Intermittent diarrhea Faltering growth Weight: -2.69 SD Height: -2.72 SD No diarrhea Faltering growth Weight: -3.89 SD Height: -1.84 SD Diarrhea, Faltering growthb Weight: -1.62 SD Height: -1.83 SD

Autosomal recessive chronic granulomatous disease

Intermittent diarrhea Weight: -0.4 SD Height: -1.1 SD

Undefined combined immunodeficiency CTLA4 mutation

Intermittent diarrhea Weight: 0.9 SD Height: -1.15 SD Chronic diarrhea, Faltering growth Weight: -4.02 SD Height: -4.26 SD

Focal shortening of villi, mild focal inflammatory process in small bowel and colon. High calprotectin and high ASCA (IBD-like presentation) Mild inflammation in ileum and colon with moderate prominence of eosinophils Severe villous atrophy consistent with AI enteropathy, inflamed colon, IF negative for anti-enterocyte antibodies, Portal inflammation, steatosis

Severe combined immune deficiency, Reticular Dysgenesis Autosomal recessive chronic granulomatous disease X-linked chronic granulomatous disease

No diarrhea Faltering growth Weight: -2.12 SD Height: -0.91 SD

7

8

9

10

11

12

13

191

No diarrhea Faltering growth Weight: -2.05 SD Height: -1.75 SD No diarrhea Faltering growth Weight: -1.9 SD Height: -2.05 SD

Normal small bowel histology, lactase deficiency, mild eosinophilic oesophagitis

Nutritional support pretransplant Lactose-free oral diet

none

EN

EN No investigations (prompt transplant after diagnosis) Low pancreatic elastase Normal GI histology Low FSV levels

EN, Pancreatic enzymes, FSV supplements none

none Prolonged parenteral nutrition support

No investigations (prompt transplant after diagnosis)

EN

No investigations as no GI symptoms

None

No investigations as no GI symptoms

None; improved oral intake after treatment of infections

Gastro-intestinal and Nutritional outcomes post-transplant Normal GI histology, normal lactase, but diarrhea only resolved 2 years after HSCT. Weighta: 0.7 SD Height: 1.17 SD Normal GI histology 4 months post-transplant, but patient remained PN-dependent due to persistent diarrhoea; normal pancreatic elastase; Death 9 months after 2nd transplant Weight: -0.6 SD Height: -1.84 SD No GI symptoms. Persistent low pancreatic elastase Normal GI histology Weight: -1.34 SD Height: -1.07 SD No GI symptoms Normal GI histology Weight: 0.7 SD Height: -0.8 SD No GI symptoms Histology not performed Weight: -2.17 SD Height: -2.6 SD No GI symptoms Weight: -0.36 SD Height: -1.4 SD No GI symptoms Normal pancreatic elastase Normal GI histology Weight: -1.17 SD Height: -2.02 SD No GI symptoms Weight: -0.14 SD Height: -0.77 SD

No GI symptoms Weight: -0.3 SD Height: -1.3 SD Normal histology 4 months post-transplant, weaned from PN 6 months after transplant Weight: -2.18 SD Height: -2.81 SD No GI symptoms Weight: 0 SD Height: -0.6 SD No GI symptoms Weight: -1.2 SD Height: -1.16 SD Good weight gain prior to HSCT (-0.7 SD). Weight loss post-HSCT despite PN support (-1.42 SD). Death 2 months post 2nd transplant

192 193 194

AI enteropathy: auto-immune enteropathy; ASCA: anti-Saccharomyces cerevisiae antibodies; IBD: inflammatory bowel disease; IF: immunofluorescence; EN: enteral nutrition, FSV: fat-soluble vitamins; GI: gastro-intestinal; PN: parenteral nutrition; SD: standard deviation

195

a

Weight/Height at 12 months post-HSCT or the last value available for deceased patients.

196

b

Patient 7 had lost 1.5 SD at presentation although her weight and height were above -2SD.

197 198

Post-transplant

199

Survival rate was 89%; three children died at day +70, 99 and 270, respectively due to multi-

200

organ failure following sepsis and GVHD, multi-systemic CMV infection unresponsive to

201

ganciclovir and foscarnet, and respiratory failure due to interstitial lung disease of unknown

202

aetiology. These 3 children had significant morbidity and organ damage pre-transplant.

203

Immune reconstitution data after HSCT is presented in table 4. Almost all patients achieved

204

T-cell reconstitution 1 year post-HSCT (CD4 >200/mm3 with presence of naïve T cells). With

205

regards to B-cell reconstitution, 84% of children had a CD19 count >200/mm3 and half the

206

patients had stopped immunoglobulin infusions one year after HSCT (Immunoglobulin

207

conducted until the end of winter). Three-quarters of the children (19/24) had a whole blood

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chimerism >95% at 1-year post-transplant.

209

Table 4. Immune reconstitution data after last HSCT Type of donor MSD (N = 2)

MUD (N = 13)

HAPLO (N = 12)

210 211 212 213

Immune parameters a

CD4 ≥200 Naïve T cell present CD19 ≥200 b Chimerism , mean CD4>200 Naïve T cell present CD19 >200 Chimerism, mean (range) CD4>200 Naïve T cell present CD19 >200 Chimerism, mean (range)

1-month post-HSCT, n/total (27) 1/2 NA 0/2 94.5% 2/13 NA 0/13 98% (94-100)

3 months post-HSCT, n/total (26) 1/2 1/2 2/2 89.2% 2/12 3/12 6/12 97% (86-100)

6 months post-HSCT, n/total (25) 2/2 2/2 2/2 85.4% 7/12 11/12 9/12 94% (60-100)

12 months post-HSCT, n/total (24) 2/2 2/2 2/2 83% 11/11 11/11 10/11 90% (35-100)

1/12 NA 2/12 99% (95-100)

2/12 2/12 8/12 99% (91-100)

8/11 9/11 7/11 96% (88-100)

10/11 11/11 10/11 95% (75-100)

Haplo: Haploidentical; HSCT: Hematopoietic stem cell transplant; MSD: matched sibling donor; MUD: matched unrelated donor; NA: not applicable; a 3 CD4 and CD 19: number of cells per /mm b Whole blood Chimerism

214

Nutritional support

215

Pre-transplant

216

A third of patients received EN prior to conditioning therapy due to poor weight gain or low

217

oral intake (table 5). Five children (19%) had a gastrostomy inserted before HSCT as a

218

lengthy period of enteral feeding was anticipated. Two children (CTLA4 mutation and STAT3

219

gain of function) had an intestinal failure due to auto-immune enteropathy with severe villous

220

atrophy and faltering growth requiring prolonged PN for 15 and 25 months prior to transplant.

221 222

Post-transplant

223

EN was the initial nutritional support for most children. However, 81% subsequently required

224

supplemental or exclusive PN within the 1st year post-transplant. Three children (11%) did

225

not receive EN due to absence of NGT (NGT refusal in one teenager, multiple NGT removal

226

in a child with behavioral issues, and contraindication of NGT insertion in a child with

227

recurrent nasal bleeding). Sixteen children (59%) had EN for more than 100 days after

228

transplant and two children were still partially EN-dependent, 1- and 4-years post-transplant.

229

Ninety percent had a hydrolyzed formula, the remaining had an elemental formula. Children

230

with the longest duration to establish a full oral diet were mostly the youngest.

231

Seventy seven percent of patients started PN within the first week following transplantation.

232

Main indications for PN included severe diarrhea in half of cases with EN intolerance and

233

mucositis. Three children lost their NGT during the first week post-transplant and required

234

PN in addition to the three other children without NGT. Fourteen children (64%) received PN

235

> 30 days, and 4 (18%) more than 100 days including a child with acute gut GVHD, a child

236

with severe undefined combined immunodeficiency with prolonged EN intolerance, and the

237

two children with pre-transplant intestinal failure. One third had 2 or 3 episodes of PN. Late

238

PN administration was due to acute intestinal GVHD, weight loss despite EN and GI

239

bleeding. Eleven children (41%) had documented infectious enteritis after HSCT.

240

Five children (19%) had exclusive EN after transplant. These children did not have T-cell

241

immunodeficiencies except one with Wiskott-Aldrich Syndrome (WAS) without GI or

242

nutritional morbidity pretransplant. Of note, one of these children had an acute grade II gut

243

GVHD and the other a pauci-symptomatic adenovirus enteritis. Common characteristics of

244

these children included no or low-grade mucositis (5/5), reduced intensity conditioning (3/5)

245

and a shorter hospital stay (mean 35 days).

246

Table 5. Nutritional support in the pre- and post-transplant period in PID children Pre-transplant

247

Post-transplant

Enteral nutrition Yes, n (%) 9 (33) 24 (89) Duration, days, median (range) 26 (12-1700) 134 (9-1400) mean 272 233 Parenteral nutrition Yes, n (%) 2 (7) 22 (81) Duration, days, median (range) 610 (457-762) 47 (9-270) mean 610 67 Time of initiation, days, median (range) 4 (0-33) > 1 episode of PN, n (%) 7 (32%) Time to full oral diet*, days median (range) 122 (7-579) mean 154 *children deceased or still on EN have not been included in this group.

248 249

Nutritional assessment

250

Pre-transplant

251

Mean z-scores were weight -0.57, height -0.88 and BMI -0.13 SD. One-third of children had

252

a weight and/or height ≤ -2 SD. After nutritional rehabilitation, mean weight for

253

undernourished children went from -2.6 to -1.9 SD, mean height from -2 to -1.8 SD, and

254

mean BMI from -1.3 to -1.2 SD at conditioning. Nine patients (33%) were above the 0 SD for

255

weight and only 22% for height. Parental height was not available to calculate genetic target

256

height. Of note, three-quarters of the patients were exposed to steroids, before and/or after

257

transplant. Three out of the nine undernourished children did not have GI symptoms but had

258

recurrent infections. The deceased children had a normal nutritional state at time of

259

transplant. One-third of all children had nutritional screening by a dietitian prior to admission

260

for transplant.

261

Post-transplant

262

Following a moderate decrease in weight and height z-scores at 1 and 3 months post-HSCT,

263

progressive catch up was noticeable from 6 months post-transplant (figure 1). At 1-year

264

post-transplant, weight z-score exceeded pre-transplant value while height z-score did not

265

change. Weight and height at 1 year remained ≤ -2 SD in 2/24 (8%) and 4/24 (16%) children

266

respectively, but with an upward trend compared to the pre-transplant period. No child was

267

overweight before transplant, but one child was overweight at 12 months (BMI z-score 2.14)

268

despite weaning off steroids.

269

Figure 1. Mean weight, height and BMI in children with PID before and after transplant. Weight

Height

BMI or weight for length

0.5 0.4 0.3 0.2 0.1 0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1 -1.1 -1.2 -1.3 AT CONDITIONING

270 271

1 MONTH POSTHSCT

3 MONTHS POSTHSCT

6 MONTHS POST- 12 MONTHS POSTHSCT HSCT

272

Mean albumin level was similar at the start of conditioning and at discharge (34.4 g/L versus

273

34 g/L). No episodes of hypoglycaemia were recorded but 33% of patients had a serum

274

glucose level ≥10mmol/L after HSCT, all of whom had PN. Fifteen patients (55%) had

275

triglycerides level ≥ 4 mmol/L at some stage, including one patient who did not have PN.

276

None of these patients had hemophagocytic lymphohistiocytosis (HLH) as an explanation for

277

their hypertriglyceridaemia. Screening for micronutrient abnormalities was performed in 7

278

children (26%) prior to transplant, and in 20 (74%) after transplant, mainly in children

279

requiring PN >4 weeks. Data on body composition and pubertal status was not available.

280 281

4. DISCUSSION

282

This study reports for the first time the nutritional course of a cohort of children with PID who

283

underwent HSCT in a large Australian centre. It showed a high rate of nutritional deficits

284

prior to and following transplantation.

285

In the pre-transplant stage, a third of our patients were underweight and/or stunted. Red

286

flags for malnutrition in our cohort included chronic diarrhea and recurrent infections.

287

Children with SCID were found to have increased resting energy expenditure (REE),

288

regardless of diarrhea and infections[4]. It is unknown whether other PID are also associated

289

with hypermetabolism although this may be the case for combined immunodeficiencies.

290

Considering the link between pre-transplant under- or over-nutrition and post-transplant

291

morbidity and mortality[8-13], children with PID should have a nutritional assessment

292

following diagnosis for detection of macro- and/or micronutrient deficiencies. Clinical

293

assessment should include at least weight and height trends and a nutrition-focused physical

294

examination. The use of BMI alone can be misleading in this population where stunting is

295

frequent. Based on BMI, only 3 children would be classified as undernourished at

296

presentation in our group. The patient with CTLA4 haploinsufficiency presented with <-4 SD

297

for weight and height, and 0.26 SD of BMI which would have missed his severe malnutrition.

298

Body composition and functional assessment are desirable if available.

299

Nutritional support pre-HSCT was required in 40% of children in our group and mainly

300

involves the enteral route in the absence of severe enteropathy. Pre-transplant PN is

301

reserved for cases with intestinal failure, mostly in Tregopathies[6,25]. A pre-transplant

302

nutrition interview is essential to fully discuss nutrition support modalities after HSCT with the

303

patient and its family.

304

support of PID patients prior to transplant.

305

In the post-transplant stage, almost all patients undergoing HSCT will require nutritional

306

intervention regardless of their diagnosis, mainly due to GI toxicities secondary to high-dose

307

chemotherapy[7,14,16]; yet the best nutritional approach is unknown and pediatric

308

guidelines are lacking.

309

Nutritional assessment in the initial post-transplant period can be challenging. Daily weight

310

fluctuations due to fluid overload make this parameter possibly unreliable. The nutritional

311

management is generally dictated by the severity of GI symptoms, oral intake and enteral

312

tolerance[14-18]. When the GI tract is functional, enteral tube feeding should be the main

313

alternative to oral feeding owing to its advantages over PN and likely protective effect

314

against GVHD[14-19,26,27]. The timing of NGT insertion is important : after conditioning-

315

induced vomiting has settled and before mucositis starts, otherwise its insertion could be

316

compromised. EN was used in 89% of cases in our study, although its tolerance was limited

317

as expected in children with PID.

318

immune system may make EN tolerance more fragile until immune recovery, at least partial,

319

occurs. Following HSCT, innate immunity recovers within the first month; however, adaptive

320

immunity can take up to 2 years to recover[28]. Therefore, patients with pre-transplant

321

intestinal failure generally require PN during months post-HSCT until immune cells develop

322

and inhabit the GI tract to allow EN tolerance. Patients with T- or combined cell defects likely

323

require PN temporarily post-HSCT. Whenever possible, complementary PN to reach energy

324

goals should be preferred over exclusive PN.

Figure 2 summarizes a suggestion for pre-transplant nutritional

In fact, considerations peculiar to their abnormal GI

325

Objective and easy indicators of intestinal mucosal injury and absorptive capacity are

326

lacking. Besides clinical indices, citrulline could be used as a biological marker of mucosal

327

injury in HSCT recipients[29-31], including during GVHD[31,32]. It is an amino-acid

328

correlated to enterocyte mass and/or function[29]. Whether it can be used to help select

329

children requiring PN needs to be studied further. Other laboratory markers include faecal

330

analysis reflecting fat and carbohydrates absorption. Although GI histology is an important

331

indicator of gut mucosal function, a normal histology is not a correlate of immune intestinal

332

recovery. Although 2 patients with pre-transplant intestinal failure had normalized their GI

333

histology 4 months post-transplant, they could not be weaned off PN until >6 to 9 months

334

post-HSCT. Similarly, the child with XIAP deficiency had a resolution of lactase deficiency

335

and eosinophilic esophagitis 3 months post-HSCT, however his diarrhea took 2 years to

336

resolve. These specificities of PID patients could explain a higher need and duration of PN in

337

our group (67 versus 15 to 22 days in oncology series[17,33,34]) and a longer post-

338

transplant inpatient stay (73 versus 24 to 40 days in oncology patients[15-17,19,33]).

339

Hypertriglyceridemia was frequent in our cohort and could be due to poor tolerance to lipid

340

emulsions, critical illness or medications. Prolonged lipid-free PN should be avoided due to

341

the risk of essential fatty acids deficiency and energy deficit. Fish oil-containing lipid

342

emulsions could improve anti-oxidant profile by increasing vitamin E levels in HSCT

343

recipients at risk of oxidative stress[35].

344

Whatever the type of nutrition support, it is paramount not to overfeed HSCT recipients to

345

avoid metabolic complications. Most authors[14,17,19,33,36] calculate BMR based on

346

Schofield predictive equation and multiply it by a 1.4 to 1.5 factor to predict energy

347

requirements. This equation was found to be in good agreement with measured REE in

348

malignant diseases[37], but it’s unknown if it’s the case for PID. Studies using indirect

349

calorimetry showed that HSCT recipients exhibit a significant reduction in REE in the early

350

weeks post-transplant, around 80% of BMR at week 2 to 3 before returning to baseline

351

around week 4 to 5[33,36,38,39]. The authors recommend lowering PN energy prescriptions

352

from 140% to 100% of estimated BMR when indirect calorimetry is unavailable[33]. It is

353

unknown if this can be applied to PID patients and to EN as it does not account for post-

354

HSCT malabsorption; 120% of BMR may be an appropriate starting point for EN. Protein

355

requirements in HSCT are unknown: while some use normal protein requirements, others

356

use a minimum of 1.5 g/kg/day[18] or correct with a 1.2 factor for catabolism[14]. Despite

357

nutrition support, weight and height decline was observed in the first months post-HSCT with

358

no height catch-up at 12 months, which deserves further investigation.

359

Micronutrients play crucial roles in immune processes, GI integrity and growth[40-44]. HSCT

360

recipients are at risk of micronutrient deficiencies due to low intake, malabsorption,

361

increased GI and urinary losses[45]. Pre- and post-transplant deficiencies in zinc, vitamin A,

362

D, copper and selenium were reported despite standard supplementation[26,42,45-49]. Low

363

vitamin A and D levels were associated with inferior survival in HSCT including

364

PID[41,43,47,48]. Micronutrient assessment should be part of the screening but at distance

365

from the acute phase to avoid false results due to acute phase response. Bone health

366

should also be part of the nutritional checklist as low bone mineral density was reported in

367

HSCT[50-52]. An approach for nutrition assessment and management post-HSCT is

368

proposed in figure 3. The basics of this nutritional approach apply equally to children

369

undergoing HSCT in general.

370

Our study has some limitations, including its retrospective nature, the relatively small number

371

of patients and the sample heterogeneity. However, this is the first study to describe the

372

nutrition profile and outcomes in children with PID in the peri-transplant period.

373 374

5. CONCLUSION

375

Children with PID undergoing transplant are a complex patient group at high risk of

376

nutritional deficiencies. Nutritional care is an integral part of their management. An approach

377

for nutritional support is suggested to guide clinicians. Future research is needed to shed the

378

light on some unanswered questions.

379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424

Figure 2: Flowchart of nutritional management of children with PID before HSCT

RED FLAGS Chronic diarrhea Recurrent infections Tregopathies, SCID

NUTRITIONAL ASSESSMENT -Growth: weight, height, BMI, MUAC -Nutrition-focused physical examination: fat stores, muscle bulk, signs of micronutrient deficiencies -Diet history: assessment of oral intake -GI symptoms: diarrhea, abdominal pain, vomiting (grade as per NCI) a -Laboratory: micronutrient assessment b -Bone health: consider baseline DXA, especially if risk factors -Body composition: DXA if available

IF UNDERWEIGHT and/or STUNTED EARLY NUTRITIONAL INTERVENTION

1) ORAL SUPPLEMENTS

3) PARENTERAL NUTRITION

If oral intake is < EER and able to feed orally

If intestinal failure after trial of EN, mostly in Tregopathies

2) ENTERAL FEEDING

CORRECTION OF MICRONUTRIENT DEFICIENCIES

-If unable to take oral supplements or persistence of underweight despite supplements. - PEG to be considered if long-term EN is anticipated

-Enteral supplements if absence of significant malabsorption -Adjust micronutrient dose in PN if intestinal failure

If Chronic diarrhea

Gastroenterology review; As indicated: Endoscopy, Histology, Pancreatic Elastase Faecal calprotectin

No concerns about current nutritional status

Regular monitoring of nutritional status until transplant Adjust nutritional support if required to ensure normal nutritional status before transplant

PRE-TRANSPLANT INTERVIEW; inform regarding: -Risk of decrease in oral intake post-HSCT - NGT insertion as part of HSCT procedure with EN being the main nutritional alternative - Benefits and risks of EN and PN

425 426 427

BMI: body mass index; DXA: dual-energy X-ray absorptiometry; EN: enteral nutrition; GI: gastrointestinal; HSCT:

428

hematopoietic stem cell transplant; MUAC: mid-upper arm circumference; NCI: National Cancer Institute[53]; PN:

429

parenteral nutrition; SCID: severe combined immunodeficiencies.

430 431

a

Micronutrients: Zinc, Vitamin A, D, E, B12, folate, Selenium, Copper, Carnitine and CRP.

432

b

Risk factors for low bone mineral density: steroids, immobilisation, prolonged low vitamin D levels.

433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469

470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517

Figure 3: Flowchart of nutritional management of children with PID after HSCT Insert an NGT at Day -1 or Day 0 (if not required before)

NUTRITIONAL ASSESSMENT - Severity of GI toxicities: grade mucositis, diarrhea and vomiting as per NCI (inquire about type of conditioning used) - Diet: Assess daily oral intake. Low microbial diet as per institution’s directives - Growth: weight (beware of fluid overload). - Nutrition-focused physical examination

2) PARENTERAL NUTRITION SUPPORT

1) ENTERAL TUBE FEEDING SUPPORT Indications: oral intake providing <50-75% of EER for 3-5 days or before if precarious nutrition state Modalities: Use isocaloric hydrolyzed or elemental feeds to meet requirements, either overnight or over 24 hours Preventive supportive therapies: antiemetics, analgesics If NGT dislodged: discuss possibility of replacement with team Stop EN: when oral intake meets >75% of EER

Indications: a - EN providing <50-75% of EER for 3-5 days, due to severe diarrhea or vomiting in: mucositis grade III-IV, presumed immune enteral intolerance, GVHD grade III-IV, prolonged GI infections - Patients unable to have NGT with oral intake <50-75% of EER for 3-5 days - PN may need to start earlier than 3-5 days in children with altered nutritional state with EN intolerance, or in case of anticipated immune enteral intolerance with severe diarrhea (such as Tregopathies, severe combined immunodeficiencies) - Patients with pre-transplant intestinal failure should continue PN post-HSCT until adaptive immune recovery begins Modalities: - Prefer supplementary PN to exclusive PN. Keep trophic feeds when possible. - Consider decreasing lipid emulsions dose if triglyceride levels > 4 mmol/l. Avoid lipid-free PN for prolonged periods. Children requiring PN > 4 weeks: -Cycle PN when patient is stable b c - Consider serum citrulline level and faecal analysis - Progressive advancement of EN as tolerated - Stop PN: when oral or enteral intake >75% of EER and appropriate weight gain

LONG-TERM NUTRITIONAL FOLLOW-UP Growth: weight, height, BMI and puberty status at each follow-up. Refer to endocrinology if short stature or delayed puberty. Micronutrients: start monitoring at 4 weeks post-HSCT if no active inflammation (irrespective of type of nutritional support); adjust supplementation and monitoring depending on results. Bone health: DXA, frequency according to individual risk factors and results Body composition: DXA, frequency according to results and risk factors Encourage adapted physical activity including weight-bearing exercises. d Functional assessment: Lansky scale ; consider handgrip strength.

518 519 520

BMI: body mass index; DXA: dual-energy X-ray absorptiometry; EER: estimated energy requirements; EN:

521

enteral nutrition; GI: gastrointestinal; GVHD: Graft-versus-host disease; HSCT: hematopoietic stem cell

522

transplant; MUAC: mid-upper arm circumference; NCI: National Cancer Institute[53]; NGT: nasogastric tube; PN:

523

parenteral nutrition.

524 525

a

526

then adjust as required.

527

b

528

c

529

d

EER based on Schofield formula; In the first month post-HSCT, start with 100% EER for PN and 120% for EN;

A cut-off of > 20 µmol/l is frequently used[31]

Faecal fat test, PH and reducing substances Lansky scale[54]: for children ≥ 1 year and <16 years

530 531 532

Authorship:

533

BZ, TC and JY designed the study. BZ, BVD, VE, JB and DS collected data. BZ analysed

534

data and wrote the manuscript. All authors critically revised the manuscript, agree to be fully

535

accountable for ensuring the integrity and accuracy of the work. All authors approved the

536

final version of the manuscript as submitted.

537 538

Conflict of interest

539

The authors declare no conflicts of interest.

540 541

Funding

542

This research did not receive any specific grant from funding agencies in the public,

543

commercial, or not-for-profit sectors.

544

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