Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: children and adolescents

Juliana Moura Nabarrete Andrea Z Pereira Adriana Garófolo Adriana Seber Angela Mandelli Venancio Carlos Eduardo Setanni Grecco Carmem Maria Sales Bonfim Claudia Harumi Nakamura Daieni Fernandes Denise Johnsson Campos Fernanda Luisa Ceragioli Oliveira Flávia Krüger Cousseiro Flávia Feijó Panico Rossi Jocemara Gurmini Karina Helena Canton Viani Luciana Fernandes Guterres Luiz Fernando Alves Lima Mantovani Luiz Guilherme Darrigo Junior Maria Isabel Brandão Pires e Albuquerque Melina Brumatti Mirella Aparecida Neves Natália Duran Neysimelia Costa Villela Victor Gottardello Zecchin Juliana Folloni Fernandes About the authors

ABSTRACT

The Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and Adolescents was developed by dietitians, physicians, and pediatric hematologists from 10 Brazilian reference centers in hematopoietic stem cell transplantation. The aim was to emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to patient´s nutritional assessment. This consensus is intended to improve and standardize nutrition therapy during hematopoietic stem cell transplantation. The consensus was approved by the Brazilian Society of Bone Marrow Transplantation.

Keywords:
Nutrition assessment; Nutritional status; Pediatrics; Child; Adolescent; Hematopoietic stem cell transplantation; Nutrition therapy

RESUMO

O Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: crianças e adolescentes foi elaborado com a participação de nutricionistas, médicos nutrólogos e médicos hematologistas pediátricos de 10 centros brasileiros que são referência em transplante de células-tronco hematopoiéticas. O objetivo foi salientar a importância do estado nutricional e da composição corporal durante o tratamento, bem como as principais características relacionadas à avaliação nutricional do paciente. As intenções, ao se estabelecer o consenso, foram aprimorar e padronizar a terapia nutricional durante o transplante de células-tronco hematopoiéticas. O consenso foi aprovado pela Sociedade Brasileira de Transplante de Médula Óssea.

Descritores:
Avaliação nutricional; Estado nutricional; Pediatria; Criança; Adolescente; Transplante de células-tronco hematopoéticas; Terapia nutricional

INTRODUCTION

Types of childhood hematopoietic stem cell transplantation and their applications

Hematopoietic stem cell transplantation (HSCT) is the infusion of cells involved for blood production to replicate inside the recipient and produce normal blood cells.(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.) The term “blood marrow transplantation” (BMT) has been used for many years, since blood marrow was the first source of blood stem cells used for transplantation.(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.)

Hematopoietic stem cell transplantation are performed successfully since the 1960’s: three infants with congenital immunodeficiency received the marrow of their siblings and recovered from their disease, growing up to be healthy adults.(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.) It was a long journey until the milestone of 1 million transplantations worldwide was achieved in 2014.(22 Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, Gratwohl M, Bouzas LF, Confer D, Frauendorfer K, Gluckman E, Greinix H, Horowitz M, Iida M, Lipton J, Madrigal A, Mohty M, Noel L, Novitzky N, Nunez J, Oudshoorn M, Passweg J, van Rood J, Szer J, Blume K, Appelbaum FR, Kodera Y, Niederwieser D; Worldwide Network for Blood and Marrow Transplantation (WBMT). One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2(3):e91-100. Erratum in: Lancet Haematol. 2015;2(5):e184.) Currently, there are more than 1,500 centers performing transplantations in at least 75 countries. A large part of these centers report their results to the Center for International Blood and Marrow Transplant Research (CIBMTR) or the European Bone Marrow Transplantation (EBMT) and, on their websites, one can find summary statistical data, protocols, treatment guidelines and dozens of educational sessions and meetings.(33 D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417-21.55 European Society for Blood and Marrow Transplantation (EBMT). Inborn erros working party ESID EBMT HSCT guidelines 207. Guidelines for haematopoietic stem cell transplantation for primary immunodeficiencies. EBMIT/ESID; 2017 [cited 2019 Dec 10]. Available from: https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf
https://www.ebmt.org/sites/default/files...
)

In Brazil, the Bone Marrow Transplantation (BMT) service of the Hospital de Clínicas under the Universidade Federal do Paraná was the first to initiate its activities in 1979. In 2016, 2,186 HSCTs were reported to the Brazilian Transplantation Registry (RBT) under the Brazilian Association for Organ Transplantation (ABTO). The overall transplantation rate per million inhabitants in our country reported to ABTO is 10.7, while countries such as England, Spain, the United States and Germany perform more than 50 transplantations per million inhabitants.(22 Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, Gratwohl M, Bouzas LF, Confer D, Frauendorfer K, Gluckman E, Greinix H, Horowitz M, Iida M, Lipton J, Madrigal A, Mohty M, Noel L, Novitzky N, Nunez J, Oudshoorn M, Passweg J, van Rood J, Szer J, Blume K, Appelbaum FR, Kodera Y, Niederwieser D; Worldwide Network for Blood and Marrow Transplantation (WBMT). One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2(3):e91-100. Erratum in: Lancet Haematol. 2015;2(5):e184.,66 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.,77 Associação Brasileira de Transplante de Órgãos (ABTO). Registro Brasileiro de Transplantes (RBT). Dimensionamento dos transplantes no Brasil e em cada estado (2009-2016). Ano XXII Nº 4. São Paulo: ABTO; 2016 [citado 2019 Nov 21]. Disponível em: www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
www.abto.org.br/abtov03/Upload/file/RBT/...
)

In solid organ transplants, ABO compatibility (A, B, AB, O) is very important, but, in HSCTs, recipients’ red blood cells will switch to the donor blood group. In this case, the most important factor is human leukocyte antigen (HLA) compatibility.(77 Associação Brasileira de Transplante de Órgãos (ABTO). Registro Brasileiro de Transplantes (RBT). Dimensionamento dos transplantes no Brasil e em cada estado (2009-2016). Ano XXII Nº 4. São Paulo: ABTO; 2016 [citado 2019 Nov 21]. Disponível em: www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
www.abto.org.br/abtov03/Upload/file/RBT/...
)

Human leukocyte antigen is fully encoded in chromosome 6, and altogether inherited ‘en bloc’ from each parent including alleles A, B, C (class I), DR, DP and DQ (class II). Depending on the number of alleles typed, matching could be of six antigens (A, B and DR), eight (A, B, C and DR), ten (A, B, C, DR, and DQ) or twelve.(77 Associação Brasileira de Transplante de Órgãos (ABTO). Registro Brasileiro de Transplantes (RBT). Dimensionamento dos transplantes no Brasil e em cada estado (2009-2016). Ano XXII Nº 4. São Paulo: ABTO; 2016 [citado 2019 Nov 21]. Disponível em: www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
www.abto.org.br/abtov03/Upload/file/RBT/...
) Therefore, siblings have a chance of having inherited two identical or distinct HLA chromosomes in 25% of the cases, and half of siblings have a chance of having inherited one equal and one different chromosome, known as haploidentical. In other words, we are always haploidentical to our parents and children.(77 Associação Brasileira de Transplante de Órgãos (ABTO). Registro Brasileiro de Transplantes (RBT). Dimensionamento dos transplantes no Brasil e em cada estado (2009-2016). Ano XXII Nº 4. São Paulo: ABTO; 2016 [citado 2019 Nov 21]. Disponível em: www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
www.abto.org.br/abtov03/Upload/file/RBT/...
)

There are several types of HSCT, which are classified based on cell donor, cell source, degree of compatibility between donor and recipient, and type of conditioning, according to table 1.

Table 1
Types of childhood hematopoietic stem cell transplantations

Before the start of conditioning, patients need a semi-implantable central venous catheter (permanent, such as Hickman, Permcath, or temporary), used for serial collection of test samples and for administration of chemotherapy, hydration, blood products and other medications. The days preceding the stem cell infusion are counted as negative and, after infusion, as positive.

The day before transplantation (D-1) is usually a one-day “break” to wait for chemotherapy metabolism and excretion, so that cells are not affected when infused. However, it is important to wait at least two terminal half-lives of the chemotherapy regimen before the infusion, which means less than 2 hours for agents such as melphalan or up to 4 days for carboplatin.(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.)

The chemotherapy agents most commonly used in conditioning are cyclophosphamide, busulfan, cytarabine, etoposide, melphalan, carmustine, thiotepa, among others. Each chemotherapy agent has a distinct toxicity pattern. The drugs with the highest gastrointestinal toxicity are busulfan, etoposide, melphalan and thiotepa, as well as total body irradiation (TBI).(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.)

The day of infusion, or the day of transplantation, is defined as day zero (D0).(11 Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.)

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION

Cell harvesting procedure

In autologous transplants, the patient’s own stem cells are usually harvested from peripheral blood, cryopreserved and re-infused after the patient receives high-dose chemotherapy (conditioning or preparative regimen). Thus, it is possible to use myeloablative doses of chemotherapy and then provide hematological recovery.

For mobilization, the patient is subjected to a few steps. It starts with chemotherapy (optional, usually 1g/m2/day to 2g/m2/day cyclophosphamide).

Daily use of granulocyte colony-stimulating factor (G-CSF) in one or two intravenous (IV) or subcutaneous applications is then initiated, until stem cells can be harvested by leukapheresis or are considered to have failed mobilization. Throughout this period, the number of CD34+ stem cells in peripheral blood is monitored by flow cytometry, and when the appropriate level is reached (usually higher than 10 cells/mcL to 20 cells/mcL), that is usually the ideal time for harvesting by means of a dual lumen central venous catheter suitable for hemodialysis – temporary (e.g., Shilley) or permanent (for example: Permcath) –, and the start of leukapheresis.

In leukapheresis, the patient’s blood is continuously processed in a cell separation device. Leukocytes are slowly collected into a specific bag, and red blood cells and plasma are continuously returned through the lumen of the catheter. Leukapheresis takes a few hours and can be repeated the next day if not enough cells are harvested for transplantation – usually 3 to 5 million CD34 cells/kg of body weight per transplant are required. Some pediatric regimens for central nervous system tumors, neuroblastoma, and germ cell tumors require up to three sequential cycles of high-dose chemotherapy, and a large number of cells may be required.

The harvested cells are frozen (cryopreserved) at specialized laboratories using solutions containing dimethyl sulfoxide (DMSO), a cryoprotectant that minimizes damage caused by freezing and thawing. Stem cells can be stored in a freezer at -80°C for several months and in nitrogen tanks for decades until they are needed.

During transplantation

For transplantations, children need a permanent semi-implantable catheter (Hickman, Permcath or others) or a temporary semi-implantable catheter to receive the cells and the prior chemotherapy.

On negative days (D-6, D-5, D-4, D-3, and D-2), the conditioning or preparative regimen with high-dose chemotherapy is administered to destroy tumor cells resistant to conventional chemotherapy regimens and doses. Then there is a “break” from chemotherapy, usually on D-1.

On D0, autologous cells are thawed and infused through the central venous catheter. The infusion may have several adverse effects due to the presence of the cryoprotectant, the most frequent of which are characteristic smell in the breath due to DMSO excretion (described as corn cream, garlic etc.), bradycardia, pressure changes, nausea, and vomiting.

As of D+1, the day after infusion, patients may be initiated (or not) on daily G-CSF, in addition to drugs for anti-infection prophylaxis (viruses, fungi, and bacteria), which may vary according to institutional protocols. In the days following infusion, patients may also present with substantial chemotherapy-induced gastrointestinal toxicity, with oral mucositis, nausea, vomiting and diarrhea, which may cause intense discomfort and pain, requiring potent analgesics.

Due to bone marrow suppression, patients have anemia and thrombocytopenia, requiring frequent transfusions, as well as neutropenia, with high susceptibility to infections. Patients commonly have fever which, even without a defined focus, requires management with broad-spectrum antibiotics.

The “bone marrow engraftment” is the first of 3 consecutive days after chemotherapy nadir, in which patients with 500 neutrophils/mm3 or more in their blood count. The definition of platelet engraftment, in general, is the first day with more than 20 thousand platelets/mm3 after 7 or more days without transfusion.

The complexity and complications are lower in autologous transplantations when compared with allogeneic. From the nutritional standpoint, however, some patients have been receiving chemotherapy for several months when they undergo BMT and, therefore, may have significant nutritional deficits. Also, some children need to receive radiation therapy after transplantation. When the radiation field involves the esophagus or abdomen, this may lead to mucosal injury, nausea, vomiting and diarrhea, further delaying nutritional recovery.

Autologous transplantations are the most frequent modality in adults, used in the treatment of multiple myeloma and lymphomas.(66 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.) In pediatrics, there is evidence that autologous BMT can provide greater survival in Hodgkin’s lymphoma, non-Hodgkin’s lymphomas in second or greater remissions, and chemosensitive solid tumors, such as germ cell tumors in second remission or high-risk neuroblastoma.(66 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.) In infants with central nervous system tumors, autologous HSCT may be used to replace or postpone radiation therapy, whose long-term harmful effects on the developing brain would be devastating.(66 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.) Some studies indicate the benefit of BMT in the treatment of Ewing sarcoma, metastatic or in second remission; central nervous system primitive tumors, disseminated or in second remission; extraocular retinoblastoma; and Wilms’ tumor after the second remission.

Autologous transplants can also be used to eradicate self-reactive cells in the treatment of severe autoimmune diseases, and in countries with appropriate infrastructure, autologous stem cells can be used for laboratory-based genetic repair, also known as “gene therapy”.

Allogeneic transplantation

In allogenic transplants, classical myeloablative conditioning regimens in children are 120mg/kg to 200mg/kg cyclophosphamide with 1,200 cGy TBI for conditioning of acute lymphocytic leukemia, and 200mg/kg cyclophosphamide with busulfan for myeloid leukemias. For non-malignant diseases, busulfan and fludarabine or melphalan are often used.(55 European Society for Blood and Marrow Transplantation (EBMT). Inborn erros working party ESID EBMT HSCT guidelines 207. Guidelines for haematopoietic stem cell transplantation for primary immunodeficiencies. EBMIT/ESID; 2017 [cited 2019 Dec 10]. Available from: https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf
https://www.ebmt.org/sites/default/files...
)

In addition to chemotherapy, the preparative regimen includes drugs to reduce the chance of recipients destroying donor cells (rejection), such as anti-thymocyte globulin, mainly in unrelated transplants, and cyclosporine, and the chance of donor cells attacking the recipient, causing graft versus host disease (GVHD).(33 D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417-21.,55 European Society for Blood and Marrow Transplantation (EBMT). Inborn erros working party ESID EBMT HSCT guidelines 207. Guidelines for haematopoietic stem cell transplantation for primary immunodeficiencies. EBMIT/ESID; 2017 [cited 2019 Dec 10]. Available from: https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf
https://www.ebmt.org/sites/default/files...
)

Donor stem cells are usually harvested and infused on D0. To treat malignancies, cells can be harvested from peripheral blood, using G-CSF alone, without chemotherapy, if leukapheresis is feasible by peripheral venous access, without the need for a central venous catheter.

Bone marrow is the most common source for allogeneic HSCT.(33 D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417-21.) For bone marrow harvesting, the donor is taken to the operating room and, under general anesthesia and/or spinal block (epidural), cells are harvested from posterior iliac crests with needles and syringes. Approximately 15mL of bone marrow/kg of recipient body weight to 20mL/kg of donor body weight is retrieved. Harvesting takes about 1 to 2 hours and, usually, the donor is discharged on the same day or the next day. In unrelated transplantations, it may be necessary to harvest cells up to 2 days before infusion, which generally grants excellent viability.

Other drugs used after transplantation to prevent GVHD are cyclosporine, tacrolimus (calcineurin inhibitors), methotrexate (D+1, D+3, D+6 and sometimes also on D+11) and mycophenolate mofetil. Recently, high-dose cyclophosphamide, infused on D+3 and D+4, has been used, mainly in haploidentical transplants.

Allogeneic transplantations are mainly used in the treatment of leukemias, myelodysplasia and bone marrow failures, among others.(66 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.) Donor cells are infused after administration of the conditioning regimen, which includes high dose-chemotherapy or TBI.

Although donor cells can recognize the recipient as foreign and attack it (GVHD), these same cells can recognize and destroy tumor cells, decreasing the chance of recurrent malignancy (graft versus tumor effect or graft-versus-leukemia – GVL).

The maximum toxicity associated with HSCT is usually expressed as transplant-related mortality (TRM), i.e., mortality in the first 100 days after infusion of stem cells due to any causes, except recurrence of the underlying disease. Transplant-related mortality increases greatly if the disease is in advanced stages. Results published by the CIBMTR show 2% to 10% of TRM in autologous HSCT, 7% to 22% in related allogeneic, and 10% to 25% in unrelated allogeneic.(44 Pasquini M, Wang Z, Horowitz MM, Gale RP. 2013 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl. 2013:187-97.)

The toxicities presented can be grouped as acute and frequent, and less frequent and more severe, according to table 2.

Table 2
Allogeneic hematopoietic stem cells transplantation-related toxicities

Infectious complications usually follow a somewhat constant pattern. In the first 30 days, patients with neutropenia and mucositis are predisposed to infections by the herpes simplex virus, respiratory viruses, Gram-positive and negative bacteria, and Candida sp. From then on, GVHD becomes the main predisposing factor for infections. Respiratory viruses, adenovirus, cytomegalovirus, and filamentous fungal infections remain the main infectious agents between months 1 and 2.

After engraftment, severe immunodeficiency persists for several months, particularly after allogeneic and autologous transplants with rituximab therapy for lymphomas. Infections by cytomegalovirus, adenovirus, herpes-zoster, Pneumocystis carinii, and toxoplasmosis are frequent and, in patients who develop chronic GVHD (cGVHD) or splenectomy patients, there is a risk of fulminant infections by encapsulated bacteria.

Splenectomy patients with prior splenic radiation therapy or who had cGVHD must be extensively educated on the higher risk for fulminant sepsis, as well as receive continuous prophylaxis against encapsulated bacteria and be instructed to seek a referral medical facility in case of fever, to have a blood culture collected and appropriate antibiotics immediately initiated, such as amoxicillin-clavulanate or ceftriaxone.

Due to the short- and long-term risks associated with transplants, their indication is restricted to diseases in which survival with HSCT is higher than survival with conventional treatment (e.g., chemotherapy), or when transplantation can promote a significant improvement in quality of life, such as eliminating the need for hypertransfusion and long-term complications in patients with hemoglobinopathies.

Hematopoietic stem cell transplantation indications are the object of ongoing reevaluation. Ideally, transplant indications should be based on results from randomized clinical studies, but this is not always possible. The only way to make precise indications is knowing the results of conventional treatment and HSCT in our reality.

As therapeutic advances arise, some diseases for which HSCT was once indicated may evolve to more appropriate approaches, such as the use of imatinib mesylate (Glivec®) in the treatment of chronic myeloid leukemia. However, diseases for which HSCT was not even considered are now managed with this procedure, such as sickle cell anemia and deposit diseases.

In pediatrics, the most common indications of allogeneic transplantation are acute lymphocytic leukemia in second bone marrow remission, acute myeloid leukemia, myelodysplastic syndromes, bone marrow failure syndromes, such as severe bone marrow aplasia and Fanconi anemia, immunodeficiencies, some cases of hemoglobinopathies and hereditary metabolic diseases.

In Brazil, diseases that can be treated with transplantation under the Unified Health System (SUS - Sistema Único de Saúde) are listed in ordinance 940 of December 21, 2006 (Table 3), and have not been revised as of 2020.(88 Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Portaria SAS nº. 940 de 21 de Dezembro de 2006. Altera o atributo NOME dos procedimentos referentes a TCTH. Brasília (DF): Diário Oficial do Brasil; 2006 Dez de 21[citado 2020 Mar 10]. Disponível em: https://www.normasbrasil.com.br/norma/portaria-940-2006_197770.html
https://www.normasbrasil.com.br/norma/po...
)

Table 3
Criteria for hematopoietic stem cell transplantation indication in pediatric diseases

Survival after BMT for cancer treatment depends on several factors, such as underlying disease, prior treatment, duration of disease, age group and number of recurrences. Overall, 50% to 60% of children are cured, depending on the stage of the disease at which the transplant is performed.

Currently, the greatest challenge is to increase the chance of curing children. To do this, the toxicity of transplants must be reduced, and their results improved. In addition, it is essential to know the treatment reality of our patients, with and without transplantation, allowing for better selection of HSCT candidates.

Importance of nutritional status in hematopoietic stem cell transplantation

It is a common situation for patients to be hospitalized in good nutritional status and present with significant impairment over the course of HSCT.(99 Farias CL, Campos DJ, Bonfin CM, Vilela RM. Phase angle from BIA as a prognostic and nutritional status tool for children and adolescents undergoing hematopoietic stem cell transplantation. Clin Nutr. 2013;32(3):420-5.) Both the toxicity and potential complications of this therapy lead to a reduction in food acceptance and/or impairment of adequate nutrient absorption. This situation is even more alarming in children and adolescents, who are in the process of growing and developing. Patients undergoing TBI have more height impairment compared with chemotherapy-only conditioning regimens.(1010 Cohen A, Duell T, Socié G, van Lint MT, Weiss M, Tichelli A, et al. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1999;23(10):1043-7.)

The relationship between nutritional status and transplant outcomes has been explored in the last decade with publications initially in adult patients reporting, for example, lower overall survival and higher toxicity, risk of acute GVHD, length of hospital stay and time for engraftment of platelets and neutrophils in malnourished patients or those who had severe weight loss during transplantation.(1111 Fuji S, Mori T, Khattry N, Cheng J, Do YR, Yakushijin K, et al. Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality. Bone Marrow Transplant. 2015;50(1):100-5.1313 Hadjibabaie M, Tabeefar H, Alimoghaddam K, Iravani M, Eslami K, Honarmand H, et al. The relationship between body mass index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Transplant. 2012;26(1):149-55.) Although it is not possible to extrapolate all these results to pediatrics, effects of this impaired nutritional status are believed to have an even greater impact on children and adolescents, not only due to sequelae affecting growth and development, but also due to the lower body mass and what the loss of body mass represents in this age group.

The presence of malnutrition in pediatric HSCT is associated with lower overall survival and higher relapse-free mortality, as well as greater risk of malignancy recurrence.(99 Farias CL, Campos DJ, Bonfin CM, Vilela RM. Phase angle from BIA as a prognostic and nutritional status tool for children and adolescents undergoing hematopoietic stem cell transplantation. Clin Nutr. 2013;32(3):420-5.,1414 Hoffmeister PA, Storer BE, Macris PC, Carpenter PA, Baker KS. Relationship of body mass index and arm anthropometry to outcomes after pediatric allogeneic hematopoietic cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2013;19(7):1081-6.) In addition, there was a greater presence of post-transplant weakness and a higher risk of chronic GVHD.(99 Farias CL, Campos DJ, Bonfin CM, Vilela RM. Phase angle from BIA as a prognostic and nutritional status tool for children and adolescents undergoing hematopoietic stem cell transplantation. Clin Nutr. 2013;32(3):420-5.,1515 Bouma S, Peterson M, Gatza E, Choi SW. Nutritional status and weakness following pediatric hematopoietic cell transplantation. Pediatr Transplant. 2016;20(8):1125-31.) Patients in this nutritional condition also seem to take longer to restore the weight and lean mass lost during HSCT.(1616 Campos DJ, Boguszewski CL, Funke VA, Bonfim CM, Kulak CA, Pasquini R, et al. Bone mineral density, vitamin D, and nutritional status of children submitted to hematopoietic stem cell transplantation. Nutrition. 2014;30(6):654-9.)

Similarly, weight loss during transplantation is associated with significant risks to pediatric patients, such as higher prevalence of multi-organ GVHD and presence of lower standardized phase angle, measured by bioimpedance.(1616 Campos DJ, Boguszewski CL, Funke VA, Bonfim CM, Kulak CA, Pasquini R, et al. Bone mineral density, vitamin D, and nutritional status of children submitted to hematopoietic stem cell transplantation. Nutrition. 2014;30(6):654-9.,1717 Browning B, Thormann K, Seshadri R, Duerst R, Kletzel M, Jacobsohn DA. Weight loss and reduced body mass index: a critical issue in children with multiorgan chronic graft-versus-host disease. Bone Marrow Transplant. 2006;37(5):527-33.) This latter parameter is related to higher mortality and increased risk of chronic GVHD.

Although, for the time being, there are few publications, overweight and obese children and adolescents have been recently studied. Similarly to malnourished patients, overweight patients also have a higher prevalence of post-transplant weakness, lower overall survival and a potentially increased risk for cGVHD.(1515 Bouma S, Peterson M, Gatza E, Choi SW. Nutritional status and weakness following pediatric hematopoietic cell transplantation. Pediatr Transplant. 2016;20(8):1125-31.,1818 White M, Murphy AJ, Hallahan A, Ware RS, Fraser C, Davies PS. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr. 2012;66(10):1120-3.,1919 Pine M, Wang L, Harrell FE Jr, Calder C, Manes B, Evans M, et al. The effect of obesity on outcome of unrelated cord blood transplant in children with malignant diseases. Bone Marrow Transplant. 2011;46(10):1309-13.)

Malnutrition as a whole, including both undernutrition and overweight/obesity, as well as severe weight loss, can cause dramatic consequences to children and adolescents undergoing HSCT. Current evidence suggests that nutritional follow-up of these patients is key to the success of the proposed therapy.

Nutritional evaluation

Several factors determine HSCT success in the short and long term. They include diagnosis and disease stage, type of transplantation performed, presence of donor incompatibility, conditioning regimen, cell source, age, prior treatments and nutritional status.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
) For the latter, all patients eligible for HSCT are considered to be at nutritional risk. In order to reduce the negative impact of the disease and treatment, adequate nutritional evaluation is recommended both in pre- and post-transplant cases.(2121 Ladas EJ, Sacks N, Brophy P, Rogers PC. Standards of nutritional care in pediatric oncology: results from a nationwide survey on the standards of practice in pediatric oncology. A Children’s Oncology Group study. Pediatr Blood Cancer. 2006;46(3):339-44.) Therefore, this evaluation must include: nutritional history, with clinical, nutritional and socioeconomic information; description of anthropometric data; complete physical examination; investigation of the eating patterns; and laboratory tests, particularly blood test and biochemistry.

Anthropometry

Anthropometry has been widely used for assessment of nutritional status in the pediatric population because it is a practical, non-invasive and low-cost method. The commonly used measurements are weight, height and body mass index (BMI).(2222 Viani K, Yonamine G, Gandolfo AS, Lemos PS. Avaliação Nutricional. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. Barueri: Manole; 2017. p. 28-46.)

The classification is based on the parameters recommended by the World Health Organization (WHO) in 2006 and 2007. Weight and height data are reviewed according to age and sex, and classified according to the z-score: weight/age (W/A), height or length/age (H/A), weight/height (W/H) and BMI/age (BMI/A). In addition to the individual review of each parameter, according to tables 4 and 5, the final classification is according to the age group: under 2 years of age, W/H z-score and, over 2 years of age, BMI/A. The patient’s evolution must also be followed based on growth charts according to the parameter, sex and age.(2323 Sociedade Brasileira de Pediatria (SBP). Avaliação nutricional da criança e do adolescente: manual de orientação. Departamento de Nutrologia. Rio de Janeiro:SBP; 2009. Capítulo 5. Avaliação da composição corporal. p. 46-51.2626 Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007;85(9):660-7.)

Table 4
Anthropometric index determining nutritional status by age group, zero to 10 years
Table 5
Anthropometric index determining nutritional status by age group, 10 to 19 years

Body composition

Assessment of body composition as one of the tools of nutritional therapy has become increasingly valued in recent years, since calculating weight or BMI for age is not enough to evaluate fat and lean mass in children and adolescents with chronic diseases.(2727 Baracos V, Caserotti P, Earthman CP, Fields D, Gallagher D, Hall KD, et al. Advances in the science and application of body composition measurement. JPEN J Parenter Enteral Nutr. 2012;36(1):96-107.3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.) Furthermore, these indicators are not much sensitive to variations in nutritional status, since body weight is affected by significant water changes caused by HSCT. There are several methods to assess body composition, such as waist circumference and skin folds, magnetic resonance, computed tomography, body densitometry, ultrasound, bioimpedance analysis, total body potassium and air plethysmography.(2929 Prado CM, Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and intervention. JPEN J Parenter Enteral Nutr. 2014;38(8):940-53. Review. Erratum in: JPEN J Parenter Enteral Nutr. 2016;40(5):742.3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.)

In pediatrics, and in association with allogeneic HSCT, many studies use body densitometry for this evaluation, which is not performed in most Brazilian services due to its high cost and/or unavailability.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.,3232 Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.) Both obesity and undernutrition are risk factors in this procedure, with highlight to lower muscle mass and higher peripheral and visceral fat.(1818 White M, Murphy AJ, Hallahan A, Ware RS, Fraser C, Davies PS. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr. 2012;66(10):1120-3.,3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.3535 Liu P, Wang B, Yan X, Cai J, Wang Y. Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases. Chin J Cancer Res. 2016;28(6):626-33.)

Triceps skinfold (TSF) and subscapular skinfold are the most commonly used in pediatrics because they have population reference values for this age group.(2525 WHO Multicentre Growth Reference Study Group – WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr. 2006;95(Suppl 450):76-85.,3636 Rodgers C, Wills-Alcoser P, Monroe R, Mc Donald L, Trevino M, Hockenberry M. Growth patterns and gastrointestinal symptoms in pediatric patients after hematopoietic stem cell transplantation. Oncol Nurs Forum. 2008;35(3):443-8.,3737 Frisancho AR. Anthropometric standards: an interactive nutritional reference of body size and body composition for children and adults. 2nd ed. Michigan: University of Michigan Press; 2008. p. 144-59.) When these values are below the 5th percentile or above the 90th percentile, there are health risks. TSF measurement is a convenient way to indirectly establish body fat mass.(3838 White M, Davies P, Murphy A. Validation of percent body fat indicators in pediatric oncology nutrition assessment. J Pediatr Hematol Oncol. 2008;30(2):124-9.,3939 White M, Davies P, Murphy A. Correlation between nutrition assessment data and percent body fat via plethysmography in pediatric oncology patients. JPEN J Parenter Enteral Nutr. 2011;35(6):715-22.) Arm and arm muscle circumference are primarily used to obtain the amount and variation of skeletal muscle protein. One should remember that, under anasarca, the arm circumference and TSF have limited applicability.

Despite the lack of publications on children during HSCT, some current studies point to the use of TSF, arm circumference and arm muscle area as the best indicators of body composition in pediatric cancer patients, since they are easy to measure, low-cost and non-invasive, having good correlation with other parameters considered gold standard for body composition in this population. Studies have recommended measuring arm anthropometry based on comparison with weight indices and non-referenced malnutrition measurements.(2222 Viani K, Yonamine G, Gandolfo AS, Lemos PS. Avaliação Nutricional. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. Barueri: Manole; 2017. p. 28-46.,3939 White M, Davies P, Murphy A. Correlation between nutrition assessment data and percent body fat via plethysmography in pediatric oncology patients. JPEN J Parenter Enteral Nutr. 2011;35(6):715-22.4343 Montejo González JC, Culebras-Fernández JM, García de Lorenzo y Mateos A. [Recommendations for the nutritional assessment of critically ill patients]. Rev Med Chil. 2006;134(8):1049-56. Review. Spanish.)

High-dose cranial irradiation used in the TBI can cause hypothalamus abnormalities, including changes in growth hormone, thyroid and gonadal functions, as well as abnormal sensitivity to leptin, ghrelin and insulin.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.) These changes are associated with obesity, particularly post-HSCT, including increased visceral fat and fatty infiltration of the liver.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.,3333 Wei C, Thyagiarajan MS, Hunt LP, Shield JP, Stevens MC, Crowne EC. Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes. Pediatr Blood Cancer. 2015;62(11):1992-9.) Patients who receive TBI for conditioning, when compared with those receiving only chemotherapy or obese controls, have lower lean mass, with a higher prevalence of lean mass loss and more visceral and intramuscular fat.(3333 Wei C, Thyagiarajan MS, Hunt LP, Shield JP, Stevens MC, Crowne EC. Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes. Pediatr Blood Cancer. 2015;62(11):1992-9.)

In addition to irradiation, GVHD, one of the most common complications of HSCT, correlates to changes in body composition.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.) In intestinal GVHD, weight loss is greater, with decrease of muscle mass – in most cases, without increase in visceral fat.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.) The use of corticosteroids in the management of GVHD contributes to increasing visceral and peripheral fat, as well as reducing lean mass in these patients.(1818 White M, Murphy AJ, Hallahan A, Ware RS, Fraser C, Davies PS. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr. 2012;66(10):1120-3.,3232 Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.)

In HSCT survivors, the higher propensity to obesity and decreased lean mass is related to a higher risk of cardiovascular disease, metabolic syndrome, growth and bone deficiency, leading to higher morbidity and mortality in these children.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.,3232 Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.,3434 Inaba H, Yang J, Kaste SC, Hartford CM, Motosue MS, Chemaitilly W, et al. Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(32):3991-7.)

Allogeneic HSCT, TBI, use of corticosteroids and GVHD are important risk factors for body composition changes in survivors, associated with increased fat mass and loss of muscle mass.(1818 White M, Murphy AJ, Hallahan A, Ware RS, Fraser C, Davies PS. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr. 2012;66(10):1120-3.,3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.,3232 Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.,3434 Inaba H, Yang J, Kaste SC, Hartford CM, Motosue MS, Chemaitilly W, et al. Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(32):3991-7.3636 Rodgers C, Wills-Alcoser P, Monroe R, Mc Donald L, Trevino M, Hockenberry M. Growth patterns and gastrointestinal symptoms in pediatric patients after hematopoietic stem cell transplantation. Oncol Nurs Forum. 2008;35(3):443-8.) Patients with these factors should have their body composition closely monitored as an early therapeutic measure, to reduce the risk of morbidity and mortality.(3131 Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.,3232 Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.,3535 Liu P, Wang B, Yan X, Cai J, Wang Y. Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases. Chin J Cancer Res. 2016;28(6):626-33.) The phase angle measured by bioimpedance seems promising as a proxy measure of nutritional status, and may be an option in the follow-up of these patients. In a Brazilian study published in 2013, children with lower phase angle had severe weight loss, higher incidence of GVHD and lower survival.(99 Farias CL, Campos DJ, Bonfin CM, Vilela RM. Phase angle from BIA as a prognostic and nutritional status tool for children and adolescents undergoing hematopoietic stem cell transplantation. Clin Nutr. 2013;32(3):420-5.)

Although in other fields of nutrition the evaluation of body composition is included in institutional protocols, in most Brazilian pediatric HSCT services, there is no consistency. It is advised that this evaluation be carried out at all stages of HSCT, before, during and after, to improve the survival and quality of life of these patients. Each service must choose the method that has the best cost-benefit and convenience among those validated.

Laboratory parameters

Laboratory parameters are important when evaluating nutritional status, and provide clear measures of abnormalities, with the advantage of enabling follow-up over time and early interventions.(4343 Montejo González JC, Culebras-Fernández JM, García de Lorenzo y Mateos A. [Recommendations for the nutritional assessment of critically ill patients]. Rev Med Chil. 2006;134(8):1049-56. Review. Spanish.) In addition, they may assist in nutritional monitoring and decision-making regarding specific nutritional therapies. Thus, it is possible to divide laboratory parameters into two large groups: nutritional status and nutritional therapy monitoring.

Nutritional status

It should be borne in mind that, although different biochemical tests can offer important information regarding nutritional status, none of them should be used in isolation, since changes may occur during the clinical evolution of the patient. Among the biochemical variables of interest in nutrition, regarding the nutritional status of patients undergoing HSCT, we highlight:

  • Albumin: considered the main protein synthesized by the liver and, consequently, the most widely used to evaluate nutritional status. Serum albumin concentrations lower than 3g/dL are indicative of protein malnutrition. This decrease also correlates with an increased incidence of clinical complications, morbidity and mortality. In severe patients, albumin levels have prognostic value when measured on admission to the hospital. However, serum albumin is not sensitive to changes during acute complications, since its half-life is relatively long (±20 days), and it may take several weeks to respond to variations in dietary-protein intake.(4444 Maicá AO, Schweigert ID. Nutritional assessment of the severely ill patient. Rev Bras Ter Intensiva. 2008;20(3):286-95.4646 Vannucchi H, Unamuno MR, Marchini JS. Avaliação do estado nutricional. Medicina (Ribeirão Preto). 1996;29(1):5-8.) During HSCT, weekly albumin testing is recommended. Values lower than 2.5mg/dL are potentially associated with intravascular volume overload, systemic capillary extravasation syndrome, diarrhea or liver diseases.(4747 Macris PC, McMillen KK. Nutrition support of the hematopoietic cell transplant recipient. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 4th ed. Vol. I. New Jersey (USA): Wiley-Blackwell; 2009. Chapter 99. p.1551-69.)

  • Pre-albumin: in serum, prealbumin carries about 70% of thyroxin, and is also the carrier of retinol-binding protein (RBP), both of which are decreased in energy-protein malnutrition, as well as in infections, cirrhosis, hepatitis, inflammation, stress and chronic diseases. As a marker of metabolic stress, it can help determine the need for nutritional intervention. Both pre-albumin and RBP have short half-lives, and are considered important for evaluating visceral protein status. Retinol binding protein has a half-life of only a few hours (±12 hours) and pre-albumin (PA), of 2 days. Due to their short half-lives, they are considered some of the most sensitive parameters to nutritional changes.(4848 Jeejeebhoy KN. Nutritional assessment. Gastroenterol Clin North Am. 1998;27(2):347-69. Review.) Levels <10mg/dL are considered abnormal in children.(4747 Macris PC, McMillen KK. Nutrition support of the hematopoietic cell transplant recipient. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 4th ed. Vol. I. New Jersey (USA): Wiley-Blackwell; 2009. Chapter 99. p.1551-69.)

  • Transferrin: beta-globulin synthesized in the liver and responsible for transporting certain nutrients, particularly iron. It has an average life of 4 to 8 days, and thus abnormal levels can be detected much sooner than for albumin, in case of protein depletion, and this makes it an important tool for diagnosing subclinical malnutrition. However, it has low sensitivity and specificity when used in isolation, with its levels increasing in iron deficiency anemia and decreasing in liver diseases, sepsis, malabsorption and inflammatory changes.(4747 Macris PC, McMillen KK. Nutrition support of the hematopoietic cell transplant recipient. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 4th ed. Vol. I. New Jersey (USA): Wiley-Blackwell; 2009. Chapter 99. p.1551-69.,4848 Jeejeebhoy KN. Nutritional assessment. Gastroenterol Clin North Am. 1998;27(2):347-69. Review.) In patients eligible for HSCT, multiple blood transfusions prevent transferrin from being a good evaluation parameter. Values between 200 and 400mg/dL are considered normal. Values below 200mg/dL are considered indicative of mild to moderate protein deficiency, while levels below 100mg/dL suggest severe deficiency. One should avoid using transferrin to evaluate protein depletion in patients with iron deficiency anemia, since in these cases, its levels are increased, reflecting the increase in iron transport.(4949 Carrazza FR, Kimura HM. Avaliação do Estado Nutricional. In: Andriolo A, Carrazza FR. Diagnóstico laboratorial em Pediatria. 2a ed. São Paulo: Sarvier; 2007. p. 325-33.)

The reference values for hepatic proteins (albumin, prealbumin and transferrin) are shown in table 6.

Table 6
Reference values for hepatic proteins

However, it is important to bear in mind that these proteins have a limited role in severe patients, due to hemodilution and liver function changes for production of acute phase proteins decreasing visceral protein levels. As a result of these changes, lower values in these patients reflect more the severity of the disease than the nutritional status.(5252 Raguso CA, Dupertuis YM, Pichard C. The role of visceral proteins in the nutritional assessment of intensive care unit patients. Curr Opin Clin Nutr Metab Care. 2003;6(2):211-6. Review.) It is important to note that some authors have correlated transferrin and prealbumin changes to GVHD.(5353 Muscaritoli M, Conversano L, Cangiano C, Capria S, Laviano A, Arcese W, et al. Biochemical indices may not accurately reflect changes in nutritional status after allogeneic bone marrow transplantation. Nutrition. 1995;11(5):433-6.)

  • Creatinine height index (CHI): an appropriate parameter to evaluate body muscle mass based on the fact that 98% of creatinine is stored in the muscles.(5454 Ritter L, Gazzola J. Avaliação nutricional no paciente cirrótico: uma abordagem objetiva, subjetiva ou multicompartimental? Arq Gastroenterol. 2006; 43(1):66-70.) It is used to evaluate muscle mass and indirectly assess nitrogen balance. Malnourished patients present with severe skeletal muscle degradation, which can be estimated from urinary creatinine levels, a metabolite of the breakdown of creatinine, which is constantly synthetized. It is, therefore, a marker of muscular catabolism.(4242 Garófolo A, Lopez FA, Petrilli AS. High prevalence of malnutrition among patients with solid non-hematological tumors as found by using skinfold and circumference measurements. Sao Paulo Med J. 2005;123(6):277-81.) The CHI is calculated as a percentage of a standard, by dividing urinary creatinine excretion by a standard value for the patient’s height. A normal CHI is around 1. Values lower than 60% of the standard detect patients at increased risk for malnutrition.(4646 Vannucchi H, Unamuno MR, Marchini JS. Avaliação do estado nutricional. Medicina (Ribeirão Preto). 1996;29(1):5-8.) This assessment has some disadvantages, such as being reliable only in patients with normal kidney function, the need for 24-hour urine sampling, interference of age and dietary protein content, among others.(5555 Jeejeebhoy KN. Nutritional assessment. Nutrition. 2000;16(7-8):585-90. Review.)

  • Nitrogen balance: this is a useful method for evaluating protein status. It allows to determine the level of balance between nitrogen intake and urinary nitrogen excretion. When the intake is sufficient to cover losses, the balance is positive. If, on the contrary, losses exceed gains, the balance is negative. It is good for estimating protein intake and degradation and therefore, an important tool in the follow-up and treatment monitoring of transplanted patients.(5656 Paz LS, Couto AV. Avaliação nutricional em pacientes críticos: revisão de literatura. Braspen J. 2016;31(3):269-77.,5757 Acuña K, Cruz T. Avaliação do estado nutricional de adultos e idosos e situação nutricional da população brasileira. Arq Bras Endocrinol Metabol. 2004;48(3):345-61.) Some authors consider that nitrogen balance should not be used as a malnutrition parameter in early treatment phases, due to the impossibility of a positive balance being achieved at this stage, even in patients with adequate nutritional support.(4444 Maicá AO, Schweigert ID. Nutritional assessment of the severely ill patient. Rev Bras Ter Intensiva. 2008;20(3):286-95.)

  • Cholesterol: hypocholesterolemia (under 160mg/dL) has been associated with malnutrition and, consequently, increased mortality in critical patients. However, low serum cholesterol levels are also observed in kidney and liver failure, as well as malabsorption. Increased cholesterol levels are known to be a risk factor for coronary disease.(4444 Maicá AO, Schweigert ID. Nutritional assessment of the severely ill patient. Rev Bras Ter Intensiva. 2008;20(3):286-95.,5757 Acuña K, Cruz T. Avaliação do estado nutricional de adultos e idosos e situação nutricional da população brasileira. Arq Bras Endocrinol Metabol. 2004;48(3):345-61.)

Nutritional therapy algorithms

Some routine examinations in HSCT patients help in decision-making regarding the best nutritional therapy. Although these parameters can be affected by bone marrow adaptation, they are used as a complement for defining the nutritional approach. Their applicability during HSCT is shown in table 7.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
,2222 Viani K, Yonamine G, Gandolfo AS, Lemos PS. Avaliação Nutricional. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. Barueri: Manole; 2017. p. 28-46.)

Table 7
Laboratory parameters their applicability in nutritional therapy during hematopoietic stem cell transplantation

The assessment of nutritional status using biochemistry parameters allows for early diagnosis of nutritional problems, even before anthropometric changes or onset of clinical signs and symptoms, making them an important tool in the follow-up of these patients, combined with other evaluation parameters.(5252 Raguso CA, Dupertuis YM, Pichard C. The role of visceral proteins in the nutritional assessment of intensive care unit patients. Curr Opin Clin Nutr Metab Care. 2003;6(2):211-6. Review.)

Physical examination

Physical examination in pediatrics is an indicator of several pediatric diseases. Despite the potential biases due to the HSCT-related toxicity, the physical examination is recommended as part of the nutritional evaluation, in order to identify clinical signs of malnutrition prior to or resulting from treatment.(2323 Sociedade Brasileira de Pediatria (SBP). Avaliação nutricional da criança e do adolescente: manual de orientação. Departamento de Nutrologia. Rio de Janeiro:SBP; 2009. Capítulo 5. Avaliação da composição corporal. p. 46-51.)

Table 8 shows the main clinical signs that should be observed in the physical examination, and to which diagnosis they may be related in the pediatric age group.(2323 Sociedade Brasileira de Pediatria (SBP). Avaliação nutricional da criança e do adolescente: manual de orientação. Departamento de Nutrologia. Rio de Janeiro:SBP; 2009. Capítulo 5. Avaliação da composição corporal. p. 46-51.)

Table 8
Clinical signs and diagnoses in pediatric patients

Food intake

Nutritional assistance in HSCT must take into account increased energy and nutrient requirements, as well as dietary restrictions for a frail patient, who can often go on to having an unhealthy diet, when it comes to preventing chronic diseases.(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.)

After HSCT, the diet has particular characteristics, and health-related aspects are prioritized at this stage over nutritional aspects.(5959 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.,6060 Raynard B, Nitenberg G, Gory-Delabaere G, Bourhis JH, Bachmann P, Bensadoun RJ, et al. [Standards, options and recommendations for nutritional support in bone marrow transplant patients]. Bull Cancer. 2002;89(4):381-98. French.) The non-consumption of raw foods and other restrictions in food choices lead to dietary deficiencies that must be compensated with dietary supplements and/or drugs. In the post-HSCT phase, it is common to see an increase in intake of low nutritional quality foods, such as unhealthy snacks and fried food. In this sense, the diet does not comply with qualitative recommendations for the prevention of chronic diseases.(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.) Since nutritional requirements after transplantation tend to increase, patients often choose foods that are not so healthy but have a role in weight preservation.(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.)

Food intake is assessed by means of a 24-hour food journal for children over 8 years of age and, for children under 8, this requires support from parents or guardians. It aims to evaluate the qualitative and quantitative intake of calories, micronutrients and macronutrients(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.,6161 Mendes TG, Benedetti FJ. Fatores nutricionais associados ao câncer em crianças e adolescentes. Disciplinarum Scientia. 2013;14(2):265-72.) appropriate to the age group, according to tables 9 to 11.

Table 9
Feeding schedule for breastfed infants (aged zero to 12 months)
Table 10
Feeding schedule for formula-fed infants (aged 0 to 12 months) (age-appropriate formula/milk)
Table 11
Feeding schedule for preschool-age children (1 to 6 years), school-age children (7 to 12 years) and adolescents (over 12 years)

Nutritional requirements

Energy and nutrient recommendations specific to children change according to the age. Since energy should be directed toward maintaining metabolic needs as well as growth and development, energy and nutrient requirements in children and adolescents are increased, placing them at high nutritional risk.(6262 Garófolo A. Diretrizes para terapia nutricional em crianças com câncer em situação crítica. Rev Nutr. 2005;18(4):513-27.6666 Jones L, Watling RM, Wilkins S, Pizer B. Nutritional support in children and young people with cancer undergoing chemotherapy. Cochrane Database Syst Rev. 2010;(7):CD003298. Review. Update in: Cochrane Database Syst Rev. 2015;8:CD003298.)

During the transplant period, many factors can change nutritional requirements, such as a high-dose chemotherapy conditioning regimen, whether or not combined with TBI, mucositis, lack of appetite, nausea, vomiting, diarrhea or anorexia. These manifestations have negative implications for calorie and protein supply as well as nutrient absorption, in addition to leading to increased energy requirements or protein catabolism.(6363 Garófolo A. Contribuição da alimentação e da terapia nutricional para a necessidade de energia em pacientes submetidos ao transplante de medula óssea (TMO). Mundo Saúde. 2011;35(2):193-200.,6464 Ringwald-Smith KA, Heslop HE, Krance RA, Mackert PW, Hancock ML, Stricklin LM, et al. Energy expenditure in children undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30(2):125-30.,6767 Cohen J, Maurice L. Adequacy of nutritional support in pediatric blood and marrow transplantation. J Pediatr Oncol Nurs. 2010;27(1):40-7.7272 Abreu ES, Simony RF, Takahashi AA, Santos CR. Recomendações nutricionais para crianças que realizaram transplante de medula óssea. Rev Ciênc Méd Biol. 2012;11(1):54-9.) In general, patients undergoing allogeneic HSCT are usually more immunocompromised and at higher risk for general complications when compared with autologous HSCT.(6363 Garófolo A. Contribuição da alimentação e da terapia nutricional para a necessidade de energia em pacientes submetidos ao transplante de medula óssea (TMO). Mundo Saúde. 2011;35(2):193-200.) These very aggressive changes that cause metabolic and nutritional abnormalities.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
https://www.ncbi.nlm.nih.gov/books/NBK56...
,7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.)

The reduced energy and protein intake may influence immune function during metabolic stress. Therefore, meeting energy and protein requirements is of extreme importance in order to maintain an adequate nitrogen balance.(7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.) Adequate growth and development in children and adolescents depend on a balanced diet, with satisfactory supply of energy, macro and micronutrients.(6969 Papadopoulou A, Williams MD, Darbyshire PJ, Booth IW. Nutritional support in children undergoing bone marrow transplantation. Clin Nutr. 1998;17(2):57-63.,7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.)

After discharge, patients may have several nutrition-related problems, such as malnutrition due to insufficient oral intake or metabolic disorders. Nutritional support plays an important role in the different types of HSCT.(7575 Fuji S, Einsele H, Savani BN, Kapp M. Systematic nutritional support in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2015;21(10):1707-13. Review.)

In sum, adequate nutritional support before and after transplantation is a potentially important support measure.(7676 Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.) The changes in these patients predominantly affect protein, energy and micronutrient metabolism. During HSCT, energy and protein requirements of children and adolescents must be taken into account to ensure that nutritional support is adapted and adequate to the individual needs of children.(7777 White M, Murphy AJ, Hastings Y, Shergold J, Young J, Montgomery C, et al. Nutritional status and energy expenditure in children pre-bone-marrow-transplant. Bone Marrow Transplant. 2005;35(8):775-9.)

Energy requirements

Energy requirements depend on factors such as baseline nutritional status, age, weight and degree of metabolic stress.(7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.) Although it has been demonstrated that the energy expenditure of patients undergoing HSCT may differ among allogeneic and autologous transplants, there are studies showing that energy requirements of HSCT recipients can reach 130% to 150% of the predicted resting energy expenditure.(7070 Pinheiro SM, Rodrigues VD, Pinto MA, Carvalho CN, Oliveira CL, Rodrigues CS. Metabolic alteration in children with blood cancer undergoing homologous bone marrow transplantation. Ceres (Rio de Janiero). 2010;5(1):27-36.,7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.,7878 Sheean P. Nutrition support of blood or marrow transplant recipients: How much do we really know? Pract Gastro. 2005;29(4):84-97 [Nutrition Issues in Gastroenterology, Series #26].,7979 Chamouard Cogoluenhes V, Chambrier C, Michallet M, Gordiani B, Ranchere JY, Combret D, et al. Energy expenditure during allogeneic and autologous bone marrow transplantation. Clin Nutr. 1998;17(6):253-7.)

It is necessary to know the energy requirements of children during HSCT to ensure appropriate nutritional support.(7777 White M, Murphy AJ, Hastings Y, Shergold J, Young J, Montgomery C, et al. Nutritional status and energy expenditure in children pre-bone-marrow-transplant. Bone Marrow Transplant. 2005;35(8):775-9.)

Energy recommendations can be determined based on a standard estimation equation and the use of indirect calorimetry, the latter being a more accurate measurement of energy requirements.(6464 Ringwald-Smith KA, Heslop HE, Krance RA, Mackert PW, Hancock ML, Stricklin LM, et al. Energy expenditure in children undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30(2):125-30.,6565 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
https://diretrizes.amb.org.br/_Bibliotec...
,7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.)

Bechard et al.,(8080 Bechard LJ, Feldman HA, Venick R, Gura K, Gordon C, Sonis A, et al. Attenuation of resting energy expenditure following hematopoietic SCT in children. Bone Marrow Transplant. 2012;47(10):1301-6.) looked at anthropometric data, food intake, caloric requirements based on the Schofield equation, and resting energy expenditure by calorimetry between HSCT D0 and D+30. In this period, resting energy expenditure is reduced, particularly between D0 and D+21, as well as food intake. Despite controversial studies, the authors suggested that, when indirect calorimetry is not available, the basal metabolic rate and a caloric target of 100% to 140% should be used, and excess supply should be avoided.

Energy requirements should be estimated using standard formulas (Table 12) and adjusted based on the clinical evolution.(6565 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
https://diretrizes.amb.org.br/_Bibliotec...
)

Table 12
Summary of energy requirements of pediatric patients undergoing hematopoietic stem cell transplantation.

During parenteral nutrition, it is recommended that energy requirements be 80% to 90% of the recommendations for enteral nutrition.(6565 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
https://diretrizes.amb.org.br/_Bibliotec...
)

Protein requirements

Protein requirements in pediatric patients are also increased(5959 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.,7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.) and should be qualitatively and quantitatively adequate.(6565 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
https://diretrizes.amb.org.br/_Bibliotec...
) They vary according to age and weight.(5757 Acuña K, Cruz T. Avaliação do estado nutricional de adultos e idosos e situação nutricional da população brasileira. Arq Bras Endocrinol Metabol. 2004;48(3):345-61.) These additional quantities of protein are intended to restore or preserve body lean mass and provide substrate for the hypercatabolic state after HSCT. It is worth noting that, in case of impaired kidney or liver function, these requirements are modified and must be adjusted individually.(7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.)

Reduced protein supply can negatively affect immune function during metabolic stress. Therefore, it is important to adapt protein requirements for a zero nitrogen balance.(6363 Garófolo A. Contribuição da alimentação e da terapia nutricional para a necessidade de energia em pacientes submetidos ao transplante de medula óssea (TMO). Mundo Saúde. 2011;35(2):193-200.) Nutritional support that is adequate to prevent protein loss, without providing too many calories and promoting fat accumulation, is essential for the survival of patients undergoing transplantation.(6464 Ringwald-Smith KA, Heslop HE, Krance RA, Mackert PW, Hancock ML, Stricklin LM, et al. Energy expenditure in children undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30(2):125-30.)

Protein requirements are estimated (Table 13) in order to provide substrate for tissue repair after cytoreduction and decrease lean mass loss after HSCT. Overall, values range from 1.4g/kg to 3.0g/kg body weight.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
https://www.ncbi.nlm.nih.gov/books/NBK56...
,7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.)

Table 13
Summary of energy requirements in pediatric patients undergoing hematopoietic stem cell transplantation

Micronutrient requirements

Vitamins are considered important for growth and vary according to age.(6565 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
https://diretrizes.amb.org.br/_Bibliotec...
)

Levels of vitamins, both water-soluble and fat-soluble, are abnormal in patients undergoing HSCT, as a result of low intake or malabsorption. Other factors also play a role, such as cyclosporine and radiotherapy, which lead to increased vitamin requirements.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
https://www.ncbi.nlm.nih.gov/books/NBK56...
,7575 Fuji S, Einsele H, Savani BN, Kapp M. Systematic nutritional support in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2015;21(10):1707-13. Review.)

For all patients not receiving parenteral nutrition, it is advised to offer oral multivitamin and mineral supplements, due to their limited intake regular foods, often for a prolonged period.(8181 Akbulut G. Medical nutritional therapy in hematopoietic stem cell transplantation (HSCT). Int J Hematol Oncol. 2013;23(1):55-65.)

Some micronutrients are particularly relevant in HSCT:

  • Vitamin D or cholecalciferol: Vitamin D deficiencies are prevalent in patients with GVHD. This vitamin has an endocrine role as a key regulator of calcium absorption and bone homeostasis and also immune system regulation. It is required for development and maintenance of bone tissue and maintenance of calcium and phosphorus homeostasis. Without vitamin D, only 10% to 15% of the calcium ingested and approximately 60% of the phosphorus would be absorbed.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
    https://www.ncbi.nlm.nih.gov/books/NBK56...
    ,7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.) Patients undergoing HSCT present with vitamin D insufficiency or deficiency, possibly due to post-transplant decreased food intake and avoiding sun exposure.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
    https://www.ncbi.nlm.nih.gov/books/NBK56...
    ,7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.)

  • Vitamin K: low levels in HSCT increase the risk of severe hemorrhage. The etiology of vitamin K deficiency is often multifactorial and often results from drug antagonism, liver dysfunction, malabsorption, anorexia and/or inadequate intake of nutrients.(8282 Barron MA, Doyle J, Zlotkin S. Vitamin K deficiency in children pre-bone marrow transplantation. Bone Marrow Transplant. 2006;37(2):151-4.)

  • Zinc: Zinc deficiency is prevalent in patients after allogeneic HSCT, particularly in those with diarrhea. Zinc is necessary for good genetic functioning, immunity, red blood cell formation, organs, muscle and bone function, and cell membrane stability, in addition to cell growth, division and genetic differentiation. It also plays an important role in the context of metabolic response to injury and wound healing.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.) Zinc sulphate is considered a promising agent for prevention of mucositis, which occurs during HSCT, for being an essential cofactor in several cellular processes, such as DNA, RNA polymerase and reverse transcriptase synthesis, and having an effect on wound healing, growth and immunity.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.) Clinical manifestations of zinc deficiency, such as anorexia, rash, diarrhea and infections, are also common.(6969 Papadopoulou A, Williams MD, Darbyshire PJ, Booth IW. Nutritional support in children undergoing bone marrow transplantation. Clin Nutr. 1998;17(2):57-63.,7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
    https://www.ncbi.nlm.nih.gov/books/NBK56...
    )

  • Ferritin: an intracellular iron storage and transport protein, directly related with proper intake of this micronutrient, and found in virtually all cells of the body, mainly in hepatocytes and body fluids. In plasma, it is present in small concentrations and correlates with iron stocks in the body. Its primary function is to accumulate intracellular iron, which, in its biologically available form, is vital for cellular processes, protecting proteins, lipids and DNA, in addition to playing an important role in inflammatory conditions.(7171 Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
    https://www.ncbi.nlm.nih.gov/books/NBK56...
    )

Micronutrient needs for HSCT patients are not fully established, and usually, the Dietary Reference Intake (DRI) recommendations for healthy populations should be followed, but some items are worth highlighting, as shown in table 14.

Table 14
Recommended differential intake of some micronutrients for children during hematopoietic stem cell transplantation

Frequent nutritional complications

The immunosuppressive therapy used is aggressive and has high toxicity, causing clinical signs and symptoms such as nausea, vomiting, abdominal pain, altered sense of taste, oropharyngeal mucositis, odynophagia, xerostomia, esophagitis, diarrhea, infections, bleeding and anemia.(8585 de Castro CG Jr, Gregianin LJ, Brunetto AL. Clinical and epidemiological analysis of bone marrow transplantation in a pediatric oncology unit. J Pediatr (Rio J). 2003;79(5):413-22.8989 Orasch C, Weisser M, Mertz D, Conen A, Heim D, Christen S, et al. Comparison of infectious complications during induction/consolidation chemotherapy versus allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(3):521-6.) These changes may persist for weeks after transplantation, with negative consequences for the patient, mainly in caloric, protein and nutrient supply, leading to progressive impairment of nutritional status.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
)

In addition to increased energy requirements in these patients, aiming to maintain adequate development in this age group, professionals should be mindful of the catabolic effects of the underlying disease, as well as signs and symptoms related to treatments, which can decrease patients’ caloric intake.(9090 Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur J Oncol Nurs. 2005;9 Suppl 2:S51-63. Review.)

The daily routine of these patients is deeply affected by these symptoms, warranting the need for effective management by their healthcare provider.(9191 Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51(4):232-48; quiz 249-52. Erratum in: CA Cancer J Clin. 2001;51(5):320.)

Nausea and vomiting

The diagnosis of nausea is clinical and based on the history reported by patients and their family, due to its subjective nature. It is important to question the patient about their desire to eat, feeling of weakness, mechanical difficulty to swallow, presence of thirst and/or hunger, reaction to certain foods and odors, and symptom-triggering factors. Assessment of the patient’s nutritional status and signs of dehydration can contribute to the diagnosis of chronic and/or intense nausea. A diagnosis of vomiting is also based on clinical history, and it is important to quantify episodes and the volume in each episode.(9292 Maciel MG, Bettega R. Náusea e vômito. In: Carvalho RT, Parsons HA. Manual de cuidados paliativos Academia Nacional de Cuidados Paliativos. 2a ed. ampl. e atualizado. São Paulo: ANCP; 2012. p.168-75. Parte 2 – Controle de sintomas.)

During HSCT, nausea and vomiting may be associated with the conditioning protocol (chemotherapy or radiotherapy), as well as other causes, such as medications (antimicrobials and opioids); systemic infections; metabolic abnormalities, such as hyperkalemia and hyponatremia; adrenocortical insufficiency; increased intracranial pressure; gastric irritations and/or ulcerations; constipation; intestinal obstruction, such as gastroesophageal reflux and gastric stasis; and psychological alterations, such as anxiety and emotional stress. Many patients suffer with nausea and vomiting, which may cause severe discomfort, such as pain, dehydration, hiccups, heartburn and anorexia.(9292 Maciel MG, Bettega R. Náusea e vômito. In: Carvalho RT, Parsons HA. Manual de cuidados paliativos Academia Nacional de Cuidados Paliativos. 2a ed. ampl. e atualizado. São Paulo: ANCP; 2012. p.168-75. Parte 2 – Controle de sintomas.) Proper care and management of these symptoms are key to providing comfort and quality of life to children or adolescents and their families during all treatment phases.(9292 Maciel MG, Bettega R. Náusea e vômito. In: Carvalho RT, Parsons HA. Manual de cuidados paliativos Academia Nacional de Cuidados Paliativos. 2a ed. ampl. e atualizado. São Paulo: ANCP; 2012. p.168-75. Parte 2 – Controle de sintomas.)

For successful management and control of nausea and vomiting in the pediatric population, a complete evaluation is necessary, considering possible causes, such self-reports by children or adolescents and their caregivers. A detailed past history of nausea and vomiting, the frequency of these symptoms, periods in which they most present, their description and intensity, such as quantity and characteristic of the content expelled, times of the episodes, and associated and/or predisposing factors are extremely important for the efficacy of the treatment of choice.(9393 Santucci G, Mack JW. Common gastrointestinal symptoms in pediatric palliative care: nausea, vomiting, constipation, anorexia, cachexia. Pediatr Clin North Am. 2007;54(5):673-89, x. Review.)

Dietary measures must be adequate to each patient’s individual needs, preferences and eating habits,(9494 Benarroz MO, Faillace GB, Barbosa LA. Bioética e nutrição em cuidados paliativos oncológicos em adultos. Cad Saude Publica. 2009;25(9):1875-82.) and, when used together with antiemetic agents, can potentially help reduce their frequency and dose.(9393 Santucci G, Mack JW. Common gastrointestinal symptoms in pediatric palliative care: nausea, vomiting, constipation, anorexia, cachexia. Pediatr Clin North Am. 2007;54(5):673-89, x. Review.) Some simple measures may help in the control of nausea and vomiting, such as diet fractionation in small meals at shorter intervals, eating meals in quiet and well-ventilated environments, observance of established hours for meals, and the supply of small quantities of carbohydrates and foods preferred by the patient.(9191 Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51(4):232-48; quiz 249-52. Erratum in: CA Cancer J Clin. 2001;51(5):320.,9292 Maciel MG, Bettega R. Náusea e vômito. In: Carvalho RT, Parsons HA. Manual de cuidados paliativos Academia Nacional de Cuidados Paliativos. 2a ed. ampl. e atualizado. São Paulo: ANCP; 2012. p.168-75. Parte 2 – Controle de sintomas.) In addition, it is important that the patient’s head be kept elevated for up to 1 to 2 hours after eating; avoid extreme temperatures, favoring foods at room temperature or cold; keep patients away from the kitchen when means are being prepared, since the smell of foods during cooking can aggravate the nausea; and avoid deep-fried, greasy, spicy, savory, acidic, sugary foods, as well as those with strong odors.(9191 Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51(4):232-48; quiz 249-52. Erratum in: CA Cancer J Clin. 2001;51(5):320.)

Graft versus host disease in children

GVHD is one of the main post-procedural complications of BMT. It can be classified as acute (aGVHD) and chronic (cGVHD). Acute GVHD classically occurs in the first 100 days after BMT and affects mostly the skin, liver and gastrointestinal tract (GIT). Chronic GVHD classically starts more than 100 days after BMT and may affect one or more organs. The main sites involved in GVHD are skin, liver, mouth, eyes, musculoskeletal system, lungs and genitals. It can last from several months to years and is similar to an autoimmune disease, characterized by the presence of inflammation and, later, fibrosis of the affected tissues and organs.(9595 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.,9696 Funke VA, Moreira MC, Vigorito AC. Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. Rev Assoc Med Bras (1992). 2016;62(Suppl 1):44-50. Review.)

In the GIT, the main clinical manifestations of GVHD, both acute and chronic, are nausea, vomiting, anorexia, diarrhea, abdominal pain and dysphagia. Depending on the intensity of symptoms, patients may develop mild, moderate and severe forms. The condition may also be aggravated by immunosuppressive treatment, which consists, in most cases, of high-dose corticosteroids associated or not with calcineurin inhibitors (cyclosporine and tacrolimus). These medications can potentially exacerbate symptoms, either by direct effect or by facilitating infections. As a result, patients develop severe protein-caloric malnutrition, usually multifactorial, due to reduced food intake, malabsorption and increased energy expenditure. Also, as a result of GVHD and its management, the metabolism of carbohydrates, lipids and proteins is disrupted. In this context, nutritional therapy is extremely important as treatment support, to fight the harmful effects of GVHD and to circumvent the adverse effects of medications.(7676 Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.,8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.,9595 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.,9696 Funke VA, Moreira MC, Vigorito AC. Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. Rev Assoc Med Bras (1992). 2016;62(Suppl 1):44-50. Review.)

Patients with GVHD have difficulty eating foods for various reasons, depending on the organ involved. Often, they require dietary changes, oral supplements, and nutritional support therapy (NST) to prevent or manage malnutrition.(9595 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.) According to Bassim et al.,(9797 Bassim CW, Fassil H, Dobbin M, Steinberg SM, Baird K, Cole K, et al. Malnutrition in patients with chronic GVHD. Bone Marrow Transplant. 2014;49(10):1300-6.) the main indications for the onset of NST are uncontrolled nausea and vomiting, voluminous diarrhea, oral mucosal and esophageal pain, dysphagia, dysgeusia, xerostomia, anorexia, early satiety and weight loss. In particular, aGVHD in the GIT and oral, gastrointestinal and pulmonary cGVHD lead to severe malnutrition and impairment of patients’ functional capacity and quality of life – hence the need for early onset of NST.

According to the Oncology Nutrition Consensus of the National Cancer Institute José de Alencar,(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
) some nutritional interventions may be oriented to improving and controlling gastrointestinal symptoms.

Regardless of the type and grade of GVHD, when patients’ food intake is less than 70% of energy requirements for the last 3 days, and symptoms impair adequate nutrition, it is important to intervene with hypercaloric and hyperproteic nutritional supplements.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
)

If food intake is less than 60% of energy requirements in the last 3 days, or oral route is contraindicated, enteral nutrition therapy (ENT) may be prescribed.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
) The enteral route, if tolerable and clinically feasible, can be selected because it maintains digestive function and mucous barrier integrity, preventing bacterial translocation in the digestive tract.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.)

According to a systematic review by Baumgartner et al.,(7676 Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.) several studies have compared ENT with parenteral nutrition therapy (PNT), showing superior results for the enteral route, and moderate to high tolerance of the tube, whereas PNT is recommended only in cases of gastrointestinal insufficiency. ENT is contraindicated in the presence of hemodynamic instability and/or worsening of abdominal pain, abdominal distension, mucositis, diarrhea, incoercible vomiting, paralytic ileus and intestinal bleeding.(2020 Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
https://www.inca.gov.br/sites/ufu.sti.in...
)

However, particularly among patients with GVHD in the GIT, most often there is no tolerance to oral or enteral nutrition. In the presence of severe diarrhea (>1L a day), oral fasting for days to weeks is essential to alleviate gastrointestinal complaints. Nutritional support consists of PNT.(8282 Barron MA, Doyle J, Zlotkin S. Vitamin K deficiency in children pre-bone marrow transplantation. Bone Marrow Transplant. 2006;37(2):151-4.) Studies have shown that patients with grade III to IV GVHD receive more PNT than patients with grade zero to II GVHD, and are not free from clinical complications related to the progression of days on PNT. (7474 Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.)

As the volume of diarrhea decreases during intestinal GVHD (<500mL per day), oral feeding can be resumed, but certain foods may be better tolerated than others.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.) Many centers use nutritional therapy based on a phased diet, which, according to symptoms and patient tolerance, may progress or regress. According to the general guidelines of the Seattle Cancer Care Alliance,(9898 lowers ME, McDonald G, Carpenter P, Boeckh M, Sanders J, Deeg J, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. Seattle (WA): Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 2019. p.88 [cited 2019 Nov 26]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/physician.pdf
https://www.fredhutch.org/content/dam/pu...
) progression of specific diets should include limited contents of fat, fibers, lactose, acid foods and gastric irritants, to be gradually reintroduced based on patient tolerance, as shown in table 15.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.)

Table 15
Progression of nutritional therapy for graft versus host disease in the gastrointestinal tract based on the Seattle Cancer Care Alliance protocol

Immunosuppression with corticosteroids is the foundation of first-line therapy in aGVHD and cGVHD.(100100 Garnett C, Apperley JF, Pavlů J. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol. 2013;4(6):366-78. Review.) The use of calcineurin inhibitors is also common for prevention and management of these two types of GVHD.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.)

During treatment with high-dose glucocorticoids and/or calcineurin inhibitors, proper patient guidance is important. Frequent and smaller meals are recommended, as well as soluble and insoluble fiber-rich foods, high-protein diet, with low-simple, high-glycemic carbs, low sodium, adequate water intake, and adequate intake of foods that are sources of vitamin D, calcium, magnesium and zinc and, if necessary, supplementation of these elements.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.,101101 Cuppari L. Guia de Medicina Ambulatorial e Hospitalar Nutrição da clínica ESPM/UNIFESP. Nutrição: clínica no adulto. 3a ed. Barueri, SP: Manole; 2013. p.167.)

Monitoring vitamin and mineral levels is of paramount importance in the GIT GVHD, due to the presence of diarrhea and poor nutrient absorption in these patients.(102102 Mattsson J, Westin S, Edlund S, Remberger M. Poor oral nutrition after allogeneic stem cell transplantation correlates significantly with severe graft-versus-host disease. Bone Marrow Transplant. 2006;38(9):629-33.) Vitamin B12 levels should be observed more carefully due to intrinsic factor insufficiency in patients with gastric GVHD. Similarly, zinc levels are relevant for their role in maintaining intestinal mucosal integrity and taste acuity, and improving dysgeusia.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.)

Supplementation of other nutrients, such as omega 3, glutamine, arginine and nucleotides, seems beneficial in patients with GVHD, however studies are scarce and with small populations, and more scientific evidence is needed for safe prescription.(8383 van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.)

aGVHD and cGVHD, complications that evolve with severe nutritional changes, make patients susceptible to malnutrition. If not managed properly, they reduce patient survival and quality of life, and follow-up is required for those affected, as well as nutritional intervention.

Mucositis

Oral mucositis is an inflammatory condition(103103 Viet CT, Corby PM, Akinwande A, Schmidt BL. Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res. 2014;93(9):868-75. Review.105105 Al-Ansari S, Zecha JA, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Health Rep. 2015;2(4):202-11. Review.) and one of the main complications associated with HSCT, affecting 60% to 80% of cases undergoing myeloablative conditioning regimens.(106106 Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27(3):159-64. Review.,107107 Duncan M, Grant G. Oral and intestinal mucositis - causes and possible treatments. Aliment Pharmacol Ther. 2003;18(9):853-74. Review.)

Although it can occur throughout the digestive tract, oral mucositis is considered one of the most uncomfortable and painful experiences during treatment,(103103 Viet CT, Corby PM, Akinwande A, Schmidt BL. Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res. 2014;93(9):868-75. Review.,108108 Sonis ST. Oral mucositis in head and neck cancer: risk, biology, and management. Am Soc Clin Oncol Educ Book. 2013;33:e236-40. Review.) and is often the main cause of discomfort in early stages of treatment. In this phase, it is common to see reduced food intake, nutritional impairment, weight loss, infectious complications, need for parenteral nutrition, use of opioids and, sometimes, prolonged hospital stay.(106106 Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27(3):159-64. Review.,109109 Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, et al. The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant. 2016;22(4):605-16. Review.)

The most commonly used criteria for mucositis classification are those defined by the WHO and the National Cancer Institute (NCI),(110110 American National Standards Institute (ANSI). National Institute of Cancer. Common terminology criteria for adverse events v3.0 (CTCAE). New York: CTCAE; 2006 [cited 2019 Nov 25]. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
http://ctep.cancer.gov/protocolDevelopme...
) which take into account signs and symptoms such as pain, erythema, ulcerations, function and feeding capacity (Table 16).

Table 16
Grading scale classification of oral mucositis

Mucositis is clinically characterized by pain, edema, erythema, ulcerations and formation of pseudomembranes. These changes are associated with limitation of oral cavity, speech and swallowing functions, impacting the quality of life of patients.(103103 Viet CT, Corby PM, Akinwande A, Schmidt BL. Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res. 2014;93(9):868-75. Review.105105 Al-Ansari S, Zecha JA, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Health Rep. 2015;2(4):202-11. Review.,111111 Bensinger W, Schubert M, Ang KK, Brizel D, Brown E, Eilers JG, et al. NCCN task force report. prevention and management of mucositis in cancer care. J Natl Comp Canc Netw. 2008;6(Suppl 1):S1-21; quiz S22-4. Review.)

The etiology of pain in oral mucositis is of both nociceptive and neuropathic origin. Mechanical nociception results in oral dysfunction of patients with oral mucositis. Neuropathic pain is caused by neuronal sensitization resulting from the action of chemotherapeutic agents and inflammatory mediators (glutamate, neuropeptides and proinflammatory cytokines, such as interleukin – IL – 1, IL-6 and tumor necrosis factor alpha – TNF-α), which aggravates neuronal sensitization.(103103 Viet CT, Corby PM, Akinwande A, Schmidt BL. Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res. 2014;93(9):868-75. Review.)

The clinical course of mucositis is usually predictable, with the first signs appearing between 3 and 4 days after onset of conditioning and ulcerations appearing soon afterwards, and more intensely between days 7 and 14, usually with spontaneous resolution in the following week or concomitant to grafting.(106106 Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27(3):159-64. Review.,111111 Bensinger W, Schubert M, Ang KK, Brizel D, Brown E, Eilers JG, et al. NCCN task force report. prevention and management of mucositis in cancer care. J Natl Comp Canc Netw. 2008;6(Suppl 1):S1-21; quiz S22-4. Review.)

The incidence and severity of mucositis cases are associated with treatment-related factors,(112112 Turner L, Mupparapu M, Akintoye SO. Review of the complications associated with treatment of oropharyngeal cancer: a guide for the dental practitioner. Quintessence Int. 2013;44(3):267-79. Review.) such as myeloablative conditioning regimens,(113113 Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R, et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol. 2000;110(2):292-9.) particularly those containing TBI, high-dose melphalan and busulfan, and use of methotrexate for GVHD prophylaxis.(105105 Al-Ansari S, Zecha JA, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Health Rep. 2015;2(4):202-11. Review.,109109 Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, et al. The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant. 2016;22(4):605-16. Review.,114114 Lionel D, Christophe L, Marc A, Jean-Luc C. Oral mucositis induced by anticancer treatments: physiopathology and treatments. Ther Clin Risk Manag. 2006;2(2):159-68.)

The pathogenesis of mucositis is multifactorial, and current models include different biological events during the course of mucositis, with a chronological process of five different, independent phases, which involve, in chronological order, cell initiation/death; generation of oxidative agents/activation of inflammatory cytokines; amplification and signaling; ulceration and recovery/cure, as shown in figure 1.(104104 Sonis ST. Oral mucositis in cancer therapy. J Support Oncol. 2004;2(6 Suppl 3): 3-8. Review.,106106 Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27(3):159-64. Review.,113113 Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R, et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol. 2000;110(2):292-9.,115115 Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005;11(5):383-8.)

Figure 1
Development phases of mucositis

Management of mucositis involves management of symptoms and prevention of complications, including pain control, nutritional support, prophylaxis and treatment of secondary infections, as shown in table 17.(105105 Al-Ansari S, Zecha JA, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Health Rep. 2015;2(4):202-11. Review.,116116 Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am. 2008;52(1):61-77, viii. Review.)

Table 17
General care for mucositis prophylaxis

After oral mucositis is present, management should be palliative only. Glutamine (L-glutamine or L-alanyl-L-glutamine) is used at high concentrations by rapidly dividing cells, so its use in prevention and management of oral mucositis has been studied, although its relevance has not yet been proven.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.)

Cryotherapy is widely used in the prevention of mucositis caused by chemotherapy agent with a short half-life, such as bolus 5-fluorouracil or high-dose melphalan in HSCT conditioning regimes. It is usually performed with ice water or ice chips. In pediatrics, it is possible to encourage this practice by offering ice cream and popsicles or using frozen pacifiers or bottle nipples by dipping them in drinking water and then chilling them in a freezer, or even freeze breast milk or formula in the form of popsicles and offer to the infant 10 minutes before the start until the end of the drug infusion.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.)

After oral mucositis is present, oral nutritional therapy consists of dietary adaptations, according to table 18, and/or parenteral nutrition. If the patient already has a nasoenteral tube, enteral diet can be used. Otherwise, passing a nasoenteral tube not indicated in patients with established severe oral mucositis.

Table 18
Dietary changes in oral diet for patients with oral mucositis

Anorexia and cachexia

Anorexia (loss of appetite) is a common concomitant symptom in people with cancer. Cancer anorexia has many causes, but the primary cause is often an increase in proinflammatory cytokines or lactate. These two factors, therefore, modulate the neurotransmitter cascades of the central nervous system.(121121 Davis MP, Dickerson D. Cachexia and anorexia: cancer’s covert killer. Support Care Cancer. 2000;8(3):180-7. Review.)

Cancer cachexia is a multifactorial syndrome covering a spectrum from initial weight loss (pre-cachexia) to a state of severe disability incompatible with life. The main defining characteristics of cachexia in humans are weight loss, reduced food intake and systemic inflammation. Nutritional support in cachexia can stabilize and improve nutritional status, function and quality of life.(121121 Davis MP, Dickerson D. Cachexia and anorexia: cancer’s covert killer. Support Care Cancer. 2000;8(3):180-7. Review.)

There is a large prospective study in which post-BMT patients were followed up for up to 6 years and had a lean mass index lower than that of healthy controls. Those with cGVHD and on corticosteroids were the most affected.(122122 Kyle UG, Chalandon Y, Miralbell R, Karsegard VL, Hans D, Trombetti A, et al. Longitudinal follow-up of body composition in hematopoietic stem cell transplant patients. Bone Marrow Transplant. 2005;35(12):1171-7.)

Factors such as persistent vomiting and nausea, constipation, diarrhea (induced by chemotherapy, infection and GVHD), mucositis (induced by chemotherapy, infection and GVHD), altered or lost sense of taste, as well altered sense of smell and metabolic disorders, may cause patients undergoing HSCT to reduce their food intake and lose weight.(123123 Muscaritoli M, Bossola M, Aversa Z, Bellantone R, Rossi Fanelli F. Prevention and treatment of cancer cachexia: new insights into an old problem. Eur J Cancer. 2006;42(1):31-41. Review.)

More than any other, anorexia is seen as the main symptom of onset of clinical and metabolic signs that precede cachexia, potentially causing significant and involuntary weight loss.(124124 Manzoli B, Bouchabki G, Nabarrete J, Oliveira V. Manejo de sintomas e complicações. In. Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 127-51.)

In patients with CTT, socioeconomic, medical and physical factors may lead to anorexia-cachexia syndrome, even after hospital discharge.(121121 Davis MP, Dickerson D. Cachexia and anorexia: cancer’s covert killer. Support Care Cancer. 2000;8(3):180-7. Review.) therefore, signs and symptoms, such as anorexia, weight loss, changes in biochemical tests and changes in body composition, should be frequently followed up, so that nutritional intervention occurs as early as possible, avoiding interference in the performance status and quality of life of the patient, As well as with the increased risk of complications, such as GVHD.(125125 Barber MD. The pathophysiology and treatment of cancer cachexia. Nutr Clin Pract. 2002;17(4):203-9.127127 Jatoi A, Loprinzi CL. Anorexia and weight loss. In: Berger AM, Portenoy RK, Weissman DE, editors. Principles and practice of palliative care and supportive oncology. 2nd ed. Philadelphia (PA): Lippincott Williams & Wilkin; 2002. p. 169-77.)

Therefore, it is necessary to think about all the symptoms present and how to manage them. The work of the nutrition team is to show the patient and their family the importance of eating, however, with no pressure and without ever forcing the patient to eat. The goal is to increase the amount of food ingested, in addition to normalizing appetite and food acceptance, to meet or get as close as possible to nutritional requirements.(124124 Manzoli B, Bouchabki G, Nabarrete J, Oliveira V. Manejo de sintomas e complicações. In. Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 127-51.)

Some nutritional recommendations may be made before these symptoms appear, such as(124124 Manzoli B, Bouchabki G, Nabarrete J, Oliveira V. Manejo de sintomas e complicações. In. Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 127-51.) increasing meal fractionation; reducing meal volume, eating smaller portions (e.g. finger food); replacing meals with complete snacks; modifying food consistency, if necessary; avoiding greasy or rich sauce preparations; improving the presentation of meals, using different utensils, such as casseroles and colored plates; eating meals in pleasant surroundings; allowing to choose meals according to acceptance, at different treatment stages, as a strategy to increase intake; avoiding excessive pressure to eat; avoiding drinking too much liquids, especially during meals; increasing caloric density of preparations, using nutritional supplements, if necessary; and using enteral and/or parenteral diet, if necessary, according to the patient’s nutritional and clinical condition.

Drug-related nephrotoxicity

Renal complications are very frequent and contribute to procedure-related morbidity and mortality. The causes may be conditioning chemotherapy, TBI, nephrotoxic agents (e.g., calcineurin inhibitors), infections, liver SOS (formerly known as veno-occlusive disease - VOD), transplant-associated thrombotic microangiopathy, and GVHD.(128128 Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-67. Review.)

We know that the incidence of acute kidney injury (AKI) is less frequent in autologous transplantation and more prevalent mainly in myeloablative allogeneic transplantation. The onset (within the first 30 days after transplantation) and severity of kidney function worsening are associated with a gradual increase in the risk of death decrease in overall survival. In patients requiring dialysis, mortality may vary between 55% and 100% of the cases.(128128 Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-67. Review.) The incidence of chronic kidney disease (CKD) varies greatly, from 7% to 48% of cases, and it can occur from 6 months to 10 years after transplantation.(129129 Pulsipher MA, Skinner R, McDonald GB, Hingorani S, Armenian SH, Cooke KR, et al. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012;18(3):334-47.)

In the initial evaluation of patients undergoing HSCT who present with signs of kidney impairment, one should attempt to establish the cause of this deterioration. It is important to obtain a complete urine examination, the urinary albumin-urine-creatinine ratio, a complete blood count with blood smear evaluation, and serum lactate dehydrogenase, haptoglobin and calcineurin inhibitors levels. Viral screening, particularly BK and adenovirus, should also be carried out. In individualized cases, kidney biopsy can be considered, to potentially identify GVHD, endothelial lesion and chronic inflammation.(128128 Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-67. Review.,129129 Pulsipher MA, Skinner R, McDonald GB, Hingorani S, Armenian SH, Cooke KR, et al. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012;18(3):334-47.)

Nephrotoxic agents frequently used in transplantation can be divided into three major classes: chemotherapeutic agents (e.g., cyclophosphamide, carboplatin and fludarabine); antimicrobials, antivirals and antifungal agents (e.g., vancomycin, acyclovir and amphotericin) and immunosuppressants (e.g. calcineurin inhibitors such as cyclosporin and tacrolimus).(128128 Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-67. Review.)

Up to 70% of children and adults undergoing HSCT have hypertension for the first 2 years after the procedure. Systemic arterial hypertension in children and adolescents is defined as systolic or diastolic BP above the 95th percentile for gender, age and height, measured in at least three different occasions. Predisposing factors include treatment with cyclosporine, acute kidney injury, TBI, obesity and diabetes. Hypertension has been associated with a higher probability of CKD. Its management must include dietary and lifestyle modifications, in addition to drug therapy, when necessary.(129129 Pulsipher MA, Skinner R, McDonald GB, Hingorani S, Armenian SH, Cooke KR, et al. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012;18(3):334-47.,130130 National High Blood Pressure Education Progra Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555-76.)

When AKI is established, not only water, electrolytic and acid-basic metabolism is affected, but there is also interference in the metabolism of all macronutrients, leading to pro-inflammatory, pro-oxidative and hypercatabolic situations. In addition to consequences related to AKI itself, there are also contributions of the underlying disease, HSCT and its complications, which may worsen the patient’s nutritional depletion, leading to the so-called protein-energy wasting syndrome (PEW).(131131 Berbel MN, Pinto MP, Ponce D, Balbi AL. Nutritional aspects in acute kidney injury. Rev Assoc Med Bras (1992). 2011;57(5):600-6. Review.)

The therapeutic approaches targeted at delaying progression of kidney injury include reduction of protein intake to control the glomerular filtration rate (GFR). Progressive loss of renal function leads to CKD, classified in stages 1 to 5 based on GFR changes, which determine when dialysis should be initiated.(132132 Takakura CY, Murakami DK. Nefropatias. In: da Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 383-92.)

Recommended protein amounts follow the recommendations of the National Kidney Foundation and Kidney Disease Outcomes Quality Initiative (NFK KDOQUI)™, as shown in table 19.(132132 Takakura CY, Murakami DK. Nefropatias. In: da Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 383-92.)

When dialysis is needed, be it hemodialysis or peritoneal dialysis, protein supply should be maintained at 100% of DRI for ideal weight plus the amount corresponding to proteins and amino acids lost in the process (Table 20).(132132 Takakura CY, Murakami DK. Nefropatias. In: da Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 383-92.)

Table 19
Protein recommendation in stage 3 to 5 chronic kidney disease
Table 20
Protein recommendations in dialysis

Carbohydrates, lipids, sodium, potassium, calcium, phosphorus and liquids vary according to the level of kidney function impairment and comply with the recommendations in tables 21 and 22.(132132 Takakura CY, Murakami DK. Nefropatias. In: da Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 383-92.)

Table 21
Recommendations for macronutrients
Table 22
Recommendations for micronutrients and liquids

Sinusoidal obstruction syndrome

SOS, formerly called VOD, can be a serious complication after HSCT. It was initially described in patients who consumed tea containing pyrrolizidine alkaloids. Although it may occur in many other settings, such as after liver irradiation, exposure to hepatotoxic chemotherapy agents, use of azathioprine, or, more recently, gemtuzumab ozogamycin, SOS is most commonly seen in the context of high-dose chemotherapy with HSCT, and was first described in 1979.(133133 Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-9. Review.)

It usually develops within the first 30 days after HSCT, although it may occur later. Historically, its incidence varies from approximately 5% to 60% in adults, and this variation is not only related to the intensity of the conditioning regimen, the type of transplantation and the presence of risk factors, but also to the clinical criteria used in diagnosis. In general, the frequency and severity of SOS have decreased in recent years as a result of changes in preparative regimens. Severity varies greatly, ranging from mild forms, which resolve within a few weeks, to a severe syndrome, defined by the presence of multiple organ failure and associated with high mortality.(134134 Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.)

The incidence of SOS in pediatric patients undergoing HSCT ranges from 11% to 31%, with an associated mortality rate of up to 50%.(135135 Lee SH, Yoo KH, Sung KW, Koo HH, Kwon YJ, Kwon MM, et al. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant. 2010; 45(8):1287-93.)

SOS occurs due to damage caused by the conditioning regimen to liver sinusoidal endothelial cells and hepatocytes, with fibrinogen deposition, factor VIII, and erythrocyte congestion, resulting in sinusoidal enlargement and occlusion, which can progress to abnormal liver architecture and centrilobular necrosis. In late stages of the disease, there is fibrosis and occlusion of terminal venules, leading to liver failure and possibly death. In parallel to physical damage, there is a procoagulant state with increased levels of plasminogen activator inhibitor 1 and low levels of antithrombin, protein C and factor VII.(136136 Chao N. How I treat sinusoidal obstruction syndrome. Blood. 2014; 123(26):4023-6.)

Understanding the risk factors associated with SOS development is important for early treatment or prophylaxis. Overall, risk factors can be divided into two categories: pre-transplant patient characteristics and transplant-related factors. The main transplant-related risk factors related for SOS are(134134 Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.) allo HSCT, unrelated donor, HLA-incompatible donor, myeloablative conditioning regimen, busulfan- or TBI-based conditioning regimen, non-T-cell-depleted grafts, and second HSCT. Patient-related factors are: older patients (in the adult population); women on norethisterone; Karnofsky score under 90%; genetic polymorphism (GSTM1, GSMTT1 and heparanase); advanced diseases (after second remission or recurrence); metabolic syndromes; antithrombin III deficiency, and plasminogen activator factor; activated protein C resistance and thalassemia. Liver-related factors are transaminases > 2.5 times the upper limit of normality; serum bilirubin > 1.5 time the upper limit of normality; cirrhosis; liver fibrosis; active viral hepatitis; liver irradiation; previous use of gemtuzumab ozogamycin; use of hepatotoxic drugs; and iron overload. Specific factors of the pediatric population include: hemophagocytic lymphohistiocytosis, adrenoleukodystrophy and osteopetrosis; autologous HSCT with high-dose chemotherapy in neuroblastoma; young age (under 1 to 2 years); low weight and juvenile myelomonocytic leukemia.

SOS is clinically characterized by fluid retention and ascites, jaundice, weight gain and tender hepatomegaly, in the absence of other identifiable causes of liver disease. There are two classic clinical criteria for a diagnosis of SOS. One of them is the Baltimore classification, according to which, in the first 21 days after HSCT, patients must present with bilirubin ≥2mg/dL and two or more of the following findings: tender hepatomegaly, ascites and weight gain (≥5% of baseline weight). There is also the Seattle criteria, establishing, within the first 20 days after HSCT, two or more of the following findings: bilirubin ≥2mg/dL, hepatomegaly or pain in the upper right quadrant of the abdomen and weight gain (≥2% of the baseline weight).

The triad formed by weight gain, tender hepatomegaly, and high bilirubin varies in less severe cases, and can be incomplete or delayed in pediatric patients compared with adults. These clinical criteria can be complemented by noninvasive examinations, such as ultrasound, to identify ascites, hepatomegaly, thickening of the gallbladder wall, and attenuation or reversal of hepatic venous flow. The use of invasive tests (e.g., percutaneous or transjugular liver biopsy) should be weighed against the risk of bleeding associated with these procedures. In addition to hyperbilirubinemia, other SOS-related laboratory findings include increased transaminases, prolonged prothrombin time, and signs of decreased synthetic function (e.g., low albumin).(133133 Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-9. Review.)

Although jaundice is usually present in adults, it may be absent in SOS developing late after HSCT, and is often absent in children. It should not be a prerequisite for SOS diagnosis.(137137 Naples JC, Skeens MA, Auletta J, Rangarajan H, Abu-Arja R, Horwitz E, et al. Anicteric veno-occlusive disease after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2016;51(1):135-7.,138138 Myers KC, Dandoy C, El-Bietar J, Davies SM, Jodele S. Veno-occlusive disease of the liver in the absence of elevation in bilirubin in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(2):379-81.)

SOS has been retrospectively classified as mild, moderate, or severe, based on disease severity, including the degree of liver dysfunction and the need for therapy. However, these criteria are loosely defined and cannot be used to predict risk or guide treatment.(133133 Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-9. Review.)

Considering the high mortality rate associated with severe SOS, strict daily monitoring to for early detection of signs and symptoms of the syndrome must be present from the onset of conditioning. Weight gain, fluid retention, overt edema and ascites, hepatomegaly and jaundice must be monitored on a daily basis. Patients with one of these risk factors require greater attention.

Other findings may be present, such as symptoms related to fluid retention (pleural effusion, pulmonary infiltrate, and hypoxia). Early onset of transfusion-refractory thrombocytopenia, not explained by concomitant conditions, such as sepsis, may be an initial sign of SOS, reflecting the endothelial pathophysiology of the syndrome. The presence of kidney or pulmonary dysfunction (or, less frequently, central nervous system dysfunction) defines multiple organ failure and severe SOS.(134134 Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.)

The adoption of preventive measures to potentially reduce the incidence and/or severity of SOS is imperative, especially since there are no 100% effective therapeutic measures for this disease. Preventive measures combine two approaches: reversal of risk factors and pharmacological prevention. The use of heparin is still quite controversial. Data on the usefulness of ursodesoxicolic acid are not conclusive: some randomized trials suggest that it reduces the incidence of SOS, whereas others did not find said advantage. However, patients who received this prophylaxis had lower liver toxicity, less a GVHD and better survival, which strongly suggests a beneficial effect. In addition, the use of ursodesoxicolic acid has been associated with decreased non-recurrence-related mortality.(134134 Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.)

Specifically considering the pediatric population, several strategies for SOS prevention have been investigated, including lipoprostaglandin E1, prophylaxis with danaparoid, and a prophylactic regimen combining heparin, glutamine and ursodiol. A retrospective Korean study with 374 children undergoing HSCT showed that prophylaxis with lipoprostaglandin E1 may have a protective effect against SOS.(136136 Chao N. How I treat sinusoidal obstruction syndrome. Blood. 2014; 123(26):4023-6.) A retrospective review of 188 children who received a prophylactic regimen combining intravenous heparin, oral glutamine and ursodiol prior to HSCT demonstrated low incidence of SOS using this approach (one case in 188 patients).(139139 Lakshminarayanan S, Sahdev I, Goyal M, Vlachos A, Atlas M, Lipton JM. Low incidence of hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin, oral glutamine, and ursodiol at a single transplant institution. Pediatr Transplant. 2010;14(5):618-21.) Muscaritoli et al.,(7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.) reported that glutamine administered during HSCT potentially has a protective effect in the liver against SOS. However, prospective studies are needed to better assess the impact of these strategies. Finally, a prospective, randomized, phase III study recently demonstrated a lower incidence of SOS in pediatric patients undergoing HSCT who received defibrotide prophylaxis.(140140 Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379(9823):1301-9.) Some other studies investigating the use of defibrotide prophylaxis in children also reported decreased incidence of SOS, as well as a favorable toxicity profile.(141141 Corbacioglu S, Kernan N, Lehmann L, Brochstein J, Revta C, Grupp S, et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol. 2012; 5(3):291-302. Review.)

The first step in managing SOS is symptomatic treatment. Considering that this is a potentially fatal disease, therapy should be initiated as soon as possible. Management of salt and water balance and careful use of diuretics should be introduced at the first suspicion, when SOS is still only probable. The purpose of support care is to minimize extracellular fluid overload, without worsening kidney function. Symptomatic measures can be used to reduce the discomfort caused by massive ascites or pleural effusions. Particularly in infants, when massive ascites affects breathing due to pulmonary restriction, early paracentesis can be extremely useful to prevent mechanical ventilation-associated complications. When fluid buildup and kidney failure cannot be controlled, hemodialysis/hemofiltration is required. The treatment of the severe SOS requires transfer to the intensive care unit.(133133 Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-9. Review.,134134 Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.)

Several clinical studies have shown the efficacy of defibrotide for managing SOS. In Europe, it is indicated for management of severe SOS in adults, adolescents, and children over 1 month of age. In the United States, defibrotide was recently approved by the US Food and Drug Administration for the treatment of adult and pediatric patients with SOS and kidney or pulmonary dysfunction after HSCT.(141141 Corbacioglu S, Kernan N, Lehmann L, Brochstein J, Revta C, Grupp S, et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol. 2012; 5(3):291-302. Review.,142142 Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, Lehmann L, Shore T, Tacobelli M, Miloslavsky M, Hume R, Hannah AL, Nejadnik B, Soiffer RJ; Defibrotide Study Group. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS): interim results from a treatment IND Study. Biol Blood Marrow Transplant. 2017;23(6):997-1004.)

When SOS is present, nutritional status changes occur, characterized by reduced anabolism. The main consequence is weight gain from kidney retention of sodium and water. In this case, nutritional therapy aims to favor reversal of intravascular fluids and electrolyte loss.(143143 Brasil. Ministério da Saúde. Instituto Nacional José Alencar Gomes da Silva (INCA). Tópicos em transplante de células-tronco hematopoéticas. Rio de Janeiro: INCA; 2012 [citado 2019 Nov 25]. Disponível em: http://bvsms.saude.gov.br/bvs/publicacoes/inca/topicos_transplantes.pdf
http://bvsms.saude.gov.br/bvs/publicacoe...
,144144 Albertini SM. O transplante de células-tronco hematopoéticas e o fator nutricional na evolução dos pacientes. Rev Bras Hematol Hemoter. 2010; 32(1):8-9.) Bear in mind that in the period of highest incidence for SOS, weight gain must be cautiously monitored, as one of the initial signs for SOS diagnosis.

There is no specific nutritional recommendation for SOS. Some authors cited restriction of dietary branched-chain amino acids to prevent progression to hepatic encephalopathy.(7373 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.,145145 Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.) However, no studies were found testing this restriction in these patients and supporting its indication.

In 2009, the European Society for Clinical Nutrition and metabolism (ESPEN)(146146 Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M; ESPEN. ESPEN Guidelines on Parenteral Nutrition: non-surgical oncology. Clin Nutr. 2009;28(4):445-54.) recommended restriction of dietary branched-chain amino acids only in cases of severe encephalopathy, grades 3 and 4. In the latest publication of the American Society, this measure was recommended only in cases of refractory encephalopathy in critical patients.(147147 McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient : society of critical care medicine (SCCM) and american society for parenteral and enteral nutrition (A. S. P. E. N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211. Erratum in: JPEN J Parenter Enteral Nutr. 2016; 40(8):1200.)

Thus, it is recommended that nutritional therapy be performed according to general HSCT treatment recommendations.

Endocrine and metabolic complications

Endocrine and metabolic complications may occur in children, even in those undergoing reduced intensity conditioning and no radiotherapy. This is because the endocrine system is extremely susceptible to damage by the conditioning regimen. The most common endocrine complications are hypothyroidism, gonadal failure, reduced bone mineral density and short stature due to growth hormone deficiency or hypopituitarism. This is an issue that has been increasingly explored in the scientific literature and is an important concern, particularly in pre-pubertal children and adolescents, who are still growing and developing.(148148 Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra71.)

Growth deficits in children undergoing HSCT occur due to a myriad of factors.(149149 Dahllöf G, Hingorani SR, Sanders JE. Late effects following hematopoietic cell transplantation for children. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):88-93. Review. Erratum in: Biol Blood Marrow Transplant. 2008; 14(11):1317-8.) A study carried out with 181 patients subjected to HSCT during childhood, who had reached their final height, showed that 80% of them had a height within normal parameters. Greater impairment was observed in boys than in girls, in children transplanted at a younger age or who received TBI.(1010 Cohen A, Duell T, Socié G, van Lint MT, Weiss M, Tichelli A, et al. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1999;23(10):1043-7.) Total body irradiation also leads to thyroid function abnormalities. Hypothyroidism can be an immediate and also late post-HSCT complication, identified as late as years after the procedure. Approximately 15% of patients develop primary hypothyroidism, which should be properly treated to prevent greater clinical repercussions.(1010 Cohen A, Duell T, Socié G, van Lint MT, Weiss M, Tichelli A, et al. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1999;23(10):1043-7.)

Reductions in bone mineral density are common both a few months after HSCT and several years after (more than 10), with a prevalence of osteopenia and osteoporosis in this population between 24% and 57%. Presence of cGVHD, use of corticosteroids and low serum vitamin D levels are risk factors for reduced bone mineral density in post-HSCT children.(1717 Browning B, Thormann K, Seshadri R, Duerst R, Kletzel M, Jacobsohn DA. Weight loss and reduced body mass index: a critical issue in children with multiorgan chronic graft-versus-host disease. Bone Marrow Transplant. 2006;37(5):527-33.) Several studies have demonstrated the high prevalence of vitamin D deficiency, alerting to the association between low levels of this vitamin and presence or progression of GVHD, since vitamin D may be involved in immune response control, inhibiting T-cell proliferation and cytokine production; vitamin D testing and supplementation are recommended before and after HSCT,(1616 Campos DJ, Boguszewski CL, Funke VA, Bonfim CM, Kulak CA, Pasquini R, et al. Bone mineral density, vitamin D, and nutritional status of children submitted to hematopoietic stem cell transplantation. Nutrition. 2014;30(6):654-9.,150150 Kreutz M, Eissner G, Hahn J, Andreesen R, Drobnik W, Holler E. Variations in 1 alpha,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 serum levels during allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;33(8):871-3.) based on the DRI. It is important to evaluate dietary calcium intake, particularly in patients with GVHD or receiving corticosteroids, where the recommended intake of this mineral is higher. Supplementation should be prescribed to complement food intake when the latter does not meet the Recommended Dietary Allowance (RDA) (Table 23). Calcium intake beyond these recommendations can be harmful due to interference in absorption of other nutrients.

Table 23
Recommendations for daily calcium and vitamin D

Type 2 diabetes is another complication that can occur after HSCT, but at a lower prevalence than other endocrine complications, with risk factors including family history of diabetes, non-Caucasian race and leukemia diagnosis.(149149 Dahllöf G, Hingorani SR, Sanders JE. Late effects following hematopoietic cell transplantation for children. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):88-93. Review. Erratum in: Biol Blood Marrow Transplant. 2008; 14(11):1317-8.,151151 Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. 2006;37(12):1109-17.) The use of corticosteroids can also induce diabetes during use of these drugs.(151151 Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. 2006;37(12):1109-17.) Children undergoing HSCT are also at risk for development of insulin resistance and abdominal fat accumulation.(152152 Bizzarri C, Pinto RM, Ciccone S, Brescia LP, Locatelli F, Cappa M. Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2015;62(9):1650-5.) Metabolic syndrome, characterized by hypertension, dyslipidemia, obesity and impaired glucose metabolism, leads to increased risk of early cardiovascular disease and type 2 diabetes, and occurs in 7% to 32% of children undergoing HSCT.(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.,153153 Turcotte LM, Yingst A, Verneris MR. Erratum to: “Metabolic syndrome after hematopoietic cell transplantation: at the intersection of treatment toxicity and immune dysfunction” [Biol Blood Marrow Transplant 2016;22:1159-66]. Biol Blood Marrow Transplant. 2016;22(12):2286.,154154 Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(5):619-25. Review.)

For monitoring and prevention of endocrine and metabolic changes, the international consensus on late effects after HSCT in pediatric patients recommends(131131 Berbel MN, Pinto MP, Ponce D, Balbi AL. Nutritional aspects in acute kidney injury. Rev Assoc Med Bras (1992). 2011;57(5):600-6. Review.) to assess: thyroid function annually; growth rate annually, adding determination of bone age in those with non-ideal growth; bone mineral density by body densitometry prior to HSCT, repeated after 1 and 5 years, except for patients with reduced bone mineral density, who should be evaluated annually; and lipid profile and fasting blood glucose at least every 5 years, and annually when abnormal. Serum levels of calcium, magnesium, and vitamin D (25OHD) after HSCT should also be monitored, especially in patients with abnormal bone mineral density. Patients should be instructed to follow a healthy diet, with adequate calcium and vitamin D consumption. They should also be alerted to the negative effects of smoking, alcohol, and caffeine consumption, and encouraged to take on physical activities.

In the post-HSCT setting, patients are recommended to follow a healthy diet, aiming at prevention not only of endocrine and metabolic complications, but also of other chronic diseases and cancers. The entire family of the transplanted patient should be encouraged to follow an adequate eating pattern, to help optimize patients’ understanding and adherence, promoting health education and disease prevention throughout the family. Two of the main points to be improved are promoting adequate consumption of fruits, vegetables, and legumes, and restricting consumption of processed foods. The nutritionist should base these guidelines on materials from the Ministry of Health.(155155 Brasil. Ministério da Saúde. Secretária de Atenção à Saúde. Departamento de Atenção à Saúde. Dez passos para uma alimentação saudável: guia alimentar para crianças menores de dois anos. 2a ed. Brasília (DF): Ministério da Saúde; 2013 [citado 2019 Nov 25]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/guia_dez_passos_alimentacao_saudavel_2ed.pdf
https://bvsms.saude.gov.br/bvs/publicaco...
,156156 Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Guia alimentar para a população Brasileira. 2a ed. Brasília (DF): Ministério da Saúde; 2014 [citado 2019 Nov 25]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/guia_alimentar_populacao_brasileira_2ed.pdf
https://bvsms.saude.gov.br/bvs/publicaco...
)

Dysgeusia

Dysgeusia is defined as persistent distortion or decrease in the sense of taste.(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,158158 Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. 2009;7(2):58-65. Review.) Several mechanisms may be involved in the cause of taste and smell disorders frequently observed in patients with oncohematological diseases, such as abnormal neuronal activity (abnormal sensitization of some branches of the facial nerve), imbalance in oxidant and antioxidant levels (due to peroxidation of epithelial cells in the oral cavity), and direct destruction of olfactory and gustatory receptor cells.(158158 Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. 2009;7(2):58-65. Review.)

Chemotherapy protocols use drugs that interfere with mitotic activity, with the aim of destroying highly proliferative cells (cancer cells). Since taste bud cells are highly proliferative, the renewal of these cells is also interrupted during the treatment period.(159159 Berteretche MV, Dalix AM, d’Ornano AM, Bellisle F, Khayat D, Faurion A. Decreased taste sensitivity in cancer patients under chemotherapy. Support Care Cancer. 2004;12(8):571-6.) Damage may also occur to the epithelium of the oral mucosa, caused by direct action of radiation on taste buds in case of patients undergoing radiotherapy in the head and neck.(160160 Baharvand M, ShoalehSaadi N, Barakian R, Moghaddam EJ. Taste alteration and impact on quality of life after head and neck radiotherapy. J Oral Pathol Med. 2013;42(1):106-12.,161161 Just T, Pau HW, Witt M, Hummel T. Contact endoscopic comparison of morphology of human fungiform papillae of healthy subjects and patients with transected chorda tympani nerve. Laryngoscope. 2006;116(7):1216-22.) It is estimated that these changes range from 40 to 75%.(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,158158 Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. 2009;7(2):58-65. Review.,162162 Bozzetti F, Forbes A. The ESPEN clinical practice Guidelines on Parenteral Nutrition: present status and perspectives for future research. Clin Nutr. 2009;28(4):359-64.167167 Ravasco P, Monteiro-Grillo I, Marques Vidal P, Camilo ME. Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Head Neck. 2005;27(8):659-68.)

Dysgeusia is often associated with olfactory alterations, since the two senses are closely involved in generating the sensation of taste.(168168 Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, et al. Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial. J Dent Res. 2005;84(1):35-8. Erratum in: J Dent Res. 2005;84(4):382.) Several studies have shown association between dysgeusia and reduced oral intake, increased parenteral nutrition time, significant weight loss and reduced functional capacity in patients during treatment,(169169 Kubrak C, Olson K, Jha N, Jensen L, McCargar L, Seikaly H, et al. Nutrition impact symptoms: key determinants of reduced dietary intake, weight loss, and reduced functional capacity of patients with head and neck cancer before treatment. Head Neck. 2010;32(3):290-300.171171 Boltong A, Keast RS, Aranda SK. A matter of taste: making the distinction between taste and flavor is essential for improving management of dysgeusia. Support Care Cancer. 2011;19(4):441-2.) with a negative impact on patient quality of life, and being one of the main causes of refusal to eat in children.(161161 Just T, Pau HW, Witt M, Hummel T. Contact endoscopic comparison of morphology of human fungiform papillae of healthy subjects and patients with transected chorda tympani nerve. Laryngoscope. 2006;116(7):1216-22.,172172 Okada N, Hanafusa T, Abe S, Sato C, Nakamura T, Teraoka K, et al. Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention. Support Care Cancer. 2016;24(9):3979-85.,173173 Bressan V, Stevanin S, Bianchi M, Aleo G, Bagnasco A, Sasso L. The effects of swallowing disorders, dysgeusia, oral mucositis and xerostomia on nutritional status, oral intake and weight loss in head and neck cancer patients: a systematic review. Cancer Treat Rev. 2016;45:105-19. Review.)

In the context of pediatric HSCT, some types of conditioning, such as those using high-dose melphalan, and the presence of oral mucositis are independent risk factors for dysgeusia, whereas the use of cryotherapy seems to be an independent protective factor.(172172 Okada N, Hanafusa T, Abe S, Sato C, Nakamura T, Teraoka K, et al. Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention. Support Care Cancer. 2016;24(9):3979-85.) Oral cryotherapy leads to vasoconstriction and decreased blood flow in the oral cavity, reducing exposure of the oral mucosa to chemotherapy and reducing the incidence of oral mucositis.(174174 Lilleby K, Garcia P, Gooley T, McDonnnell P, Taber R, Holmberg L, et al. A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006;37(11):1031-5.176176 Vokurka S, Bystricka E, Scudlova J, Mazur E, Visokaiova M, Vasilieva E, et al. The risk factors for oral mucositis and the effect of cryotherapy in patients after the BEAM and HD-l-PAM 200 mg/m(2) autologous hematopoietic stem cell transplantation. Eur J Oncol Nurs. 2011;15(5):508-12) The procedure consists of sucking small ice cubes 30 minutes before, during the 60 minutes of chemotherapy infusion (e.g. melphalan), and 30 minutes after infusion.(177177 Mori T, Yamazaki R, Aisa Y, Nakazato T, Kudo M, Yashima T, et al. Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer. 2006;14(4):392-5.)

Several drug treatments have been described, but still without proven efficacy:(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,178178 Bloise R, Davis MP. Dysgeusia #304. J Palliat Med. 2016;19(4):462-3. Review.,179179 Halyard MY. Taste and smell alterations in cancer patients-real problems with few solutions. J Support Oncol. 2009;7(2):68-9.)

  • Zinc supplementation (alkaline phosphatase cofactor): has shown efficacy in improving gustatory function and overall quality of life scores in patients with idiopathic dysgeusia.(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,168168 Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, et al. Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial. J Dent Res. 2005;84(1):35-8. Erratum in: J Dent Res. 2005;84(4):382.) Studies carried out later in patients with head and neck cancer undergoing radiotherapy and/or chemotherapy showed slight improvement in dysgeusia symptoms in patients undergoing chemotherapy and/or radiotherapy.(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,179179 Halyard MY. Taste and smell alterations in cancer patients-real problems with few solutions. J Support Oncol. 2009;7(2):68-9.,180180 Halyard MY, Jatoi A, Sloan JA, Bearden JD 3rd, Vora SA, Atherton PJ, et al. Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebo-controlled trial from the North Central Cancer Treatment Group (N01C4). Int J Radiat Oncol Biol Phys. 2007;67(5):1318-22.)

  • Amifostine (cytoprotective agent): despite the proven effect in decreasing the incidence and severity of chemotherapy and/or radiotherapy-induced toxicity due to its antioxidant effect, studies have not demonstrated any benefits in prevention and/or management of dysgeusia.(158158 Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. 2009;7(2):58-65. Review.,181181 Büntzel J, Schuth J, Küttner K, Glatzel M. Radiochemotherapy with amifostine cytoprotection for head and neck cancer. Support Care Cancer. 1998;6(2):155-60.,182182 Komaki R, Lee JS, Milas L, Lee HK, Fossella FV, Herbst RS, et al. Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phys. 2004;58(5):1369-77.)

  • Individualized nutritional advice: through direct verbal guidance, leaflets and/or audio lessons, it seems to have a beneficial effect in decreasing symptoms, with a better effect on long-term than early-onset dysgeusia. The main guidelines are described in table 24.(157157 Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.,183183 Ravasco P, Monteiro-Grillo I, Camilo M. Individualized nutrition intervention is of major benefit to colorectal cancer patients: long-term follow-up of a randomized controlled trial of nutritional therapy. Am J Clin Nutr. 2012; 96(6):1346-53.,184184 Ravasco P, Monteiro Grillo I, Camilo M. Cancer wasting and quality of life react to early individualized nutritional counselling! Clin Nutr. 2007;26(1):7-15. Review.)

Table 24
Summary of nutritional guidance to decrease symptoms of dysgeusia

The use of lime juice, the intake of candy and sugary juices before meals, the use of plastic utensils and straws, and water rinsing with salt or mouth wash, despite the limited scientific evidence, were also cited as adjuvants in symptom management.(185185 Speck RM, DeMichele A, Farrar JT, Hennessy S, Mao JJ, Stineman MG, et al. Taste alteration in breast cancer patients treated with taxane chemotherapy: experience, effect, and coping strategies. Support Care Cancer. 2013;21(2):549-55.) Some studies suggest that the use of seasonings such as salt, sodium or potassium glutamate, and sugar may be beneficial in managing dysgeusia.(186186 Wismer WV. Assessing alterations in taste and their impact on cancer care. Curr Opin Support Palliat Care. 2008;2(4):282-7. Review.) Acupuncture has not shown any benefits.(187187 Hummel T, Landis BN, Hüttenbrink KB. Smell and taste disorders. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2011;10:Doc04.)

Other empirical therapies have already been suggested, but without proven benefit in trials, such as the use of corticosteroids, vitamin A, Ginkgo biloba, glutamine and gabapentin.(188188 Heckmann SM, Heckmann JG, Ungethüm A, Hujoel P, Hummel T. Gabapentin has little or no effect in the treatment of burning mouth syndrome - results of an open-label pilot study. Eur J Neurol. 2006;13(7):e6-7.,189189 Strasser F, Demmer R, Böhme C, Schmitz SF, Thuerlimann B, Cerny T, et al. Prevention of docetaxel- or paclitaxel-associated taste alterations in cancer patients with oral glutamine: a randomized, placebo-controlled, double-blind study. Oncologist. 2008;13(3):337-46.) New perspectives include the use of Cannabis (dronabinol) and alpha lipoic acid.(190190 Spanemberg JC, Rodríguez de Rivera Campillo E, Salas EJ, López López J. Burning Mouth Syndrome: update. Oral Health Dent Manag. 2014;13(2):418-24.193193 Cannabis-In-Cachexia-Study-Group, Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24(21):3394-400.)

Some studies, most of which carried out in adults, showed that dysgeusia could last from 1 to 3 years after the end of treatment. A recent study carried out in pediatric patients undergoing HSCT showed resolution of dysgeusia at an average of 6 months after grafting. Discrepancy in the results can be explained by the higher rate of receptor regeneration in children than in adults.(194194 Majorana A, Amadori F, Bardellini E, Campus G, Conti G, Strohmenger L, et al. Taste dysfunction in patients undergoing hematopoietic stem cell transplantation: clinical evaluation in children. Pediatr Transplant. 2015; 19(5):571-5.)

Diarrhea

Diarrheal disease is one of the most frequent gastrointestinal complications of allogenic HSCT and may occur in other types of transplants.(195195 Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012;18(16):1851-60. Review.) Diarrheal disease usually occurs between days 6 and 11 after transplantation, but may be present in all phases of HSCT. Energy intake was decreased in these periods due to nausea, vomiting, diarrhea and loss of appetite.(196196 Walrath M, Bacon C, Foley S, Fung HC. Gastrointestinal side effects and adequacy of enteral intake in hematopoietic stem cell transplant patients. Nutr Clin Pract. 2015;30(2):305-10.) Severe diarrheal disease can be defined as more than six evacuations – according to the Bristol scale, six or seven.(197197 Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32(9):920-4.) Another definition is severe fecal loss with a volume greater than 30mL/kg, corresponding to fecal loss caused by cholera.(198198 Brasil. Ministério da Saúde. Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC). Protocolo clínico e diretrizes terapêuticas doença falciforme. Relatorio de recomendação. Imunossupressão pós transplante de medula óssea. Brasilia (DF): Ministério da Saúde; 2016 [citado 2019 Nov 25]. Disponível em: http://conitec.gov.br/images/Consultas/Relatorios/2016/Relatorio_PCDT_DoencaFalciforme_CP_2016_v2.pdf
http://conitec.gov.br/images/Consultas/R...
)

The causes of diarrheal disease in HSCT can be classified into four large groups, according to table 25.

Table 25
Causes of diarrheal disease in pediatric hematopoietic stem cell transplantation

The impairment of intestinal structures, dysfunction of organs responsible for nutrient digestion, and the use of intestinal microbiota-modifying drugs contribute to the genesis of diarrheal disease. Villus injury favors the impairment of lactase activity, leading to different degrees of lactose intolerance. Moreover, rupture of the intestinal barrier facilitates the exposure of macroproteins, which can cause multiple allergies, such as cow’s milk, soy and gluten.(199199 Robak K, Zambonelli J, Bilinski J, Basak GW. Diarrhea after allogeneic stem cell transplantation: beyond graft-versus-host disease. Eur J Gastroenterol Hepatol. 2017;29(5):495-502. Review.)

Infectious etiology of diarrheal disease should always be ruled out since it is very frequent in immunosuppressed patients and in HSCT.

An algorithm to evaluate the causes of diarrheal disease in allogeneic HSCT was proposed by Robak et al.,(199199 Robak K, Zambonelli J, Bilinski J, Basak GW. Diarrhea after allogeneic stem cell transplantation: beyond graft-versus-host disease. Eur J Gastroenterol Hepatol. 2017;29(5):495-502. Review.) Infectious causes should be ruled out first; then, GVHD should be ruled out and, finally, other causes.

In patients with acceptance of oral diet reaching 80% of energy and micronutrient requirements, it is recommended to monitor acceptance and advise on dietary supplementation.(223223 Nannya Y, Shinohara A, Ichikawa M, Kurokawa M. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(3):430-4.) The diet offered should be low residue. In addition, meal food fractionation should be advised, with six to eight portions per day, ensuring adequate hydration for the age group. The acceptance of some gastric irritant foods, such as deep-fried foods or sweets, and specific nutrients such as lactose, sucrose, gluten and caffeine, should be assessed individually, and if necessary, intake can be restricted if diarrhea occurs.(124124 Manzoli B, Bouchabki G, Nabarrete J, Oliveira V. Manejo de sintomas e complicações. In. Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 127-51.)

Enteral nutrition using nasogastric or post-pyloric tubes is required in patients with nutritional impairment whose oral intake does not reach 70% to 80% of energy and micronutrient requirements, and diet administration and the type of protein used (polymeric or extensively hydrolyzed diet) should be monitored. The tube should be passed at the onset of conditioning until the first week after transplantation, when oral intake is compromised. Enteral diet infusion should always be performed with an infusion pump, aiming to control infused volume.(224224 Langdana A, Tully N, Molloy E, Bourke B, O´Meara A. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant. 2001;27(7):741-6.) If the enteral nutrition volume progression does not reach 70% of the basal metabolic rate, or after 3 days of fasting, parenteral nutrition is considered.

Nutritional intervention

According to the guidelines for nutritional therapy during HSCT, all patients undergoing this procedure with myeloablative conditioning regimes are at nutritional risk.(7676 Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.,9595 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.,225225 Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11-48.)

Nutritional follow-up is important at all treatment phases, and it is possible to adequately identify nutritional risk and implement nutritional therapy as early as possible, according to the conditions and needs of children and adolescents, meeting criteria that ensure the best decision, increasing the benefits of this support and avoiding the risks of inadequate indication.(7676 Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.,9595 August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.,225225 Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11-48.)

The general objective of nutritional therapy is to improve treatment response, reduce the risk of complications and optimize survival and quality of life.

The goals of nutritional therapy can be separated by treatment phase, according to table 26.

Table 26
Nutritional goals according to treatment phases

Nutritional therapy

Food acceptance may be affected by the numerous side effects of HSCT. The diet offered should meet the needs of the current moment of the patient. In this context, two topics related to oral nutritional therapy are worth highlighting: neutropenic diet and oral supplementation.

Neutropenic diet

After HSCT conditioning, immunity is impaired, and there is a period of neutropenia and high susceptibility to infections. Historically, dietary restrictions known as “clean”, “low bacteria,” “microbial” or “neutropenic” diets have been prescribed to reduce the risk of foodborne infection.(229229 Carr SE, Halliday V. Investigating the use of the neutropenic diet: a survey of U.K. dietitians. J Hum Nutr Diet. 2015;28(5):510-5.)

Neutropenia is defined as a total neutrophil count under 500/mm³ or expected to decrease below that level in the next 48 hours.(230230 Nabarrete J, Leão AC, Oliveira V. Dieta para neutropenia. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 173-87.) The duration of neutropenia varies according to the type of HSCT and the presence or absence of complications, such as GVHD and bone marrow engraftment failure.(231231 Nucci M, Maiolino A. Infecções em transplante de medula óssea. Medicina (Ribeirão Preto). 2000;33(3):278-93.)

After the preparative regimen, during neutropenia, the patient may have mucosal damage throughout the GIT, caused by conditioning, which may be an inlet for Gram-negative pathogens, such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella and Proteus, in different foods. When foods are cooked, baked, fried or heated, the number of microorganisms can be reduced considerably, and there is a strong recommendation for diets with cooked foods during the period of bone marrow aplasia.(232232 Vicenski PP, Alberti P, Amaral DJ. Dietary recommendations for immunosuppressed patients of 17 hematopoietic stem cell transplantation centers in Brazil. Rev Bras Hematol Hemoter. 2012;34(2):86-93.)

The HSCT diet is based on food safety, and aims to prevent foodborne infections and bacterial translocation, during aplasia and bone marrow fragility. Nutritional advice should be focused on good hygiene and food preparation practices, for both training of staff handling patient meals during hospitalization and guiding children’s caregivers after discharge. In addition, some foods must be excluded from the diet because of their increased risk of containing pathogens.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.)

The foods with the highest risk for patients are raw eggs, non-pasteurized dairy products, fruits, vegetables and legumes without proper washing, among others (Table 27).(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.)

Table 27
Dietary guidelines for hematopoietic stem cell transplantation

A survey of different professionals who used this diet found that there is a range of restricted foods, and contradictions are frequent. The most frequently restricted foods were seafood and fish.(229229 Carr SE, Halliday V. Investigating the use of the neutropenic diet: a survey of U.K. dietitians. J Hum Nutr Diet. 2015;28(5):510-5.)

The HSCT diet or neutropenic diet starts at conditioning and continues until the withdrawal of immunosuppressants.(9999 Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.) Some Brazilian authors recommend that the neutropenic diet be extended up to 100 days after allogeneic HSCT or 60 days for autologous. However, other authors suggest that, for allogeneic HSCT, the diet should continue until withdrawal of all immunosuppressants and, in autologous HSCT, up to 1 month after discontinuation of corticosteroids or 3 months after complete resolution of gastrointestinal lesions.(233233 Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Terapia Nutricional no Transplante de Célula Hematopoiética. Projeto Diretrizes. São Paulo: AMBCFM; 2011 [citado 2019 Nov 25]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/terapia_nutricional_no_transplante_de_celula_hematopoietica.pdf
https://diretrizes.amb.org.br/_Bibliotec...
) The timing of diet suspension is not yet a consensus among reference centers.

Differences in practice can be attributed to the lack of robust, high-quality evidence.(229229 Carr SE, Halliday V. Investigating the use of the neutropenic diet: a survey of U.K. dietitians. J Hum Nutr Diet. 2015;28(5):510-5.) Perhaps preparation, storage and quality of raw materials are more important than the food type restricted, considering the reality of the hospital and population served.

Thus, the role of the neutropenic diet in the incidence of infections in HSCT is still controversial.(234234 Braun LE, Chen H, Frangoul H. Significant inconsistency among pediatric oncologists in the use of the neutropenic diet. Pediatr Blood Cancer. 2014;61(10):1806-10.) Studies are limited, either in pediatric or adult populations. Another bias is that there are few studies portraying the reality of our population. Further studies are required, not only high-quality, but also studies that truly portrait the reality of our population.

Oral supplements (homemade or commercial)

The indication of oral nutritional supplements should be assessed individually and occur when food intake is <70% to 80% of nutritional recommendations for 3 to 5 consecutive days, considering the level of nutritional risk; the expected time of improvement in food intake and the predicted grafting time; GIT and conditioning.(235235 Bowman LC, Williams R, Sanders M, Ringwald-Smith K, Baker D, Gajjar A. Algorithm for nutritional support: experience of the metabolic and infusion support service of St. Jude Children´s Research Hospital. Int J Cancer Suppl. 1998;11:76-80.237237 Ladas EJ, Arora B, Howard SC, Rogers PC, Mosby TT, Barr RD. A framework for adapted nutritional therapy for children with cancer in low- and middle-income countries: a report from the SIOP PODC Nutrition Working Group. Pediatr Blood Cancer. 2016;63(8):1339-48.) Therefore, it is recommended that food intake calculations be performed on a daily basis.

Supplements may be commercial or homemade.

The decision to initiate oral supplementation must take some criteria into account: reduced food intake, regardless of other indicators; risk of malnutrition, meaning any weight loss or deceleration in the growth curve; reduced fat reserves or muscle mass; gastrointestinal abnormalities, regardless of other indicators; and patient submitted to HSCT, regardless of other conditions.

When choosing which supplement to use, some criteria should also be considered, such as age group; taste, form, and quantity; nutritional and catabolic status (normo or hypercaloric and/or protein supplements may be necessary); GIT (hydrolyzed or otherwise modified supplements may be required); metabolic condition (changes in serum glucose or lipids; systemic inflammation); comorbidities (liver, kidney, pancreatic abnormalities, among others) and socioeconomic situation.

Commercial supplements can help with nutritional therapy, but their high price makes them difficult to buy, and limit their widespread use. Furthermore, there are not many oral supplement options for the pediatric age group, which warrants the use of homemade alternatives using attractive preparations, with ingredients that can provide higher energy-protein density and micronutrients.

Thus, homemade supplements obtained by homemade modulation of dietary ingredients can be a less expensive option than commercial products. Nevertheless, there are some disadvantages, when comparing homemade and commercial supplements, such as poorer microbiological control and greater manipulation, more complex preparation, and difficulty ensuring equal nutritional value.(238238 Garófolo A, Alves FR, Rezende MA. Suplementos orais artesanais desenvolvidos para pacientes com câncer: análise descritiva. Rev Nutr. 2010;23(4):523-33.,239239 Garófolo A, Maia PS, Petrilli AS, Ancona-Lopez F. Outcomes of the implementation of an enteral nutrition algorithm in children and adolescents with cancer. Rev Nutr. 2010;23(5):715-30.)

Maia et al.(240240 Maia PS, Tsutsumi RC, Pedro BM, Garófolo A, Petrilli AS, Lopez FA. Suplementação oral em pacientes pediátricos com câncer. Nutr Rev Soc Bras Aliment Nutr. 2010;35(1):85-96.) showed that oral supplementation, whether commercial or homemade, can prevent further deterioration of nutritional status, particularly in patients with good compliance with nutritional appointments and following guidance. However, commercial supplements seem to elicit a favorable response in a higher percentage of patients.

Usually, the presence of more severe malnutrition requires other nutritional therapy measures, since patients in these circumstances have more difficulty meeting requirements by oral feeding.(238238 Garófolo A, Alves FR, Rezende MA. Suplementos orais artesanais desenvolvidos para pacientes com câncer: análise descritiva. Rev Nutr. 2010;23(4):523-33.,239239 Garófolo A, Maia PS, Petrilli AS, Ancona-Lopez F. Outcomes of the implementation of an enteral nutrition algorithm in children and adolescents with cancer. Rev Nutr. 2010;23(5):715-30.)

Thus, the use of oral supplements can be a viable alternative to prevent nutritional loss, as well as more severe thinness and sarcopenia. Commercial supplements ensure a homogeneous supply of nutrients and are more practical for routine preparation. However, their taste can be unappealing to children. The combination of homemade and commercial supplements is an important strategy for preventing malnutrition. When resources are too limited for commercial supplements, homemade supplements should be recommended.

Often, protein intake can be impaired, which tends to intensify catabolism and sarcopenia. Protein requirements in these patients are high, and the use of commercial protein supplements or homemade supplementation strategies are required to achieve the necessary supply.

The initial prescription of this therapy should account for 45% to 50% of the patients’ nutritional requirements for effective nutritional contribution. Programmed weaning from oral supplements can be carried out when oral intake rises to ≥70% to 80% of the calculated nutritional requirements for 2 or 3 days, until it reaches 100% of requirements without oral supplements.(240240 Maia PS, Tsutsumi RC, Pedro BM, Garófolo A, Petrilli AS, Lopez FA. Suplementação oral em pacientes pediátricos com câncer. Nutr Rev Soc Bras Aliment Nutr. 2010;35(1):85-96.)

Enteral nutrition

For ENT, the functional capacity of the GIT tract must be evaluated. Situations that modify digestion and absorption systems, such as mucositis, infections, GVHD, among others, may compromise the proper uptake of nutrients and be inefficient, if poorly indicated.(241241 Lewandowski CG. Aspectos nutricionais no transplante de células-tronco hematopoéticas alogênico em crianças e adolescentes em um hospital terciário [dissertação]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2016. 60 f.,242242 Garófolo A. Enteral nutrition during bone marrow transplantation in patients with pediatric cancer: a prospective cohort study. Sao Paulo Med J. 2012;130(3):159-66.)

Based on the concept that prolonged fasting causes atrophy of the intestinal mucosa, breaking the immunological integrity of the GIT and increasing the risk of bacterial translocation, food is an important stimulus to maintain the function and structure of the intestinal mucosa, leading to the release of pancreatic secretions, bile and hormonal factors.(241241 Lewandowski CG. Aspectos nutricionais no transplante de células-tronco hematopoéticas alogênico em crianças e adolescentes em um hospital terciário [dissertação]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2016. 60 f.,242242 Garófolo A. Enteral nutrition during bone marrow transplantation in patients with pediatric cancer: a prospective cohort study. Sao Paulo Med J. 2012;130(3):159-66.)

This route of nutritional support must be prioritized in patients with a functioning or partially functioning GIT, before an indication for parenteral nutrition, since it preserves the tropism of the intestinal mucosa.(243243 Bicakli DH, Yilmaz MC, Aksoylar S, Kantar M, Cetingul N, Kansoy S. Enteral nutrition is feasible in pediatric stem cell transplantation patients. Pediatr Blood Cancer. 2012;59(7):1327-9.)

Langdana et al.,(244244 Langdana A, Tully N, Molloy E, Bourke B, O’Meara A. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant. 2001;27(7):741-6.) observed that nutritional therapy was feasible through an intensive enteral nutrition program in the pediatric population undergoing HSCT, including patients receiving TBI conditioning.

Another Brazilian study observed that the use of tube nutrition in children and adolescents with cancer during HSCT is feasible, and there were no severe complications associated with therapy. Minor complications occurred in 55% of patients, namely: more intense episodes of vomiting or diarrhea as diet volume increased (16%), displaced tube (19%), fungal infection in the oral cavity (9.7%) and obstructed tube (6.5%).(242242 Garófolo A. Enteral nutrition during bone marrow transplantation in patients with pediatric cancer: a prospective cohort study. Sao Paulo Med J. 2012;130(3):159-66.)

Some trials have considered enteral nutrition as effective as parenteral nutrition, but with lower complication rates. In addition, enteral nutrition was associated with better survival, lower incidence of aGVDH and cGVDH, and faster neutrophil recovery rate associated with lower risk of infection.(227227 Dioguardi J, Bryson E, Ahmed-Winston S, Vaughn G, Slater S, Driscoll J, et al. A multi-institutional retrospective study suggests that optimal enteral nutrition (EN) influences outcomes after hematopoietic stem cell transplantation in children and adults. Biol Blood Marrow Transplant. 2015;21(2):S248-9.,243243 Bicakli DH, Yilmaz MC, Aksoylar S, Kantar M, Cetingul N, Kansoy S. Enteral nutrition is feasible in pediatric stem cell transplantation patients. Pediatr Blood Cancer. 2012;59(7):1327-9.,245245 Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr. 2014;33(3):533-8.,246246 Baumgartner A, Bargetzi M, Bargetzi A, Zueger N, Medinger M, Passweg J, et al. Nutritional support practices in hematopoietic stem cell transplantation centers: a nationwide comparison. Nutrition. 2017;35:43-50.)

Data from another study suggest that nutritional therapy in both pre- and during HSCT correlated with better nutritional recovery after HSCT.(227227 Dioguardi J, Bryson E, Ahmed-Winston S, Vaughn G, Slater S, Driscoll J, et al. A multi-institutional retrospective study suggests that optimal enteral nutrition (EN) influences outcomes after hematopoietic stem cell transplantation in children and adults. Biol Blood Marrow Transplant. 2015;21(2):S248-9.)

ENT has been widely recommended for pediatric patients undergoing HSCT, and enteral tube feeding is the preferential route, in the absence of severe GIT toxicity.(244244 Langdana A, Tully N, Molloy E, Bourke B, O’Meara A. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant. 2001;27(7):741-6.,247247 Sefcick A, Anderton D, Byrne JL, Teahon K, Russell NH. Naso-jejunal feeding in allogeneic bone marrow transplant recipients: results of a pilot study. Bone Marrow Transplant. 2001;28(12):1135-9.,248248 Hastings Y, White M, Young J. Enteral nutrition and bone marrow transplantation. J Pediatr Oncol Nurs. 2006;23(2):103-10.)

ENT through feeding tube or stoma is indicated when oral feeding is not possible (grade 1 and 2 mucositis), when food intake is insufficient (oral intake <70-80% of requirements) for 3 to 5 consecutive days, with insufficient food and supplements (below 100% of basal energy requirements), associated with undernutrition or weight loss, considering a high-risk nutritional status, expected improvement time and estimated time for grafting, severe undernutrition or impossibility of oral feeding.(4141 Antillon F, Rossi E, Molina AL, Sala A, Pencharz P, Valsecchi MG, et al. Nutritional status of children during treatment for acute lymphoblastic leukemia in Guatemala. Pediatr Blood Cancer. 2013;60(6):911-5.,240240 Maia PS, Tsutsumi RC, Pedro BM, Garófolo A, Petrilli AS, Lopez FA. Suplementação oral em pacientes pediátricos com câncer. Nutr Rev Soc Bras Aliment Nutr. 2010;35(1):85-96.) For this purpose, it is suggested that daily dietary intake calculations be performed to determine whether ENT is indicated.

Delayed indication of nutritional therapy may make it difficult to use tube feeding and predispose to a higher risk of complications. Thus, a greater number of patients will benefit from early indication of tube feeding, which reduces need for parenteral nutrition or at least the duration and risks of this type of therapy.

The treatment phase, presence of gastrointestinal toxicity, clinical condition and current nutritional status must be considered for enteral nutrition weaning. Programmed weaning from tube feeding can be initiated when oral intake reaches ≥70% to 80% of nutritional requirements calculated for 2 or 3 days.

Parenteral nutrition

Historically, total parenteral nutrition was the most commonly used method to provide nutrients during HSCT. The importance of nutrition, especially parenteral nutrition, was clearly shown in the results of the randomized study by Weisdorf et al.,(249249 Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL, Goldman A, et al. Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation. 1987;43(6):833-8.) demonstrating that the administration of prophylactic parenteral nutrition during the course of HSCT increased survival in the treated group, after 3 years of follow-up.

However, the use of parenteral nutrition is also associated with an increased risk of complications, especially infectious and metabolic complications, particularly among patients with severe immunosuppression, such as patients undergoing HSCT.

Despite evidence of positive nutritional results with total parenteral nutrition in children and adolescents during HSCT,(250250 Wedrychowicz A, Spodaryk M, Krasowska-Kwiecień A, Goździk J. Total parenteral nutrition in children and adolescents treated with high-dose chemotherapy followed by autologous haematopoietic transplants. Br J Nutr. 2010;103(6):899-906.) there are few studies in this context, and information on the effects of total parenteral nutrition in this population is limited. The recommendations are based on results of the studies already discussed here, including data on adults, which also support the principles of nutritional therapy in children and adolescents with cancer.

In pediatric oncology, some diagnoses, and neoplastic agents, such as chemotherapy with thiotepa, melphalan and cisplatin, and total body irradiation, will make patients much more likely to require parenteral nutrition.

Some important aspects related to parenteral nutrition include monitoring and metabolic control of supply and the type of catheter used. Since there is a great risk of metabolic changes due to the inflammatory process and infections due to catheter manipulation, special attention should be given while managing this therapy.

The main indications for parenteral nutrition include total or partial impossibility of using the GIT: severe thrombocytopenia not resolved after platelet infusion in patients on enteral therapy, and difficulty achieving nutritional requirements by full enteral nutrition within 5 days, considering the nutritional status and estimated time until grafting.

Finally, the routine use of parenteral nutrition is not recommended unless GI toxicity or serious GI complications prevent full enteral feeding.

Nutritional therapy algorithms

Defining criteria for nutritional therapy decision-making, improving processes, and ensuring that adequate therapy yields more benefits than complications is fundamental for the therapeutic planning of patients.

According to a survey on nutritional therapy routes, the following algorithms are suggested, separated by HSCT phase: nutritional therapy algorithm in pediatric patients pre-HSCT (Figure 2), nutritional therapy algorithm in pediatric patients undergoing HSCT (Figure 3), and nutritional therapy algorithm in pediatric patients post-HSCT (Figure 4).

Figure 2
Nutritional therapy algorithm in pediatric patients pre-hematopoietic stem cell transplantation
Figure 3
Nutritional therapy algorithm in pediatric patients undergoing hematopoietic stem cell transplantation
Figure 4
Nutritional therapy algorithm in pediatric patients post-hematopoietic stem cell transplantation

Use of probiotics

Recently, the intestinal microbiota trajectory has been studied in children during HSCT, as well as its role in aGVHD, and it has been demonstrated that intestinal microbial diversity can predict survival in these patients. HSCT causes temporary structural and functional changes to the intestinal microbiota ecosystem, which shows signs of recovery at 100 days after transplantation and aggravates in case of acute GVHD.(251251 Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-82.253253 Docampo MD, Auletta JJ, Jenq RR. Emerging influence of the intestinal microbiota during allogeneic hematopoietic cell transplantation: control the gut and the body will follow. Biol Blood Marrow Transplant. 2015;21(8):1360-6. Review.) Italian authors reported the association of acute GVHD with specific bacteria, both during restoration of the intestinal flora immediately after HSCT, curiously, even before the transplantation. In a study published in 2015, pre-transplant samples of patients without acute GVHD showed greater presence of a type of propionate-producing bacterium, which persisted even after disruption of the ecosystem by the transplant. These results suggest the possibility of manipulating the pre-HSCT intestinal microbiota configuration to favor the success of the procedure.(252252 Biagi E, Zama D, Nastasi C, Consolandi C, Fiori J, Rampelli S, et al. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant. 2015;50(7):992-8.)

The use of probiotics during and immediately after HSCT is still challenged in clinical practice, due to very few studies demonstrating its safety, especially in pediatric patients, and to the supposedly high risk of bacterial translocation in connection with structural and immunological weakening of the intestinal barrier.(254254 Robin F, Paillard C, Marchandin H, Demeocq F, Bonnet R, Hennequin C. Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation. J Clin Microbiol. 2010;48(11):4317-9.256256 Van den Nieuwboer M, Brummer RJ, Guarner F, Morelli L, Cabana M, Claasen E. The administration of probiotics and synbiotics in immune compromised adults: is it safe? Benef Microbes. 2015;6(1):3-17.) An American study published in 2016(257257 Ladas EJ, Bhatia M, Chen L, Sandler E, Petrovic A, Berman DM, et al. The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. Bone Marrow Transplant. 2016;51(2): 262-6.) demonstrated that the use of Lactobacillus plantarum is safe and feasible during neutropenia in children and adolescents undergoing myeloablative HSCT, and was the first clinical trial to use probiotics in this population, which points to promising results with the aforementioned bacterial strain in this population.

Currently, and until there are further studies demonstrating the safety and benefits of the use of probiotics in children and adolescents undergoing HSCT, this consensus contraindicates this approach in this situation.

Use of glutamine

Glutamine is important for physiological functions, serving as a precursor in the synthesis of other amino acids, such as arginine, and acting as an important antioxidant and fuel for the rapid cellular proliferation of the GIT, immune system, reticulocytes and fibroblasts, mainly in the formation and maintenance of the intestinal mucosal barrier.(258258 Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB. Acquired amino acid deficiencies: a focus on arginine and glutamine. Nutr Clin Pract. 2017;32(1_suppl):30S-47S. Review.)

It is naturally found in dietary protein and considered non-essential; however, in stress situations, it becomes a conditionally essential nutrient, i.e., in situations of increased metabolic demand, such as catabolism, serious disease and prematurity, the body cannot produce enough.(259259 Tao KM, Li XQ, Yang LQ, Yu WF, Lu ZJ, Sun YM, et al. Glutamine supplementation for critically ill adults. Cochrane Database Syst Rev. 2014;2014(9):CD010050. Review.)

Administration in the form of supplements can be either orally or intravenously.

As for intravenous glutamine, to date, there is not enough evidence to recommend its use; on the contrary, it is not recommended due to toxicity reports.(260260 Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, Raber-Durlacher JE, Sonis ST, Elad S; Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453-61. Review. Erratum in: Cancer. 2015;121(8):1339.) Since the release of last two position papers about this subject, two new randomized, controlled studies have been published, however with a small number of patients.(261261 Blijlevens NM, Donnelly JP, Naber AH, Schattenberg AV, DePauw BE. A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support Care Cancer. 2005;13(10):790-6.,262262 Sornsuvit C, Komindr S, Chuncharunee S, Wanikiat P, Archararit N, Santanirand P. Pilot study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients. J Int Med Res. 2008;36(6):1383-91.) They showed positive effects of intravenous glutamine on intestinal permeability and chemotherapy-induced mucosal injury. Further evaluations on the subject are expected before any future changes in the recommendations.(263263 Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer. 2013;21(1):313-26. Review.)

Few studies have assessed the use of oral/enteral glutamine in children. Ward et al.,(264264 Ward E, Smith M, Henderson M, Reid U, Lewis I, Kinsey S, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients. Eur J Clin Nutr. 2009;63(1):134-40.) followed 76 pediatric patients on chemotherapy divided into two groups, one of them receiving once-daily 0.65g/kg oral or enteral glutamine diluted in water, starting on day 1 of chemotherapy. The study concluded that glutamine did not reduce the incidence and severity of oral mucositis but showed a reduction in the number of patients on parenteral nutrition.(264264 Ward E, Smith M, Henderson M, Reid U, Lewis I, Kinsey S, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients. Eur J Clin Nutr. 2009;63(1):134-40.) A systematic review in 2016,(265265 Sayles C, Hickerson SC, Bhat RR, Hall J, Garey KW, Trivedi MV. Oral glutamine in preventing treatment-related mucositis in adult patients with cancer: a systematic review. Nutr Clin Pract. 2016;31(2):171-9. Review.) aiming to investigate the role of oral glutamine in preventing mucositis in adult patients undergoing radiotherapy and/or chemotherapy, observed a significant reduction in the severity of lesions, with faster resolution and less weight loss in those who received the amino acid. Maximum doses of 30g per day were used, with no difference in side effects compared with the control group with no glutamine. For greater efficacy, oral glutamine should be started zero to 7 days before radiation/chemotherapy, divided in three administrations. The authors drew attention to some limitations regarding the methodology of the studies, such as the small number of patients, non-homogeneous sample, and retrospective design. This made it difficult to identify which patients could benefit from oral glutamine and at which stage of the treatment.(263263 Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer. 2013;21(1):313-26. Review.,266266 Yarom N, Ariyawardana A, Hovan A, Barasch A, Jarvis V, Jensen SB, Zadik Y, Elad S, Bowen J, Lalla RV; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21(11):3209-21. Review.) Further studies will help define whether oral glutamine could be effective for all types of cancer and as an adjuvant to anti-cancer drugs.

There is no consensus on the dose and route of administration for this amino acid. The doses ranged from 7.5g to 30g per day before treatment or fractionated into three times a day. The timing also varied in different studies, either before, during or after the chemotherapy cycle.(267267 Cheng KK, Lee V, Li CH, Yuen HL, Ip WY, He HG, et al. Impact of oral mucositis on short-term clinical outcomes in paediatric and adolescent patients undergoing chemotherapy. Support Care Cancer. 2013;21(8):2145-52.)

According to the bibliographic reviews performed, table 28 shows the indications for glutamine in cases of mucositis and/or intestinal tropism.

Table 28
Summary of glutamine indications and routes of administration

Micronutrient supplementation

The optimum use of nutrients requires other substances called micronutrients. These substances are required in minimal quantities, proportionally low when compared to their great influence on metabolism and health. Micronutrients are of two types: trace-elements and vitamins. The former are inorganic elements, while vitamins are complex organic molecules. Trace elements are an essential and integral part of enzymes, of which seven are essential for human health: iron, zinc, copper, chrome, selenium, iodine and cobalt.(269269 Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S7-12. Review.) Vitamins are usually converted in the body into complex molecules that function as coenzymes with various roles in metabolism, which cannot be synthesized and need to be provided by the diet.(269269 Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S7-12. Review.)

Vitamin and mineral supplementation is important during all phases of HSCT, since patients have long-term feeding difficulties, aggravated by dietary restrictions imposed by the neutropenic diet, and the requirements for some vitamins and minerals are increased.(5858 Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.) In addition, children’s eating habits should be considered, which, if inadequate in the long term, may lead to micronutrient deficiency. In the last decades, a higher consumption of processed foods with high caloric density and low essential nutrients has been observed in the Brazilian population, replacing the consumption of more nutritious foods, such as fruits, vegetables, and legumes. As a result of changes in the eating pattern, vitamin supplements and/or enriched foods serve as practical vitamin carriers.(223223 Nannya Y, Shinohara A, Ichikawa M, Kurokawa M. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(3):430-4.)

There are few studies evaluating serum concentrations of vitamins and minerals in children undergoing HSCT. Recent studies in adults found vitamin B1 deficiency in the pre-HSCT phase, in addition to vitamin C and zinc deficiency in the post-HSCT phase.(270270 Campbell I. Macronutrients, minerals, vitamins and energy. Anaesth Intensive Care Med. 2017;18(3):142-6.) Some nutrients with antioxidant properties, such as vitamins C and E and beta-carotene, are depleted after HSCT, as well as vitamin B1 and zinc,(5959 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.,270270 Campbell I. Macronutrients, minerals, vitamins and energy. Anaesth Intensive Care Med. 2017;18(3):142-6.) and patients presented oxidative stress during conditioning, particularly on the cyclophosphamide + TBI regimen.(271271 Slegtenhorst S, Visser J, Burke A, Meyer R. Antioxidant intake in paediatric oncology patients. Clin Nutr. 2015;34(6):1210-4.)

Patients undergoing allogeneic HSCT are also at increased risk of thiamine (vitamin B1) deficiency, leading to metabolic changes, such as lactic acidosis,(272272 Gonçalves TL, Benvegnú DM, Bonfanti G, Frediani AV, Pereira DV, Rocha JB. Oxidative stress and delta-ALA-D activity in different conditioning regimens in allogeneic bone marrow transplantation patients. Clin Biochem. 2009;42(7-8):602-10.) and neurological changes, such as Wernicke encephalopathy, and should be supplemented in doses higher than the RDA during the immediate post-HSCT period. Absorption of vitamin B12 is also reduced due to the effects of conditioning or as a result of GVHD.(8282 Barron MA, Doyle J, Zlotkin S. Vitamin K deficiency in children pre-bone marrow transplantation. Bone Marrow Transplant. 2006;37(2):151-4.,273273 Khrouf MF, Besbes H, Soussi MA, Khaled MB, Turki M, Zaouali S, et al. Acute lactic acidosis as a complication of thiamine-free parenteral nutrition in two neutropenic children. Nutr Clin Metab. 2015;29(3):159-62.,274274 Milligan DW, Quick A, Barnard DL. Vitamin B12 absorption after allogeneic bone marrow transplantation. J Clin Pathol. 1987;40(12):1472-4.) A Brazilian study involving children and adolescents undergoing allogeneic HSCT found a high prevalence of vitamin D deficiency as early as pre-HSCT, with reduction in serum levels after 6 months.(152152 Bizzarri C, Pinto RM, Ciccone S, Brescia LP, Locatelli F, Cappa M. Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2015;62(9):1650-5.,275275 Silva F, Pérez-Simón JA, Caballero-Velazquez T, Sánchez-Guijo FM, Villanueva-Gomez F, Vazquez L, et al. Effect of vitamin D treatment in chronic GVHD. Bone Marrow Transplant. 2011;46(10):1395-7.) Studies in adults have suggested that the immunomodulatory properties of this vitamin could play an important role in the prevention and treatment of GVHD.(276276 Dôres SM, Paiva SA, Campana AO. Vitamina K: metabolismo e nutrição. Rev Nutr. 2001;14(3):207-18.)

Lipid oxidation can be inhibited with supplementation of vitamin C associated with vitamin E (800IU to 1,000IU) and carotenoid (45mg).(5959 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.) Another advantage of vitamin E supplementation would be prevention of hepatic VOD.(5959 Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.) Vitamin C should also be supplemented to promote tissue recovery through post-conditioning collagen biosynthesis, with a daily recommendation of 250mg for patients below 31kg and 500mg for patients over 31kg, with contraindication when serum ferritin is greater than 1,000mg/L.(277277 Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
https://www.fredhutch.org/content/dam/pu...
) Vitamin K supplementation is also necessary; during the HSCT process, this deficiency is related to the use of some medications. During the conditioning period, many children receive phenytoin as prophylaxis for seizures, and this medication is a vitamin K antagonist.(277277 Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
https://www.fredhutch.org/content/dam/pu...
) Furthermore, some antibiotics, such as cephalosporins, can directly inhibit the hepatic epoxide-reductase enzyme, also antagonizing this vitamin.(278278 Frem J, Sarson Y, Sternberg T, Cole CR. Copper supplementation in parenteral nutrition of cholestatic infants. J Pediatr Gastroenterol Nutr. 2010;50(6):650-4.)

The recommendation for patients undergoing HSCT is to use supplements containing all vitamins and minerals, such as calcium, zinc, selenium, and iron-free, respecting the DRIs and for, at least 1 year after HSCT.(276276 Dôres SM, Paiva SA, Campana AO. Vitamina K: metabolismo e nutrição. Rev Nutr. 2001;14(3):207-18.) Iron supplementation is generally not recommended because most patients have high iron concentrations due to frequent blood transfusions.(277277 Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
https://www.fredhutch.org/content/dam/pu...
) There are few options for pediatric-specific multivitamin supplements on the Brazilian market, and, alternatively, individualized, compounded formulas may be used.

In some special situations, supplemental micronutrients should be reviewed and individualized. Patients with grade 3 and 4 skin aGVHD should receive extra doses of some vitamins and minerals to promote tissue healing and recovery,(277277 Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
https://www.fredhutch.org/content/dam/pu...
) and the nutrient requirements can be compared to those of major burn patients.

In cases of voluminous diarrhea, additional zinc supplementation is needed to restore increased losses, at a dose of 10mg to 12mg per liter of feces.(223223 Nannya Y, Shinohara A, Ichikawa M, Kurokawa M. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(3):430-4.,269269 Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S7-12. Review.,277277 Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
https://www.fredhutch.org/content/dam/pu...
) We utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving HSCT. We should remember that zinc is an essential trace-element, important for growth, wound healing, immune system maintenance and other vital functions, and should be added to all total parenteral nutrition at a dose of 100mcg/kg for children and 3mg to 4mg for adolescents.(269269 Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S7-12. Review.) In patients with liver dysfunction (with bilirubin >10mg/dL), caution is advised when adding copper and magnesium to total parenteral nutrition.(278278 Frem J, Sarson Y, Sternberg T, Cole CR. Copper supplementation in parenteral nutrition of cholestatic infants. J Pediatr Gastroenterol Nutr. 2010;50(6):650-4.,279279 Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr. 2011;35(6):736-47.)

CONCLUSION

Pediatric patients undergoing hematopoietic stem cell transplantation may develop numerous complications during and after the procedure. This document aims to empower support teams in the decision-making process for appropriate nutritional therapy to patients, considering basic needs of the age group, as well as current specific needs.

The performance of a thorough nutritional assessment (food history, anthropometric evaluation, laboratory tests and physical examination) before (identifying nutritional deficiencies and programming initial nutritional therapy), during (monitoring complications and programming strategies for nutritional intervention) and after hospital discharge, and during outpatient follow-up (monitoring of dietary intake, symptoms and ensuring age-appropriate diet) creates a surveillance network for potential nutritional complications.

REFERENCES

  • 1
    Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey (USA): Wiley-Blackwell; 2016. p.1416.
  • 2
    Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, Gratwohl M, Bouzas LF, Confer D, Frauendorfer K, Gluckman E, Greinix H, Horowitz M, Iida M, Lipton J, Madrigal A, Mohty M, Noel L, Novitzky N, Nunez J, Oudshoorn M, Passweg J, van Rood J, Szer J, Blume K, Appelbaum FR, Kodera Y, Niederwieser D; Worldwide Network for Blood and Marrow Transplantation (WBMT). One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol. 2015;2(3):e91-100. Erratum in: Lancet Haematol. 2015;2(5):e184.
  • 3
    D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417-21.
  • 4
    Pasquini M, Wang Z, Horowitz MM, Gale RP. 2013 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl. 2013:187-97.
  • 5
    European Society for Blood and Marrow Transplantation (EBMT). Inborn erros working party ESID EBMT HSCT guidelines 207. Guidelines for haematopoietic stem cell transplantation for primary immunodeficiencies. EBMIT/ESID; 2017 [cited 2019 Dec 10]. Available from: https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf
    » https://www.ebmt.org/sites/default/files/migration_legacy_files/document/Inborn%20Errors%20Working%20Party%20ESID%20EBMT%20HSCT%20Guidelines%202017.pdf
  • 6
    Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786-92.
  • 7
    Associação Brasileira de Transplante de Órgãos (ABTO). Registro Brasileiro de Transplantes (RBT). Dimensionamento dos transplantes no Brasil e em cada estado (2009-2016). Ano XXII Nº 4. São Paulo: ABTO; 2016 [citado 2019 Nov 21]. Disponível em: www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
    » www.abto.org.br/abtov03/Upload/file/RBT/2016/RBT2016-leitura.pdf
  • 8
    Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Portaria SAS nº. 940 de 21 de Dezembro de 2006. Altera o atributo NOME dos procedimentos referentes a TCTH. Brasília (DF): Diário Oficial do Brasil; 2006 Dez de 21[citado 2020 Mar 10]. Disponível em: https://www.normasbrasil.com.br/norma/portaria-940-2006_197770.html
    » https://www.normasbrasil.com.br/norma/portaria-940-2006_197770.html
  • 9
    Farias CL, Campos DJ, Bonfin CM, Vilela RM. Phase angle from BIA as a prognostic and nutritional status tool for children and adolescents undergoing hematopoietic stem cell transplantation. Clin Nutr. 2013;32(3):420-5.
  • 10
    Cohen A, Duell T, Socié G, van Lint MT, Weiss M, Tichelli A, et al. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1999;23(10):1043-7.
  • 11
    Fuji S, Mori T, Khattry N, Cheng J, Do YR, Yakushijin K, et al. Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality. Bone Marrow Transplant. 2015;50(1):100-5.
  • 12
    Espinoza M, Perelli J, Olmos R, Bertin P, Jara V, Ramírez P. Nutritional assessment as predictor of complications after hematopoietic stem cell transplantation. Rev Bras Hematol Hemoter. 2016;38(1):7-14.
  • 13
    Hadjibabaie M, Tabeefar H, Alimoghaddam K, Iravani M, Eslami K, Honarmand H, et al. The relationship between body mass index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Transplant. 2012;26(1):149-55.
  • 14
    Hoffmeister PA, Storer BE, Macris PC, Carpenter PA, Baker KS. Relationship of body mass index and arm anthropometry to outcomes after pediatric allogeneic hematopoietic cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2013;19(7):1081-6.
  • 15
    Bouma S, Peterson M, Gatza E, Choi SW. Nutritional status and weakness following pediatric hematopoietic cell transplantation. Pediatr Transplant. 2016;20(8):1125-31.
  • 16
    Campos DJ, Boguszewski CL, Funke VA, Bonfim CM, Kulak CA, Pasquini R, et al. Bone mineral density, vitamin D, and nutritional status of children submitted to hematopoietic stem cell transplantation. Nutrition. 2014;30(6):654-9.
  • 17
    Browning B, Thormann K, Seshadri R, Duerst R, Kletzel M, Jacobsohn DA. Weight loss and reduced body mass index: a critical issue in children with multiorgan chronic graft-versus-host disease. Bone Marrow Transplant. 2006;37(5):527-33.
  • 18
    White M, Murphy AJ, Hallahan A, Ware RS, Fraser C, Davies PS. Survival in overweight and underweight children undergoing hematopoietic stem cell transplantation. Eur J Clin Nutr. 2012;66(10):1120-3.
  • 19
    Pine M, Wang L, Harrell FE Jr, Calder C, Manes B, Evans M, et al. The effect of obesity on outcome of unrelated cord blood transplant in children with malignant diseases. Bone Marrow Transplant. 2011;46(10):1309-13.
  • 20
    Brasil. Ministério da Saúde. Instituto Nacional de Câncer José de Alencar Gomes da Silva (INCA). Consenso nacional de nutrição oncológica. 2a ed. rev. ampl. atual. Rio de Janeiro: INCA; 2015. p.182 [citado 2020 Jul 4]. Disponível em: https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
    » https://www.inca.gov.br/sites/ufu.sti.inca.local/files/media/document/consenso-nacional-de-nutricao-oncologica-2-edicao-2015.pdf
  • 21
    Ladas EJ, Sacks N, Brophy P, Rogers PC. Standards of nutritional care in pediatric oncology: results from a nationwide survey on the standards of practice in pediatric oncology. A Children’s Oncology Group study. Pediatr Blood Cancer. 2006;46(3):339-44.
  • 22
    Viani K, Yonamine G, Gandolfo AS, Lemos PS. Avaliação Nutricional. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. Barueri: Manole; 2017. p. 28-46.
  • 23
    Sociedade Brasileira de Pediatria (SBP). Avaliação nutricional da criança e do adolescente: manual de orientação. Departamento de Nutrologia. Rio de Janeiro:SBP; 2009. Capítulo 5. Avaliação da composição corporal. p. 46-51.
  • 24
    Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 21-6.
  • 25
    WHO Multicentre Growth Reference Study Group – WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr. 2006;95(Suppl 450):76-85.
  • 26
    Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007;85(9):660-7.
  • 27
    Baracos V, Caserotti P, Earthman CP, Fields D, Gallagher D, Hall KD, et al. Advances in the science and application of body composition measurement. JPEN J Parenter Enteral Nutr. 2012;36(1):96-107.
  • 28
    Kim J, Shen W, Gallagher D, Jones A Jr, Wang Z, Wang J, et al. Total-body skeletal muscle mass: estimation by dual-energy X-ray absorptiometry in children and adolescents. Am J Clin Nutr. 2006;84(5):1014-20.
  • 29
    Prado CM, Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and intervention. JPEN J Parenter Enteral Nutr. 2014;38(8):940-53. Review. Erratum in: JPEN J Parenter Enteral Nutr. 2016;40(5):742.
  • 30
    Heymsfield SB, Adamek M, Gonzalez MC, Jia G, Thomas DM. Assessing skeletal muscle mass: historical overview and state of the art. J Cachexia Sarcopenia Muscle. 2014;5(1):9-18.
  • 31
    Ruble K, Hayat M, Stewart KJ, Chen A. Body composition after bone marrow transplantation in childhood. Oncol Nurs Forum. 2012;39(2):186-92.
  • 32
    Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel BS, Shults J, Thayu M, et al. Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation. J Pediatr. 2012;160(1):122-8.
  • 33
    Wei C, Thyagiarajan MS, Hunt LP, Shield JP, Stevens MC, Crowne EC. Reduced insulin sensitivity in childhood survivors of haematopoietic stem cell transplantation is associated with lipodystropic and sarcopenic phenotypes. Pediatr Blood Cancer. 2015;62(11):1992-9.
  • 34
    Inaba H, Yang J, Kaste SC, Hartford CM, Motosue MS, Chemaitilly W, et al. Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(32):3991-7.
  • 35
    Liu P, Wang B, Yan X, Cai J, Wang Y. Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases. Chin J Cancer Res. 2016;28(6):626-33.
  • 36
    Rodgers C, Wills-Alcoser P, Monroe R, Mc Donald L, Trevino M, Hockenberry M. Growth patterns and gastrointestinal symptoms in pediatric patients after hematopoietic stem cell transplantation. Oncol Nurs Forum. 2008;35(3):443-8.
  • 37
    Frisancho AR. Anthropometric standards: an interactive nutritional reference of body size and body composition for children and adults. 2nd ed. Michigan: University of Michigan Press; 2008. p. 144-59.
  • 38
    White M, Davies P, Murphy A. Validation of percent body fat indicators in pediatric oncology nutrition assessment. J Pediatr Hematol Oncol. 2008;30(2):124-9.
  • 39
    White M, Davies P, Murphy A. Correlation between nutrition assessment data and percent body fat via plethysmography in pediatric oncology patients. JPEN J Parenter Enteral Nutr. 2011;35(6):715-22.
  • 40
    Mosby TT, Barr RD, Pencharz PB. Nutritional assessment of children with cancer. J Pediatr Oncol Nurs. 2009;26(4):186-97.
  • 41
    Antillon F, Rossi E, Molina AL, Sala A, Pencharz P, Valsecchi MG, et al. Nutritional status of children during treatment for acute lymphoblastic leukemia in Guatemala. Pediatr Blood Cancer. 2013;60(6):911-5.
  • 42
    Garófolo A, Lopez FA, Petrilli AS. High prevalence of malnutrition among patients with solid non-hematological tumors as found by using skinfold and circumference measurements. Sao Paulo Med J. 2005;123(6):277-81.
  • 43
    Montejo González JC, Culebras-Fernández JM, García de Lorenzo y Mateos A. [Recommendations for the nutritional assessment of critically ill patients]. Rev Med Chil. 2006;134(8):1049-56. Review. Spanish.
  • 44
    Maicá AO, Schweigert ID. Nutritional assessment of the severely ill patient. Rev Bras Ter Intensiva. 2008;20(3):286-95.
  • 45
    Marín LA, Salido JA, López A, Silva A. Preoperative nutritional evaluation as a prognostic tool for wound healing. Acta Orthop Scand. 2002;73(1):2-5.
  • 46
    Vannucchi H, Unamuno MR, Marchini JS. Avaliação do estado nutricional. Medicina (Ribeirão Preto). 1996;29(1):5-8.
  • 47
    Macris PC, McMillen KK. Nutrition support of the hematopoietic cell transplant recipient. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas’ hematopoietic cell transplantation: stem cell transplantation. 4th ed. Vol. I. New Jersey (USA): Wiley-Blackwell; 2009. Chapter 99. p.1551-69.
  • 48
    Jeejeebhoy KN. Nutritional assessment. Gastroenterol Clin North Am. 1998;27(2):347-69. Review.
  • 49
    Carrazza FR, Kimura HM. Avaliação do Estado Nutricional. In: Andriolo A, Carrazza FR. Diagnóstico laboratorial em Pediatria. 2a ed. São Paulo: Sarvier; 2007. p. 325-33.
  • 50
    Pedrón Giner C, Cuervas-Mons Vendrell M, Galera Martínez R, Gómez López L, Gomis Muñoz P, Irastorza Terradillos I, Martínez Costa C, Moreno Villares JM, Pérez-Portabella Maristany C, Pozas Del Río MᵃT, Redecillas Ferreiro SE, Prieto Bozano G; Grupo de Estandarización de la Senpe S. Pediatric parenteral nutrition: clinical practice guidelines from the Spanish Society of Parenteral and Enteral Nutrition (SENPE), the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) and the Spanish Society of Hospital Pharmacy (SEFH). Nutr Hosp. 2017;34(3):745-58.
  • 51
    Bottoni A, Oliveira GP, Ferrini MT, Waitzberg DL. Avaliação nutricional: exames laboratoriais. In: Waitzberg DL. Nutrição oral, enteral e parenteral na prática clínica. 3a ed. São Paulo: Atheneu; 2001. v. 1. p. 279-94.
  • 52
    Raguso CA, Dupertuis YM, Pichard C. The role of visceral proteins in the nutritional assessment of intensive care unit patients. Curr Opin Clin Nutr Metab Care. 2003;6(2):211-6. Review.
  • 53
    Muscaritoli M, Conversano L, Cangiano C, Capria S, Laviano A, Arcese W, et al. Biochemical indices may not accurately reflect changes in nutritional status after allogeneic bone marrow transplantation. Nutrition. 1995;11(5):433-6.
  • 54
    Ritter L, Gazzola J. Avaliação nutricional no paciente cirrótico: uma abordagem objetiva, subjetiva ou multicompartimental? Arq Gastroenterol. 2006; 43(1):66-70.
  • 55
    Jeejeebhoy KN. Nutritional assessment. Nutrition. 2000;16(7-8):585-90. Review.
  • 56
    Paz LS, Couto AV. Avaliação nutricional em pacientes críticos: revisão de literatura. Braspen J. 2016;31(3):269-77.
  • 57
    Acuña K, Cruz T. Avaliação do estado nutricional de adultos e idosos e situação nutricional da população brasileira. Arq Bras Endocrinol Metabol. 2004;48(3):345-61.
  • 58
    Spexoto MC, Oliveira MR. Consumo alimentar orientado pode prevenir a queda ponderal no pós-transplante de células-tronco hematopoéticas imediato. Rev Bras Nutr Clín. 2013;28(2):91-7.
  • 59
    Martin-Salces M, de Paz R, Canales MA, Mesejo A, Hernandez-Navarro F. Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition. 2008;24(7-8):769-75. Review.
  • 60
    Raynard B, Nitenberg G, Gory-Delabaere G, Bourhis JH, Bachmann P, Bensadoun RJ, et al. [Standards, options and recommendations for nutritional support in bone marrow transplant patients]. Bull Cancer. 2002;89(4):381-98. French.
  • 61
    Mendes TG, Benedetti FJ. Fatores nutricionais associados ao câncer em crianças e adolescentes. Disciplinarum Scientia. 2013;14(2):265-72.
  • 62
    Garófolo A. Diretrizes para terapia nutricional em crianças com câncer em situação crítica. Rev Nutr. 2005;18(4):513-27.
  • 63
    Garófolo A. Contribuição da alimentação e da terapia nutricional para a necessidade de energia em pacientes submetidos ao transplante de medula óssea (TMO). Mundo Saúde. 2011;35(2):193-200.
  • 64
    Ringwald-Smith KA, Heslop HE, Krance RA, Mackert PW, Hancock ML, Stricklin LM, et al. Energy expenditure in children undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;30(2):125-30.
  • 65
    Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Recomendações nutricionais para crianças em terapia nutricional enteral e parenteral. São Paulo: AMBCFM; 2011. p. 1-16 [citado 2019 Dez 10]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
    » https://diretrizes.amb.org.br/_BibliotecaAntiga/recomendacoes_nutricionais_para_criancas_em_terapia_nutricional_enteral_e_parenteral.pdf
  • 66
    Jones L, Watling RM, Wilkins S, Pizer B. Nutritional support in children and young people with cancer undergoing chemotherapy. Cochrane Database Syst Rev. 2010;(7):CD003298. Review. Update in: Cochrane Database Syst Rev. 2015;8:CD003298.
  • 67
    Cohen J, Maurice L. Adequacy of nutritional support in pediatric blood and marrow transplantation. J Pediatr Oncol Nurs. 2010;27(1):40-7.
  • 68
    Raynard B, Nitenberg G, Gory-Delabaere G, Bourhis JH, Bachmann P, Bensadoun RJ, Desport JC, Kere D, Schneider S, Senesse P, Bordigoni P, Dieu L; FNCLCC. Summary of the standards, options and recommendations for nutritional support in patients undergoing bone marrow transplantation (2002). Br J Cancer. 2003;89(Suppl 1):S101-6.
  • 69
    Papadopoulou A, Williams MD, Darbyshire PJ, Booth IW. Nutritional support in children undergoing bone marrow transplantation. Clin Nutr. 1998;17(2):57-63.
  • 70
    Pinheiro SM, Rodrigues VD, Pinto MA, Carvalho CN, Oliveira CL, Rodrigues CS. Metabolic alteration in children with blood cancer undergoing homologous bone marrow transplantation. Ceres (Rio de Janiero). 2010;5(1):27-36.
  • 71
    Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/
    » https://www.ncbi.nlm.nih.gov/books/NBK56070/
  • 72
    Abreu ES, Simony RF, Takahashi AA, Santos CR. Recomendações nutricionais para crianças que realizaram transplante de medula óssea. Rev Ciênc Méd Biol. 2012;11(1):54-9.
  • 73
    Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.
  • 74
    Albertini S, Ruiz MA. Nutrição em transplante de medula óssea: a importância da terapia nutricional. Arq Ciênc Saúde. 2004;11(3):182-8.
  • 75
    Fuji S, Einsele H, Savani BN, Kapp M. Systematic nutritional support in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2015;21(10):1707-13. Review.
  • 76
    Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transplant. 2017;52(4):506-13. Review.
  • 77
    White M, Murphy AJ, Hastings Y, Shergold J, Young J, Montgomery C, et al. Nutritional status and energy expenditure in children pre-bone-marrow-transplant. Bone Marrow Transplant. 2005;35(8):775-9.
  • 78
    Sheean P. Nutrition support of blood or marrow transplant recipients: How much do we really know? Pract Gastro. 2005;29(4):84-97 [Nutrition Issues in Gastroenterology, Series #26].
  • 79
    Chamouard Cogoluenhes V, Chambrier C, Michallet M, Gordiani B, Ranchere JY, Combret D, et al. Energy expenditure during allogeneic and autologous bone marrow transplantation. Clin Nutr. 1998;17(6):253-7.
  • 80
    Bechard LJ, Feldman HA, Venick R, Gura K, Gordon C, Sonis A, et al. Attenuation of resting energy expenditure following hematopoietic SCT in children. Bone Marrow Transplant. 2012;47(10):1301-6.
  • 81
    Akbulut G. Medical nutritional therapy in hematopoietic stem cell transplantation (HSCT). Int J Hematol Oncol. 2013;23(1):55-65.
  • 82
    Barron MA, Doyle J, Zlotkin S. Vitamin K deficiency in children pre-bone marrow transplantation. Bone Marrow Transplant. 2006;37(2):151-4.
  • 83
    van der Meij BS, de Graaf P, Wierdsma NJ, Langius JA, Janssen JJ, van Leeuwen PA, et al. Nutritional support in patients with GVHD of the digestive tract: state of the art. Bone Marrow Transplant. 2013;48(4):474-82. Review.
  • 84
    Padovani RM, Amaya-Farfán J, Colugnati FA, Domene SM. Dietary reference intakes: application of tables in nutritional studies. Rev Nutr. 2006;19(6):741-60.
  • 85
    de Castro CG Jr, Gregianin LJ, Brunetto AL. Clinical and epidemiological analysis of bone marrow transplantation in a pediatric oncology unit. J Pediatr (Rio J). 2003;79(5):413-22.
  • 86
    Sheean PM, Braunschweig CA. Exploring the clinical characteristics of parenteral nutrition recipients admitted for initial hematopoietic stem cell transplantation. J Am Diet Assoc. 2007;107(8):1398-403.
  • 87
    Lipkin AC, Lenssen P, Dickson BJ. Nutrition issues in hematopoietic stem cell transplantation: state of the art. Nutr Clin Pract. 2005;20(4):423-39. Review.
  • 88
    Rzepecki R, Barzal J, Sarosiek T, Oborska S, Szczylik C. Nutritional assessment during allogeneic hematopoietic stem cell transplantation: single centre experience. J BUON. 2007;12(2):253-9.
  • 89
    Orasch C, Weisser M, Mertz D, Conen A, Heim D, Christen S, et al. Comparison of infectious complications during induction/consolidation chemotherapy versus allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2010;45(3):521-6.
  • 90
    Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur J Oncol Nurs. 2005;9 Suppl 2:S51-63. Review.
  • 91
    Rhodes VA, McDaniel RW. Nausea, vomiting, and retching: complex problems in palliative care. CA Cancer J Clin. 2001;51(4):232-48; quiz 249-52. Erratum in: CA Cancer J Clin. 2001;51(5):320.
  • 92
    Maciel MG, Bettega R. Náusea e vômito. In: Carvalho RT, Parsons HA. Manual de cuidados paliativos Academia Nacional de Cuidados Paliativos. 2a ed. ampl. e atualizado. São Paulo: ANCP; 2012. p.168-75. Parte 2 – Controle de sintomas.
  • 93
    Santucci G, Mack JW. Common gastrointestinal symptoms in pediatric palliative care: nausea, vomiting, constipation, anorexia, cachexia. Pediatr Clin North Am. 2007;54(5):673-89, x. Review.
  • 94
    Benarroz MO, Faillace GB, Barbosa LA. Bioética e nutrição em cuidados paliativos oncológicos em adultos. Cad Saude Publica. 2009;25(9):1875-82.
  • 95
    August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009;33(5):472-500.
  • 96
    Funke VA, Moreira MC, Vigorito AC. Acute and chronic Graft-versus-host disease after hematopoietic stem cell transplantation. Rev Assoc Med Bras (1992). 2016;62(Suppl 1):44-50. Review.
  • 97
    Bassim CW, Fassil H, Dobbin M, Steinberg SM, Baird K, Cole K, et al. Malnutrition in patients with chronic GVHD. Bone Marrow Transplant. 2014;49(10):1300-6.
  • 98
    lowers ME, McDonald G, Carpenter P, Boeckh M, Sanders J, Deeg J, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. Seattle (WA): Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 2019. p.88 [cited 2019 Nov 26]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/physician.pdf
    » https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/physician.pdf
  • 99
    Viani K, Leao AC, Mantovani LF. Transplante de células tronco-hematopoieticas. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p.188-201.
  • 100
    Garnett C, Apperley JF, Pavlů J. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol. 2013;4(6):366-78. Review.
  • 101
    Cuppari L. Guia de Medicina Ambulatorial e Hospitalar Nutrição da clínica ESPM/UNIFESP. Nutrição: clínica no adulto. 3a ed. Barueri, SP: Manole; 2013. p.167.
  • 102
    Mattsson J, Westin S, Edlund S, Remberger M. Poor oral nutrition after allogeneic stem cell transplantation correlates significantly with severe graft-versus-host disease. Bone Marrow Transplant. 2006;38(9):629-33.
  • 103
    Viet CT, Corby PM, Akinwande A, Schmidt BL. Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res. 2014;93(9):868-75. Review.
  • 104
    Sonis ST. Oral mucositis in cancer therapy. J Support Oncol. 2004;2(6 Suppl 3): 3-8. Review.
  • 105
    Al-Ansari S, Zecha JA, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Health Rep. 2015;2(4):202-11. Review.
  • 106
    Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015;27(3):159-64. Review.
  • 107
    Duncan M, Grant G. Oral and intestinal mucositis - causes and possible treatments. Aliment Pharmacol Ther. 2003;18(9):853-74. Review.
  • 108
    Sonis ST. Oral mucositis in head and neck cancer: risk, biology, and management. Am Soc Clin Oncol Educ Book. 2013;33:e236-40. Review.
  • 109
    Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, et al. The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic review. Biol Blood Marrow Transplant. 2016;22(4):605-16. Review.
  • 110
    American National Standards Institute (ANSI). National Institute of Cancer. Common terminology criteria for adverse events v3.0 (CTCAE). New York: CTCAE; 2006 [cited 2019 Nov 25]. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
    » http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf
  • 111
    Bensinger W, Schubert M, Ang KK, Brizel D, Brown E, Eilers JG, et al. NCCN task force report. prevention and management of mucositis in cancer care. J Natl Comp Canc Netw. 2008;6(Suppl 1):S1-21; quiz S22-4. Review.
  • 112
    Turner L, Mupparapu M, Akintoye SO. Review of the complications associated with treatment of oropharyngeal cancer: a guide for the dental practitioner. Quintessence Int. 2013;44(3):267-79. Review.
  • 113
    Wardley AM, Jayson GC, Swindell R, Morgenstern GR, Chang J, Bloor R, et al. Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol. 2000;110(2):292-9.
  • 114
    Lionel D, Christophe L, Marc A, Jean-Luc C. Oral mucositis induced by anticancer treatments: physiopathology and treatments. Ther Clin Risk Manag. 2006;2(2):159-68.
  • 115
    Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L, et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant. 2005;11(5):383-8.
  • 116
    Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am. 2008;52(1):61-77, viii. Review.
  • 117
    Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer. 2017;25(5):1713-39. Review.
  • 118
    Lopes NN, Plapler H, Lalla RV, Chavantes MC, Yoshimura EM, da Silva MA, et al. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters. Lasers Surg Med. 2010;42(6):546-52.
  • 119
    Oberoi S, Zamperlini-Netto G, Beyene J, Treister NS, Sung L. Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and meta-analysis. PLoS One. 2014;9(9):e107418. Review.
  • 120
    Saadeh CE. Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment. Pharmacotherapy. 2005;25(4):540-54. Review.
  • 121
    Davis MP, Dickerson D. Cachexia and anorexia: cancer’s covert killer. Support Care Cancer. 2000;8(3):180-7. Review.
  • 122
    Kyle UG, Chalandon Y, Miralbell R, Karsegard VL, Hans D, Trombetti A, et al. Longitudinal follow-up of body composition in hematopoietic stem cell transplant patients. Bone Marrow Transplant. 2005;35(12):1171-7.
  • 123
    Muscaritoli M, Bossola M, Aversa Z, Bellantone R, Rossi Fanelli F. Prevention and treatment of cancer cachexia: new insights into an old problem. Eur J Cancer. 2006;42(1):31-41. Review.
  • 124
    Manzoli B, Bouchabki G, Nabarrete J, Oliveira V. Manejo de sintomas e complicações. In. Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 127-51.
  • 125
    Barber MD. The pathophysiology and treatment of cancer cachexia. Nutr Clin Pract. 2002;17(4):203-9.
  • 126
    Jacobsohn DA, Margolis J, Doherty J, Anders V, Vogelsang GB. Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2002;29(3):231-6.
  • 127
    Jatoi A, Loprinzi CL. Anorexia and weight loss. In: Berger AM, Portenoy RK, Weissman DE, editors. Principles and practice of palliative care and supportive oncology. 2nd ed. Philadelphia (PA): Lippincott Williams & Wilkin; 2002. p. 169-77.
  • 128
    Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med. 2016;374(23):2256-67. Review.
  • 129
    Pulsipher MA, Skinner R, McDonald GB, Hingorani S, Armenian SH, Cooke KR, et al. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012;18(3):334-47.
  • 130
    National High Blood Pressure Education Progra Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555-76.
  • 131
    Berbel MN, Pinto MP, Ponce D, Balbi AL. Nutritional aspects in acute kidney injury. Rev Assoc Med Bras (1992). 2011;57(5):600-6. Review.
  • 132
    Takakura CY, Murakami DK. Nefropatias. In: da Silva AP, Nascimento AG, Zamberlan P. Manual de dietas e condutas nutricionais em pediatria. São Paulo: Atheneu; 2014. p. 383-92.
  • 133
    Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-9. Review.
  • 134
    Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-9. Review.
  • 135
    Lee SH, Yoo KH, Sung KW, Koo HH, Kwon YJ, Kwon MM, et al. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Bone Marrow Transplant. 2010; 45(8):1287-93.
  • 136
    Chao N. How I treat sinusoidal obstruction syndrome. Blood. 2014; 123(26):4023-6.
  • 137
    Naples JC, Skeens MA, Auletta J, Rangarajan H, Abu-Arja R, Horwitz E, et al. Anicteric veno-occlusive disease after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2016;51(1):135-7.
  • 138
    Myers KC, Dandoy C, El-Bietar J, Davies SM, Jodele S. Veno-occlusive disease of the liver in the absence of elevation in bilirubin in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(2):379-81.
  • 139
    Lakshminarayanan S, Sahdev I, Goyal M, Vlachos A, Atlas M, Lipton JM. Low incidence of hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin, oral glutamine, and ursodiol at a single transplant institution. Pediatr Transplant. 2010;14(5):618-21.
  • 140
    Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379(9823):1301-9.
  • 141
    Corbacioglu S, Kernan N, Lehmann L, Brochstein J, Revta C, Grupp S, et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol. 2012; 5(3):291-302. Review.
  • 142
    Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, Lehmann L, Shore T, Tacobelli M, Miloslavsky M, Hume R, Hannah AL, Nejadnik B, Soiffer RJ; Defibrotide Study Group. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS): interim results from a treatment IND Study. Biol Blood Marrow Transplant. 2017;23(6):997-1004.
  • 143
    Brasil. Ministério da Saúde. Instituto Nacional José Alencar Gomes da Silva (INCA). Tópicos em transplante de células-tronco hematopoéticas. Rio de Janeiro: INCA; 2012 [citado 2019 Nov 25]. Disponível em: http://bvsms.saude.gov.br/bvs/publicacoes/inca/topicos_transplantes.pdf
    » http://bvsms.saude.gov.br/bvs/publicacoes/inca/topicos_transplantes.pdf
  • 144
    Albertini SM. O transplante de células-tronco hematopoéticas e o fator nutricional na evolução dos pacientes. Rev Bras Hematol Hemoter. 2010; 32(1):8-9.
  • 145
    Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi Fanelli F. Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr. 2002;75(2):183-90. Review.
  • 146
    Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M; ESPEN. ESPEN Guidelines on Parenteral Nutrition: non-surgical oncology. Clin Nutr. 2009;28(4):445-54.
  • 147
    McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient : society of critical care medicine (SCCM) and american society for parenteral and enteral nutrition (A. S. P. E. N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211. Erratum in: JPEN J Parenter Enteral Nutr. 2016; 40(8):1200.
  • 148
    Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra71.
  • 149
    Dahllöf G, Hingorani SR, Sanders JE. Late effects following hematopoietic cell transplantation for children. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):88-93. Review. Erratum in: Biol Blood Marrow Transplant. 2008; 14(11):1317-8.
  • 150
    Kreutz M, Eissner G, Hahn J, Andreesen R, Drobnik W, Holler E. Variations in 1 alpha,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 serum levels during allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;33(8):871-3.
  • 151
    Shalitin S, Phillip M, Stein J, Goshen Y, Carmi D, Yaniv I. Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence. Bone Marrow Transplant. 2006;37(12):1109-17.
  • 152
    Bizzarri C, Pinto RM, Ciccone S, Brescia LP, Locatelli F, Cappa M. Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2015;62(9):1650-5.
  • 153
    Turcotte LM, Yingst A, Verneris MR. Erratum to: “Metabolic syndrome after hematopoietic cell transplantation: at the intersection of treatment toxicity and immune dysfunction” [Biol Blood Marrow Transplant 2016;22:1159-66]. Biol Blood Marrow Transplant. 2016;22(12):2286.
  • 154
    Baker KS, Chow E, Steinberger J. Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(5):619-25. Review.
  • 155
    Brasil. Ministério da Saúde. Secretária de Atenção à Saúde. Departamento de Atenção à Saúde. Dez passos para uma alimentação saudável: guia alimentar para crianças menores de dois anos. 2a ed. Brasília (DF): Ministério da Saúde; 2013 [citado 2019 Nov 25]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/guia_dez_passos_alimentacao_saudavel_2ed.pdf
    » https://bvsms.saude.gov.br/bvs/publicacoes/guia_dez_passos_alimentacao_saudavel_2ed.pdf
  • 156
    Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Guia alimentar para a população Brasileira. 2a ed. Brasília (DF): Ministério da Saúde; 2014 [citado 2019 Nov 25]. Disponível em: https://bvsms.saude.gov.br/bvs/publicacoes/guia_alimentar_populacao_brasileira_2ed.pdf
    » https://bvsms.saude.gov.br/bvs/publicacoes/guia_alimentar_populacao_brasileira_2ed.pdf
  • 157
    Hovan AJ, Williams PM, Stevenson-Moore P, Wahlin YB, Ohrn KE, Elting LS, Spijkervet FK, Brennan MT; Dysgeusia Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer. 2010;18(8):1081-7. Review.
  • 158
    Hong JH, Omur-Ozbek P, Stanek BT, Dietrich AM, Duncan SE, Lee YW, et al. Taste and odor abnormalities in cancer patients. J Support Oncol. 2009;7(2):58-65. Review.
  • 159
    Berteretche MV, Dalix AM, d’Ornano AM, Bellisle F, Khayat D, Faurion A. Decreased taste sensitivity in cancer patients under chemotherapy. Support Care Cancer. 2004;12(8):571-6.
  • 160
    Baharvand M, ShoalehSaadi N, Barakian R, Moghaddam EJ. Taste alteration and impact on quality of life after head and neck radiotherapy. J Oral Pathol Med. 2013;42(1):106-12.
  • 161
    Just T, Pau HW, Witt M, Hummel T. Contact endoscopic comparison of morphology of human fungiform papillae of healthy subjects and patients with transected chorda tympani nerve. Laryngoscope. 2006;116(7):1216-22.
  • 162
    Bozzetti F, Forbes A. The ESPEN clinical practice Guidelines on Parenteral Nutrition: present status and perspectives for future research. Clin Nutr. 2009;28(4):359-64.
  • 163
    Sanz Ortiz J, Moreno Nogueira JA, García de Lorenzo y Mateos A. Protein energy malnutrition (PEM) in cancer patients. Clin Transl Oncol. 2008; 10(9):579-82.
  • 164
    Wickham RS, Rehwaldt M, Kefer C, Shott S, Abbas K, Glynn-Tucker E, et al. Taste changes experienced by patients receiving chemotherapy. Oncol Nurs Forum. 1999;26(4):697-706.
  • 165
    Raber-Durlacher JE, Barasch A, Peterson DE, Lalla RV, Schubert MM, Fibbe WE. Oral complications and management considerations in patients treated with high-dose chemotherapy. Support Cancer Ther. 2004;1(4):219-29.
  • 166
    Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs. 2005;9 Suppl 2:S84-91. Review.
  • 167
    Ravasco P, Monteiro-Grillo I, Marques Vidal P, Camilo ME. Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Head Neck. 2005;27(8):659-68.
  • 168
    Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, et al. Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial. J Dent Res. 2005;84(1):35-8. Erratum in: J Dent Res. 2005;84(4):382.
  • 169
    Kubrak C, Olson K, Jha N, Jensen L, McCargar L, Seikaly H, et al. Nutrition impact symptoms: key determinants of reduced dietary intake, weight loss, and reduced functional capacity of patients with head and neck cancer before treatment. Head Neck. 2010;32(3):290-300.
  • 170
    Ogama N, Suzuki S, Umeshita K, Kobayashi T, Kaneko S, Kato S, et al. Appetite and adverse effects associated with radiation therapy in patients with head and neck cancer. Eur J Oncol Nurs. 2010;14(1):3-10.
  • 171
    Boltong A, Keast RS, Aranda SK. A matter of taste: making the distinction between taste and flavor is essential for improving management of dysgeusia. Support Care Cancer. 2011;19(4):441-2.
  • 172
    Okada N, Hanafusa T, Abe S, Sato C, Nakamura T, Teraoka K, et al. Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention. Support Care Cancer. 2016;24(9):3979-85.
  • 173
    Bressan V, Stevanin S, Bianchi M, Aleo G, Bagnasco A, Sasso L. The effects of swallowing disorders, dysgeusia, oral mucositis and xerostomia on nutritional status, oral intake and weight loss in head and neck cancer patients: a systematic review. Cancer Treat Rev. 2016;45:105-19. Review.
  • 174
    Lilleby K, Garcia P, Gooley T, McDonnnell P, Taber R, Holmberg L, et al. A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006;37(11):1031-5.
  • 175
    Aisa Y, Mori T, Kudo M, Yashima T, Kondo S, Yokoyama A, et al. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer. 2005;13(4):266-9.
  • 176
    Vokurka S, Bystricka E, Scudlova J, Mazur E, Visokaiova M, Vasilieva E, et al. The risk factors for oral mucositis and the effect of cryotherapy in patients after the BEAM and HD-l-PAM 200 mg/m(2) autologous hematopoietic stem cell transplantation. Eur J Oncol Nurs. 2011;15(5):508-12
  • 177
    Mori T, Yamazaki R, Aisa Y, Nakazato T, Kudo M, Yashima T, et al. Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer. 2006;14(4):392-5.
  • 178
    Bloise R, Davis MP. Dysgeusia #304. J Palliat Med. 2016;19(4):462-3. Review.
  • 179
    Halyard MY. Taste and smell alterations in cancer patients-real problems with few solutions. J Support Oncol. 2009;7(2):68-9.
  • 180
    Halyard MY, Jatoi A, Sloan JA, Bearden JD 3rd, Vora SA, Atherton PJ, et al. Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebo-controlled trial from the North Central Cancer Treatment Group (N01C4). Int J Radiat Oncol Biol Phys. 2007;67(5):1318-22.
  • 181
    Büntzel J, Schuth J, Küttner K, Glatzel M. Radiochemotherapy with amifostine cytoprotection for head and neck cancer. Support Care Cancer. 1998;6(2):155-60.
  • 182
    Komaki R, Lee JS, Milas L, Lee HK, Fossella FV, Herbst RS, et al. Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial. Int J Radiat Oncol Biol Phys. 2004;58(5):1369-77.
  • 183
    Ravasco P, Monteiro-Grillo I, Camilo M. Individualized nutrition intervention is of major benefit to colorectal cancer patients: long-term follow-up of a randomized controlled trial of nutritional therapy. Am J Clin Nutr. 2012; 96(6):1346-53.
  • 184
    Ravasco P, Monteiro Grillo I, Camilo M. Cancer wasting and quality of life react to early individualized nutritional counselling! Clin Nutr. 2007;26(1):7-15. Review.
  • 185
    Speck RM, DeMichele A, Farrar JT, Hennessy S, Mao JJ, Stineman MG, et al. Taste alteration in breast cancer patients treated with taxane chemotherapy: experience, effect, and coping strategies. Support Care Cancer. 2013;21(2):549-55.
  • 186
    Wismer WV. Assessing alterations in taste and their impact on cancer care. Curr Opin Support Palliat Care. 2008;2(4):282-7. Review.
  • 187
    Hummel T, Landis BN, Hüttenbrink KB. Smell and taste disorders. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2011;10:Doc04.
  • 188
    Heckmann SM, Heckmann JG, Ungethüm A, Hujoel P, Hummel T. Gabapentin has little or no effect in the treatment of burning mouth syndrome - results of an open-label pilot study. Eur J Neurol. 2006;13(7):e6-7.
  • 189
    Strasser F, Demmer R, Böhme C, Schmitz SF, Thuerlimann B, Cerny T, et al. Prevention of docetaxel- or paclitaxel-associated taste alterations in cancer patients with oral glutamine: a randomized, placebo-controlled, double-blind study. Oncologist. 2008;13(3):337-46.
  • 190
    Spanemberg JC, Rodríguez de Rivera Campillo E, Salas EJ, López López J. Burning Mouth Syndrome: update. Oral Health Dent Manag. 2014;13(2):418-24.
  • 191
    Carbone M, Pentenero M, Carrozzo M, Ippolito A, Gandolfo S. Lack of efficacy of alpha-lipoic acid in burning mouth syndrome: a double-blind, randomized, placebo-controlled study. Eur J Pain. 2009;13(5):492-6.
  • 192
    López-Jornet P, Camacho-Alonso F, Leon-Espinosa S. Efficacy of alpha lipoic acid in burning mouth syndrome: a randomized, placebo-treatment study. J Oral Rehabil. 2009;36(1):52-7.
  • 193
    Cannabis-In-Cachexia-Study-Group, Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24(21):3394-400.
  • 194
    Majorana A, Amadori F, Bardellini E, Campus G, Conti G, Strohmenger L, et al. Taste dysfunction in patients undergoing hematopoietic stem cell transplantation: clinical evaluation in children. Pediatr Transplant. 2015; 19(5):571-5.
  • 195
    Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012;18(16):1851-60. Review.
  • 196
    Walrath M, Bacon C, Foley S, Fung HC. Gastrointestinal side effects and adequacy of enteral intake in hematopoietic stem cell transplant patients. Nutr Clin Pract. 2015;30(2):305-10.
  • 197
    Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32(9):920-4.
  • 198
    Brasil. Ministério da Saúde. Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC). Protocolo clínico e diretrizes terapêuticas doença falciforme. Relatorio de recomendação. Imunossupressão pós transplante de medula óssea. Brasilia (DF): Ministério da Saúde; 2016 [citado 2019 Nov 25]. Disponível em: http://conitec.gov.br/images/Consultas/Relatorios/2016/Relatorio_PCDT_DoencaFalciforme_CP_2016_v2.pdf
    » http://conitec.gov.br/images/Consultas/Relatorios/2016/Relatorio_PCDT_DoencaFalciforme_CP_2016_v2.pdf
  • 199
    Robak K, Zambonelli J, Bilinski J, Basak GW. Diarrhea after allogeneic stem cell transplantation: beyond graft-versus-host disease. Eur J Gastroenterol Hepatol. 2017;29(5):495-502. Review.
  • 200
    Morishita T, Tsushita N, Imai K, Sakai T, Miyao K, Sakemura R, et al. The efficacy of an oral elemental diet in patients undergoing hematopoietic stem cell transplantation. Intern Med. 2016;55(24):3561-9.
  • 201
    Goldberg RJ, Nakagawa T, Johnson RJ, Thurman JM. The role of endothelial cell injury in thrombotic microangiopathy. Am J Kidney Dis. 2010;56(6):1168-74.
  • 202
    Shah NN, McClellan W, Flowers CR, Lonial S, Khoury H, Waller EK, et al. Evaluating risk factors for clostridium difficile infection in stem cell transplant recipients: a national study. Infect Control Hosp Epidemiol. 2017;38(6):651-7.
  • 203
    Webb BJ, Brunner A, Ford CD, Gazdik MA, Petersen FB, Hoda D. Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2016;18(4):628-33.
  • 204
    Kwak KS, Zhou X, Solomon V, Baracos VE, Davis J, Bannon AW, et al. Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. Cancer Res. 2004;64(22):8193-8.
  • 205
    Lee JL, Leong LP, Lim SL. Nutrition intervention approaches to reduce malnutrition in oncology patients: a systematic review. Support Care Cancer. 2016;24(1):469-80. Review.
  • 206
    Watson T, MacDonald D, Song X, Bromwich K, Campos J, Sande J, et al. Risk factors for molecular detection of adenovirus in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2012;18(8):1227-34.
  • 207
    Srinivasan A, Klepper C, Sunkara A, Kang G, Carr J, Gu Z, et al. Impact of adenoviral stool load on adenoviremia in pediatric hematopoietic stem cell transplant recipients. Pediatr Infect Dis J. 2015;34(6):562-5.
  • 208
    César Pereira Santos H, Nunes Vieira Almeida T, Souza Fiaccadori F, das Dôres de Paula Cardoso D, de Moraes Arantes A, Delleon da Silva H, et al. Adenovirus infection among allogeneic stem cell transplant recipients. J Med Virol. 2017;89(2):298-303.
  • 209
    Williams D. Treatment of rotavirus-associated diarrhea using enteral immunoglobulins for pediatric stem cell transplant patients. J Oncol Pharm Pract. 2015;21(3):238-40.
  • 210
    Patel NC, Hertel PM, Hanson IC, Krance RA, Crawford SE, Estes M, et al. Chronic rotavirus infection in an infant with severe combined immunodeficiency: successful treatment by hematopoietic stem cell transplantation. Clin Immunol. 2012;142(3):399-401.
  • 211
    Liu A, Meyer E, Johnston L, Brown J, Gerson LB. Prevalence of graft versus host disease and cytomegalovirus infection in patients post-haematopoietic cell transplantation presenting with gastrointestinal symptoms. Aliment Pharmacol Ther. 2013;38(8):955-66.
  • 212
    Ye X, Van JN, Munoz FM, Revell PA, Kozinetz CA, Krance RA, et al. Noroviruses as a cause of diarrhea in immunocompromised pediatric hematopoietic stem cell and solid organ transplant recipients. Am J Transplant. 2015;15(7):1874-81.
  • 213
    Ueda R, Fuji S, Mori S, Hiramoto N, Hashimoto H, Tanaka T, et al. Characteristics and outcomes of patients diagnosed with norovirus gastroenteritis after allogeneic hematopoietic stem cell transplantation based on immunochromatography. Int J Hematol. 2015;102(1):121-8.
  • 214
    Troeger H, Loddenkemper C, Schneider T, Schreier E, Epple HJ, Zeitz M, et al. Structural and functional changes of the duodenum in human norovirus infection. Gut. 2009;58(8):1070-7.
  • 215
    Saif MA, Bonney DK, Bigger B, Forsythe L, Williams N, Page J, et al. Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support. Pediatr Transplant. 2011;15(5):505-9.
  • 216
    Ajumobi AB, Daniels JA, Sostre CF, Trevino HH. Giardiasis in a hematopoietic stem cell transplant patient. Transpl Infect Dis. 2014;16(6):984-7.
  • 217
    Bouanani N, Lamchahab M, Quachouh M, Soussi M, Quessar A, Benchekroun S. [Disseminated fusariosis during autologous stem cells transplant]. J Mycol Med. 2013;23(2):119-22. French.
  • 218
    Krones E, Högenauer C. Diarrhea in the immunocompromised patient. Gastroenterol Clin North Am. 2012;41(3):677-701. Review.
  • 219
    Milano F, Shulman HM, Guthrie KA, Riffkin I, McDonald GB, Delaney C. Late-onset colitis after cord blood transplantation is consistent with graft-versus-host disease: results of a blinded histopathological review. Biol Blood Marrow Transplant. 2014;20(7):1008-13.
  • 220
    Gupta NK, Masia R. Cord colitis syndrome: a cause of granulomatous inflammation in the upper and lower gastrointestinal tract. Am J Surg Pathol. 2013;37(7):1199-13.
  • 221
    Ball LM, Egeler RM; EBMT Paediatric Working Party. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant. 2008;41(Suppl 2): S58-64. Review.
  • 222
    Kambham N, Higgins JP, Sundram U, Troxell ML. Hematopoietic stem cell transplantation: graft versus host disease and pathology of gastrointestinal tract, liver, and lung. Adv Anat Pathol. 2014;21(5):301-20. Review.
  • 223
    Nannya Y, Shinohara A, Ichikawa M, Kurokawa M. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(3):430-4.
  • 224
    Langdana A, Tully N, Molloy E, Bourke B, O´Meara A. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant. 2001;27(7):741-6.
  • 225
    Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36(1):11-48.
  • 226
    Christensen ML, Hancock ML, Gattuso J, Hurwitz CA, Smith C, McCormick J, et al. Parenteral nutrition associated with increased infection rate in children with cancer. Cancer. 1993;72(9):2732-8.
  • 227
    Dioguardi J, Bryson E, Ahmed-Winston S, Vaughn G, Slater S, Driscoll J, et al. A multi-institutional retrospective study suggests that optimal enteral nutrition (EN) influences outcomes after hematopoietic stem cell transplantation in children and adults. Biol Blood Marrow Transplant. 2015;21(2):S248-9.
  • 228
    Bechard LJ, Guinan EC, Feldman HA, Tang V, Duggan C. Prognostic factors in the resumption of oral dietary intake after allogeneic hematopoietic stem cell transplantation (HSCT) in children. JPEN J Parenter Enteral Nutr. 2007;31(4):295-301.
  • 229
    Carr SE, Halliday V. Investigating the use of the neutropenic diet: a survey of U.K. dietitians. J Hum Nutr Diet. 2015;28(5):510-5.
  • 230
    Nabarrete J, Leão AC, Oliveira V. Dieta para neutropenia. In: Viani K, Oliveira V, Nabarrete J, Silva AP, Feferbaum R. Nutrição e câncer infanto-juvenil. São Paulo: Manole; 2017. p. 173-87.
  • 231
    Nucci M, Maiolino A. Infecções em transplante de medula óssea. Medicina (Ribeirão Preto). 2000;33(3):278-93.
  • 232
    Vicenski PP, Alberti P, Amaral DJ. Dietary recommendations for immunosuppressed patients of 17 hematopoietic stem cell transplantation centers in Brazil. Rev Bras Hematol Hemoter. 2012;34(2):86-93.
  • 233
    Sociedade Brasileira de Nutrição Parenteral e Enteral. Associação Brasileira de Cirurgia Pediátrica. Sociedade Brasileira de Clínica Médica. Associação Brasileira de Nutrologia. Projeto Diretrizes. Terapia Nutricional no Transplante de Célula Hematopoiética. Projeto Diretrizes. São Paulo: AMBCFM; 2011 [citado 2019 Nov 25]. Disponível em: https://diretrizes.amb.org.br/_BibliotecaAntiga/terapia_nutricional_no_transplante_de_celula_hematopoietica.pdf
    » https://diretrizes.amb.org.br/_BibliotecaAntiga/terapia_nutricional_no_transplante_de_celula_hematopoietica.pdf
  • 234
    Braun LE, Chen H, Frangoul H. Significant inconsistency among pediatric oncologists in the use of the neutropenic diet. Pediatr Blood Cancer. 2014;61(10):1806-10.
  • 235
    Bowman LC, Williams R, Sanders M, Ringwald-Smith K, Baker D, Gajjar A. Algorithm for nutritional support: experience of the metabolic and infusion support service of St. Jude Children´s Research Hospital. Int J Cancer Suppl. 1998;11:76-80.
  • 236
    Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Lindsley KL, Ghavimi F, et al. Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol. 1996; 14(5):1526-31.
  • 237
    Ladas EJ, Arora B, Howard SC, Rogers PC, Mosby TT, Barr RD. A framework for adapted nutritional therapy for children with cancer in low- and middle-income countries: a report from the SIOP PODC Nutrition Working Group. Pediatr Blood Cancer. 2016;63(8):1339-48.
  • 238
    Garófolo A, Alves FR, Rezende MA. Suplementos orais artesanais desenvolvidos para pacientes com câncer: análise descritiva. Rev Nutr. 2010;23(4):523-33.
  • 239
    Garófolo A, Maia PS, Petrilli AS, Ancona-Lopez F. Outcomes of the implementation of an enteral nutrition algorithm in children and adolescents with cancer. Rev Nutr. 2010;23(5):715-30.
  • 240
    Maia PS, Tsutsumi RC, Pedro BM, Garófolo A, Petrilli AS, Lopez FA. Suplementação oral em pacientes pediátricos com câncer. Nutr Rev Soc Bras Aliment Nutr. 2010;35(1):85-96.
  • 241
    Lewandowski CG. Aspectos nutricionais no transplante de células-tronco hematopoéticas alogênico em crianças e adolescentes em um hospital terciário [dissertação]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2016. 60 f.
  • 242
    Garófolo A. Enteral nutrition during bone marrow transplantation in patients with pediatric cancer: a prospective cohort study. Sao Paulo Med J. 2012;130(3):159-66.
  • 243
    Bicakli DH, Yilmaz MC, Aksoylar S, Kantar M, Cetingul N, Kansoy S. Enteral nutrition is feasible in pediatric stem cell transplantation patients. Pediatr Blood Cancer. 2012;59(7):1327-9.
  • 244
    Langdana A, Tully N, Molloy E, Bourke B, O’Meara A. Intensive enteral nutrition support in paediatric bone marrow transplantation. Bone Marrow Transplant. 2001;27(7):741-6.
  • 245
    Guièze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr. 2014;33(3):533-8.
  • 246
    Baumgartner A, Bargetzi M, Bargetzi A, Zueger N, Medinger M, Passweg J, et al. Nutritional support practices in hematopoietic stem cell transplantation centers: a nationwide comparison. Nutrition. 2017;35:43-50.
  • 247
    Sefcick A, Anderton D, Byrne JL, Teahon K, Russell NH. Naso-jejunal feeding in allogeneic bone marrow transplant recipients: results of a pilot study. Bone Marrow Transplant. 2001;28(12):1135-9.
  • 248
    Hastings Y, White M, Young J. Enteral nutrition and bone marrow transplantation. J Pediatr Oncol Nurs. 2006;23(2):103-10.
  • 249
    Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL, Goldman A, et al. Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation. 1987;43(6):833-8.
  • 250
    Wedrychowicz A, Spodaryk M, Krasowska-Kwiecień A, Goździk J. Total parenteral nutrition in children and adolescents treated with high-dose chemotherapy followed by autologous haematopoietic transplants. Br J Nutr. 2010;103(6):899-906.
  • 251
    Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-82.
  • 252
    Biagi E, Zama D, Nastasi C, Consolandi C, Fiori J, Rampelli S, et al. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant. 2015;50(7):992-8.
  • 253
    Docampo MD, Auletta JJ, Jenq RR. Emerging influence of the intestinal microbiota during allogeneic hematopoietic cell transplantation: control the gut and the body will follow. Biol Blood Marrow Transplant. 2015;21(8):1360-6. Review.
  • 254
    Robin F, Paillard C, Marchandin H, Demeocq F, Bonnet R, Hennequin C. Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation. J Clin Microbiol. 2010;48(11):4317-9.
  • 255
    Mehta A, Rangarajan S, Borate U. A cautionary tale for probiotic use in hematopoietic SCT patients-Lactobacillus acidophilus sepsis in a patient with mantle cell lymphoma undergoing hematopoietic SCT. Bone Marrow Transplant. 2013;48(3):461-2.
  • 256
    Van den Nieuwboer M, Brummer RJ, Guarner F, Morelli L, Cabana M, Claasen E. The administration of probiotics and synbiotics in immune compromised adults: is it safe? Benef Microbes. 2015;6(1):3-17.
  • 257
    Ladas EJ, Bhatia M, Chen L, Sandler E, Petrovic A, Berman DM, et al. The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. Bone Marrow Transplant. 2016;51(2): 262-6.
  • 258
    Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB. Acquired amino acid deficiencies: a focus on arginine and glutamine. Nutr Clin Pract. 2017;32(1_suppl):30S-47S. Review.
  • 259
    Tao KM, Li XQ, Yang LQ, Yu WF, Lu ZJ, Sun YM, et al. Glutamine supplementation for critically ill adults. Cochrane Database Syst Rev. 2014;2014(9):CD010050. Review.
  • 260
    Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, Raber-Durlacher JE, Sonis ST, Elad S; Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453-61. Review. Erratum in: Cancer. 2015;121(8):1339.
  • 261
    Blijlevens NM, Donnelly JP, Naber AH, Schattenberg AV, DePauw BE. A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support Care Cancer. 2005;13(10):790-6.
  • 262
    Sornsuvit C, Komindr S, Chuncharunee S, Wanikiat P, Archararit N, Santanirand P. Pilot study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients. J Int Med Res. 2008;36(6):1383-91.
  • 263
    Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer. 2013;21(1):313-26. Review.
  • 264
    Ward E, Smith M, Henderson M, Reid U, Lewis I, Kinsey S, et al. The effect of high-dose enteral glutamine on the incidence and severity of mucositis in paediatric oncology patients. Eur J Clin Nutr. 2009;63(1):134-40.
  • 265
    Sayles C, Hickerson SC, Bhat RR, Hall J, Garey KW, Trivedi MV. Oral glutamine in preventing treatment-related mucositis in adult patients with cancer: a systematic review. Nutr Clin Pract. 2016;31(2):171-9. Review.
  • 266
    Yarom N, Ariyawardana A, Hovan A, Barasch A, Jarvis V, Jensen SB, Zadik Y, Elad S, Bowen J, Lalla RV; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21(11):3209-21. Review.
  • 267
    Cheng KK, Lee V, Li CH, Yuen HL, Ip WY, He HG, et al. Impact of oral mucositis on short-term clinical outcomes in paediatric and adolescent patients undergoing chemotherapy. Support Care Cancer. 2013;21(8):2145-52.
  • 268
    Storey B. The role of oral glutamine in pediatric bone marrow transplant. J Pediatr Oncol Nurs. 2007;24(1):41-5.
  • 269
    Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S7-12. Review.
  • 270
    Campbell I. Macronutrients, minerals, vitamins and energy. Anaesth Intensive Care Med. 2017;18(3):142-6.
  • 271
    Slegtenhorst S, Visser J, Burke A, Meyer R. Antioxidant intake in paediatric oncology patients. Clin Nutr. 2015;34(6):1210-4.
  • 272
    Gonçalves TL, Benvegnú DM, Bonfanti G, Frediani AV, Pereira DV, Rocha JB. Oxidative stress and delta-ALA-D activity in different conditioning regimens in allogeneic bone marrow transplantation patients. Clin Biochem. 2009;42(7-8):602-10.
  • 273
    Khrouf MF, Besbes H, Soussi MA, Khaled MB, Turki M, Zaouali S, et al. Acute lactic acidosis as a complication of thiamine-free parenteral nutrition in two neutropenic children. Nutr Clin Metab. 2015;29(3):159-62.
  • 274
    Milligan DW, Quick A, Barnard DL. Vitamin B12 absorption after allogeneic bone marrow transplantation. J Clin Pathol. 1987;40(12):1472-4.
  • 275
    Silva F, Pérez-Simón JA, Caballero-Velazquez T, Sánchez-Guijo FM, Villanueva-Gomez F, Vazquez L, et al. Effect of vitamin D treatment in chronic GVHD. Bone Marrow Transplant. 2011;46(10):1395-7.
  • 276
    Dôres SM, Paiva SA, Campana AO. Vitamina K: metabolismo e nutrição. Rev Nutr. 2001;14(3):207-18.
  • 277
    Flowers ME, McDonald G, Carpenter P, Boeckh M, Deeg J, Cheng GS, et al. Long-term follow-up after hematopoietic stem cell transplant general guidelines for referring physicians. General Guidelines for Referring Physicians. Seattle (WA); Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance; 2019 [cited 2020 Jan 1]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
    » https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/LTFU_HSCT_guidelines_physicians.pdf
  • 278
    Frem J, Sarson Y, Sternberg T, Cole CR. Copper supplementation in parenteral nutrition of cholestatic infants. J Pediatr Gastroenterol Nutr. 2010;50(6):650-4.
  • 279
    Btaiche IF, Carver PL, Welch KB. Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. JPEN J Parenter Enteral Nutr. 2011;35(6):736-47.

Publication Dates

  • Publication in this collection
    10 Dec 2021
  • Date of issue
    2021

History

  • Received
    30 June 2019
  • Accepted
    10 Dec 2020
Instituto Israelita de Ensino e Pesquisa Albert Einstein Avenida Albert Einstein, 627/701 , 05651-901 São Paulo - SP, Tel.: (55 11) 2151 0904 - São Paulo - SP - Brazil
E-mail: revista@einstein.br