Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease
Identifieur interne : 000511 ( Pmc/Corpus ); précédent : 000510; suivant : 000512Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease
Auteurs : Andréa Z. Pereira ; Afonso Celso Vigorito ; Alessandro De Moura Almeida ; Alexandre De Almeida Candolo ; Ana Carolina Leão Silva ; Ana Elisa De Paula Brandão-Anjos ; Bianca Laselva De Sá ; Catarina Lôbo Santos De Souza ; Cláudio Galvão De Castro ; José Salvador Rodrigues De Oliveira ; Juliana Bernardo Barban ; Elaine Maria Borges Mancilha ; Juliana Todaro ; Lilian Pinheiro Lopes ; Maria Cristina Martins De Almeida Macedo ; Morgani Rodrigues ; Paulo Cesar Ribeiro ; Roberto Luiz Da Silva ; Telma Sigolo Roberto ; Thays De Cássia Ruiz Rodrigues ; Vergilio Antonio Rensi Colturato ; Eduardo José De Alencar Paton ; George Maurício Navarro Barros ; Rosana Ducatti Souza Almeida ; Maria Claudia Rodrigues Moreira ; Mary Evelyn FlowersSource :
- Einstein [ 1679-4508 ] ; ????.
Abstract
The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft-
Url:
DOI: 10.31744/einstein_journal/2020AE4799
PubMed: NONE
PubMed Central: 7069734
Links to Exploration step
PMC:7069734Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- <italic>versus</italic> -host disease</title><author><name sortKey="Pereira, Andrea Z" sort="Pereira, Andrea Z" uniqKey="Pereira A" first="Andréa Z" last="Pereira">Andréa Z. Pereira</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Vigorito, Afonso Celso" sort="Vigorito, Afonso Celso" uniqKey="Vigorito A" first="Afonso Celso" last="Vigorito">Afonso Celso Vigorito</name><affiliation><nlm:aff id="aff2"><institution content-type="orgname">Universidade Estadual de Campinas</institution><addr-line><named-content content-type="city">Campinas</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Estadual de Campinas , Campinas , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Almeida, Alessandro De Moura" sort="Almeida, Alessandro De Moura" uniqKey="Almeida A" first="Alessandro De Moura" last="Almeida">Alessandro De Moura Almeida</name><affiliation><nlm:aff id="aff3"><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Candolo, Alexandre De Almeida" sort="Candolo, Alexandre De Almeida" uniqKey="Candolo A" first="Alexandre De Almeida" last="Candolo">Alexandre De Almeida Candolo</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Silva, Ana Carolina Leao" sort="Silva, Ana Carolina Leao" uniqKey="Silva A" first="Ana Carolina Leão" last="Silva">Ana Carolina Leão Silva</name><affiliation><nlm:aff id="aff5"><institution content-type="orgname">Hospital Sírio-Libanês</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Sírio-Libanês , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Brandao Anjos, Ana Elisa De Paula" sort="Brandao Anjos, Ana Elisa De Paula" uniqKey="Brandao Anjos A" first="Ana Elisa De Paula" last="Brandão-Anjos">Ana Elisa De Paula Brandão-Anjos</name><affiliation><nlm:aff id="aff6"><institution content-type="orgname">Fundação Hospital Amaral Carvalho</institution><addr-line><named-content content-type="city">Jaú</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Sa, Bianca Laselva" sort="De Sa, Bianca Laselva" uniqKey="De Sa B" first="Bianca Laselva" last="De Sá">Bianca Laselva De Sá</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Souza, Catarina Lobo Santos" sort="De Souza, Catarina Lobo Santos" uniqKey="De Souza C" first="Catarina Lôbo Santos" last="De Souza">Catarina Lôbo Santos De Souza</name><affiliation><nlm:aff id="aff7"><institution content-type="orgdiv1">Complexo Hospitalar Universitário Professor Edgard Santos</institution><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Complexo Hospitalar Universitário Professor Edgard Santos , Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Castro, Claudio Galvao" sort="De Castro, Claudio Galvao" uniqKey="De Castro C" first="Cláudio Galvão" last="De Castro">Cláudio Galvão De Castro</name><affiliation><nlm:aff id="aff8"><institution content-type="orgname">Santa Casa de Misericórdia de Porto Alegre</institution><addr-line><named-content content-type="city">Porto Alegre</named-content><named-content content-type="state">RS</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Santa Casa de Misericórdia de Porto Alegre , Porto Alegre , RS , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Oliveira, Jose Salvador Rodrigues" sort="De Oliveira, Jose Salvador Rodrigues" uniqKey="De Oliveira J" first="José Salvador Rodrigues" last="De Oliveira">José Salvador Rodrigues De Oliveira</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Barban, Juliana Bernardo" sort="Barban, Juliana Bernardo" uniqKey="Barban J" first="Juliana Bernardo" last="Barban">Juliana Bernardo Barban</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Mancilha, Elaine Maria Borges" sort="Mancilha, Elaine Maria Borges" uniqKey="Mancilha E" first="Elaine Maria Borges" last="Mancilha">Elaine Maria Borges Mancilha</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Todaro, Juliana" sort="Todaro, Juliana" uniqKey="Todaro J" first="Juliana" last="Todaro">Juliana Todaro</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Lopes, Lilian Pinheiro" sort="Lopes, Lilian Pinheiro" uniqKey="Lopes L" first="Lilian Pinheiro" last="Lopes">Lilian Pinheiro Lopes</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Macedo, Maria Cristina Martins De Almeida" sort="Macedo, Maria Cristina Martins De Almeida" uniqKey="Macedo M" first="Maria Cristina Martins De Almeida" last="Macedo">Maria Cristina Martins De Almeida Macedo</name><affiliation><nlm:aff id="aff10"><institution content-type="orgname">Instituto Brasileiro de Controle do Câncer</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Rodrigues, Morgani" sort="Rodrigues, Morgani" uniqKey="Rodrigues M" first="Morgani" last="Rodrigues">Morgani Rodrigues</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Ribeiro, Paulo Cesar" sort="Ribeiro, 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content-type="original"> Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Roberto, Telma Sigolo" sort="Roberto, Telma Sigolo" uniqKey="Roberto T" first="Telma Sigolo" last="Roberto">Telma Sigolo Roberto</name><affiliation><nlm:aff id="aff11"><institution content-type="orgname">Hospital São Luiz</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital São Luiz , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Rodrigues, Thays De Cassia Ruiz" sort="Rodrigues, Thays De Cassia Ruiz" uniqKey="Rodrigues T" first="Thays De Cássia Ruiz" last="Rodrigues">Thays De Cássia Ruiz Rodrigues</name><affiliation><nlm:aff id="aff2"><institution content-type="orgname">Universidade Estadual de Campinas</institution><addr-line><named-content content-type="city">Campinas</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Estadual de Campinas , Campinas , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Colturato, Vergilio Antonio Rensi" sort="Colturato, Vergilio Antonio Rensi" uniqKey="Colturato V" first="Vergilio Antonio Rensi" last="Colturato">Vergilio Antonio Rensi Colturato</name><affiliation><nlm:aff id="aff6"><institution content-type="orgname">Fundação Hospital Amaral Carvalho</institution><addr-line><named-content content-type="city">Jaú</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Paton, Eduardo Jose De Alencar" sort="Paton, Eduardo Jose De Alencar" uniqKey="Paton E" first="Eduardo José De Alencar" last="Paton">Eduardo José De Alencar Paton</name><affiliation><nlm:aff id="aff12"><institution content-type="orgname">Oncobio</institution><addr-line><named-content content-type="city">Nova Lima</named-content><named-content content-type="state">MG</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Oncobio , Nova Lima , MG , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Barros, George Mauricio Navarro" sort="Barros, George Mauricio Navarro" uniqKey="Barros G" first="George Maurício Navarro" last="Barros">George Maurício Navarro Barros</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Almeida, Rosana Ducatti Souza" sort="Almeida, Rosana Ducatti Souza" uniqKey="Almeida R" first="Rosana Ducatti Souza" last="Almeida">Rosana Ducatti Souza Almeida</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Moreira, Maria Claudia Rodrigues" sort="Moreira, Maria Claudia Rodrigues" uniqKey="Moreira M" first="Maria Claudia Rodrigues" last="Moreira">Maria Claudia Rodrigues Moreira</name><affiliation><nlm:aff id="aff13"><institution content-type="orgname">Instituto Nacional de Câncer José Alencar Gomes da Silva</institution><addr-line><named-content content-type="city">Rio de Janeiro</named-content><named-content content-type="state">RJ</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA, Rio de Janeiro , RJ , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Flowers, Mary Evelyn" sort="Flowers, Mary Evelyn" uniqKey="Flowers M" first="Mary Evelyn" last="Flowers">Mary Evelyn Flowers</name><affiliation><nlm:aff id="aff14"><institution content-type="orgname">Seattle Cancer Care Alliance</institution><addr-line><named-content content-type="city">Seattle</named-content><named-content content-type="state">WA</named-content></addr-line><country country="US">United States</country><institution content-type="original"> Seattle Cancer Care Alliance , Seattle , WA , United States .</institution></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7069734</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069734</idno><idno type="RBID">PMC:7069734</idno><idno type="doi">10.31744/einstein_journal/2020AE4799</idno><idno type="pmid">NONE</idno><date when="????">????</date><idno type="wicri:Area/Pmc/Corpus">000511</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000511</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- <italic>versus</italic> -host disease</title><author><name sortKey="Pereira, Andrea Z" sort="Pereira, Andrea Z" uniqKey="Pereira A" first="Andréa Z" last="Pereira">Andréa Z. Pereira</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Vigorito, Afonso Celso" sort="Vigorito, Afonso Celso" uniqKey="Vigorito A" first="Afonso Celso" last="Vigorito">Afonso Celso Vigorito</name><affiliation><nlm:aff id="aff2"><institution content-type="orgname">Universidade Estadual de Campinas</institution><addr-line><named-content content-type="city">Campinas</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Estadual de Campinas , Campinas , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Almeida, Alessandro De Moura" sort="Almeida, Alessandro De Moura" uniqKey="Almeida A" first="Alessandro De Moura" last="Almeida">Alessandro De Moura Almeida</name><affiliation><nlm:aff id="aff3"><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Candolo, Alexandre De Almeida" sort="Candolo, Alexandre De Almeida" uniqKey="Candolo A" first="Alexandre De Almeida" last="Candolo">Alexandre De Almeida Candolo</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Silva, Ana Carolina Leao" sort="Silva, Ana Carolina Leao" uniqKey="Silva A" first="Ana Carolina Leão" last="Silva">Ana Carolina Leão Silva</name><affiliation><nlm:aff id="aff5"><institution content-type="orgname">Hospital Sírio-Libanês</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Sírio-Libanês , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Brandao Anjos, Ana Elisa De Paula" sort="Brandao Anjos, Ana Elisa De Paula" uniqKey="Brandao Anjos A" first="Ana Elisa De Paula" last="Brandão-Anjos">Ana Elisa De Paula Brandão-Anjos</name><affiliation><nlm:aff id="aff6"><institution content-type="orgname">Fundação Hospital Amaral Carvalho</institution><addr-line><named-content content-type="city">Jaú</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Sa, Bianca Laselva" sort="De Sa, Bianca Laselva" uniqKey="De Sa B" first="Bianca Laselva" last="De Sá">Bianca Laselva De Sá</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Souza, Catarina Lobo Santos" sort="De Souza, Catarina Lobo Santos" uniqKey="De Souza C" first="Catarina Lôbo Santos" last="De Souza">Catarina Lôbo Santos De Souza</name><affiliation><nlm:aff id="aff7"><institution content-type="orgdiv1">Complexo Hospitalar Universitário Professor Edgard Santos</institution><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Complexo Hospitalar Universitário Professor Edgard Santos , Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Castro, Claudio Galvao" sort="De Castro, Claudio Galvao" uniqKey="De Castro C" first="Cláudio Galvão" last="De Castro">Cláudio Galvão De Castro</name><affiliation><nlm:aff id="aff8"><institution content-type="orgname">Santa Casa de Misericórdia de Porto Alegre</institution><addr-line><named-content content-type="city">Porto Alegre</named-content><named-content content-type="state">RS</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Santa Casa de Misericórdia de Porto Alegre , Porto Alegre , RS , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="De Oliveira, Jose Salvador Rodrigues" sort="De Oliveira, Jose Salvador Rodrigues" uniqKey="De Oliveira J" first="José Salvador Rodrigues" last="De Oliveira">José Salvador Rodrigues De Oliveira</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Barban, Juliana Bernardo" sort="Barban, Juliana Bernardo" uniqKey="Barban J" first="Juliana Bernardo" last="Barban">Juliana Bernardo Barban</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Mancilha, Elaine Maria Borges" sort="Mancilha, Elaine Maria Borges" uniqKey="Mancilha E" first="Elaine Maria Borges" last="Mancilha">Elaine Maria Borges Mancilha</name><affiliation><nlm:aff id="aff9"><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Todaro, Juliana" sort="Todaro, Juliana" uniqKey="Todaro J" first="Juliana" last="Todaro">Juliana Todaro</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Lopes, Lilian Pinheiro" sort="Lopes, Lilian Pinheiro" uniqKey="Lopes L" first="Lilian Pinheiro" last="Lopes">Lilian Pinheiro Lopes</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Macedo, Maria Cristina Martins De Almeida" sort="Macedo, Maria Cristina Martins De Almeida" uniqKey="Macedo M" first="Maria Cristina Martins De Almeida" last="Macedo">Maria Cristina Martins De Almeida Macedo</name><affiliation><nlm:aff id="aff10"><institution content-type="orgname">Instituto Brasileiro de Controle do Câncer</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Rodrigues, Morgani" sort="Rodrigues, Morgani" uniqKey="Rodrigues M" first="Morgani" last="Rodrigues">Morgani Rodrigues</name><affiliation><nlm:aff id="aff1"><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Ribeiro, Paulo Cesar" sort="Ribeiro, Paulo Cesar" uniqKey="Ribeiro P" first="Paulo Cesar" last="Ribeiro">Paulo Cesar Ribeiro</name><affiliation><nlm:aff id="aff5"><institution content-type="orgname">Hospital Sírio-Libanês</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Sírio-Libanês , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Da Silva, Roberto Luiz" sort="Da Silva, Roberto Luiz" uniqKey="Da Silva R" first="Roberto Luiz" last="Da Silva">Roberto Luiz Da Silva</name><affiliation><nlm:aff id="aff10"><institution content-type="orgname">Instituto Brasileiro de Controle do Câncer</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Roberto, Telma Sigolo" sort="Roberto, Telma Sigolo" uniqKey="Roberto T" first="Telma Sigolo" last="Roberto">Telma Sigolo Roberto</name><affiliation><nlm:aff id="aff11"><institution content-type="orgname">Hospital São Luiz</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital São Luiz , São Paulo , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Rodrigues, Thays De Cassia Ruiz" sort="Rodrigues, Thays De Cassia Ruiz" uniqKey="Rodrigues T" first="Thays De Cássia Ruiz" last="Rodrigues">Thays De Cássia Ruiz Rodrigues</name><affiliation><nlm:aff id="aff2"><institution content-type="orgname">Universidade Estadual de Campinas</institution><addr-line><named-content content-type="city">Campinas</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Estadual de Campinas , Campinas , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Colturato, Vergilio Antonio Rensi" sort="Colturato, Vergilio Antonio Rensi" uniqKey="Colturato V" first="Vergilio Antonio Rensi" last="Colturato">Vergilio Antonio Rensi Colturato</name><affiliation><nlm:aff id="aff6"><institution content-type="orgname">Fundação Hospital Amaral Carvalho</institution><addr-line><named-content content-type="city">Jaú</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Paton, Eduardo Jose De Alencar" sort="Paton, Eduardo Jose De Alencar" uniqKey="Paton E" first="Eduardo José De Alencar" last="Paton">Eduardo José De Alencar Paton</name><affiliation><nlm:aff id="aff12"><institution content-type="orgname">Oncobio</institution><addr-line><named-content content-type="city">Nova Lima</named-content><named-content content-type="state">MG</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Oncobio , Nova Lima , MG , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Barros, George Mauricio Navarro" sort="Barros, George Mauricio Navarro" uniqKey="Barros G" first="George Maurício Navarro" last="Barros">George Maurício Navarro Barros</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Almeida, Rosana Ducatti Souza" sort="Almeida, Rosana Ducatti Souza" uniqKey="Almeida R" first="Rosana Ducatti Souza" last="Almeida">Rosana Ducatti Souza Almeida</name><affiliation><nlm:aff id="aff4"><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Moreira, Maria Claudia Rodrigues" sort="Moreira, Maria Claudia Rodrigues" uniqKey="Moreira M" first="Maria Claudia Rodrigues" last="Moreira">Maria Claudia Rodrigues Moreira</name><affiliation><nlm:aff id="aff13"><institution content-type="orgname">Instituto Nacional de Câncer José Alencar Gomes da Silva</institution><addr-line><named-content content-type="city">Rio de Janeiro</named-content><named-content content-type="state">RJ</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA, Rio de Janeiro , RJ , Brazil .</institution></nlm:aff></affiliation></author><author><name sortKey="Flowers, Mary Evelyn" sort="Flowers, Mary Evelyn" uniqKey="Flowers M" first="Mary Evelyn" last="Flowers">Mary Evelyn Flowers</name><affiliation><nlm:aff id="aff14"><institution content-type="orgname">Seattle Cancer Care Alliance</institution><addr-line><named-content content-type="city">Seattle</named-content><named-content content-type="state">WA</named-content></addr-line><country country="US">United States</country><institution content-type="original"> Seattle Cancer Care Alliance , Seattle , WA , United States .</institution></nlm:aff></affiliation></author></analytic><series><title level="j">Einstein</title><idno type="ISSN">1679-4508</idno><idno type="eISSN">2317-6385</idno><imprint><date when="????">????</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft- <italic>versus</italic> -host disease was approved by <italic>Sociedade Brasileira de Transplante de Medula Óssea</italic> , with the participation of 26 Brazilian hematopoietic stem cell transplantation centers. It describes the main nutritional protocols in cases of Graft- <italic>versus</italic> -host disease, the main complication of hematopoietic stem cell transplantation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Einstein (Sao Paulo)</journal-id><journal-id journal-id-type="iso-abbrev">Einstein (Sao Paulo)</journal-id><journal-id journal-id-type="publisher-id">eins</journal-id><journal-title-group><journal-title>Einstein</journal-title></journal-title-group><issn pub-type="ppub">1679-4508</issn><issn pub-type="epub">2317-6385</issn><publisher><publisher-name>Instituto Israelita de Ensino e Pesquisa Albert Einstein</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7069734</article-id><article-id pub-id-type="other">00902</article-id><article-id pub-id-type="doi">10.31744/einstein_journal/2020AE4799</article-id><article-categories><subj-group subj-group-type="heading"><subject>Special Article</subject></subj-group></article-categories><title-group><article-title>Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- <italic>versus</italic> -host disease</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-3572-6405</contrib-id><name><surname>Pereira</surname><given-names>Andréa Z</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-9990-1313</contrib-id><name><surname>Vigorito</surname><given-names>Afonso Celso</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9289-9727</contrib-id><name><surname>Almeida</surname><given-names>Alessandro de Moura</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9237-8411</contrib-id><name><surname>Candolo</surname><given-names>Alexandre de Almeida</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-1969-9363</contrib-id><name><surname>Silva</surname><given-names>Ana Carolina Leão</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5650-1360</contrib-id><name><surname>Brandão-Anjos</surname><given-names>Ana Elisa de Paula</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-7807-4550</contrib-id><name><surname>de Sá</surname><given-names>Bianca Laselva</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6511-0943</contrib-id><name><surname>de Souza</surname><given-names>Catarina Lôbo Santos</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-4610-8282</contrib-id><name><surname>de Castro</surname><given-names>Cláudio Galvão</given-names><suffix>Junior</suffix></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9862-4345</contrib-id><name><surname>de Oliveira</surname><given-names>José Salvador Rodrigues</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-7731-0061</contrib-id><name><surname>Barban</surname><given-names>Juliana Bernardo</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-5242-2561</contrib-id><name><surname>Mancilha</surname><given-names>Elaine Maria Borges</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-2709-4767</contrib-id><name><surname>Todaro</surname><given-names>Juliana</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lopes</surname><given-names>Lilian Pinheiro</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6105-9968</contrib-id><name><surname>Macedo</surname><given-names>Maria Cristina Martins de Almeida</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-0061-7882</contrib-id><name><surname>Rodrigues</surname><given-names>Morgani</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-0062-676X</contrib-id><name><surname>Ribeiro</surname><given-names>Paulo Cesar</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-5445-7194</contrib-id><name><surname>da Silva</surname><given-names>Roberto Luiz</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-0368-4052</contrib-id><name><surname>Roberto</surname><given-names>Telma Sigolo</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-4455-3283</contrib-id><name><surname>Rodrigues</surname><given-names>Thays de Cássia Ruiz</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-7842-2957</contrib-id><name><surname>Colturato</surname><given-names>Vergilio Antonio Rensi</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6790-2004</contrib-id><name><surname>Paton</surname><given-names>Eduardo José de Alencar</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-2816-3077</contrib-id><name><surname>Barros</surname><given-names>George Maurício Navarro</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-8331-6155</contrib-id><name><surname>Almeida</surname><given-names>Rosana Ducatti Souza</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-8376-7199</contrib-id><name><surname>Moreira</surname><given-names>Maria Claudia Rodrigues</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-1631-0911</contrib-id><name><surname>Flowers</surname><given-names>Mary Evelyn</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><institution content-type="orgname">Hospital Israelita Albert Einstein</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .</institution></aff><aff id="aff2"><label>2</label><institution content-type="orgname">Universidade Estadual de Campinas</institution><addr-line><named-content content-type="city">Campinas</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Estadual de Campinas , Campinas , SP , Brazil .</institution></aff><aff id="aff3"><label>3</label><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></aff><aff id="aff4"><label>4</label><institution content-type="orgname">Hospital de Câncer de Barretos,</institution><addr-line><named-content content-type="city">Barretos</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital de Câncer de Barretos, Barretos , SP , Brazil .</institution></aff><aff id="aff5"><label>5</label><institution content-type="orgname">Hospital Sírio-Libanês</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital Sírio-Libanês , São Paulo , SP , Brazil .</institution></aff><aff id="aff6"><label>6</label><institution content-type="orgname">Fundação Hospital Amaral Carvalho</institution><addr-line><named-content content-type="city">Jaú</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .</institution></aff><aff id="aff7"><label>7</label><institution content-type="orgdiv1">Complexo Hospitalar Universitário Professor Edgard Santos</institution><institution content-type="orgname">Universidade Federal da Bahia</institution><addr-line><named-content content-type="city">Salvador</named-content><named-content content-type="state">BA</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Complexo Hospitalar Universitário Professor Edgard Santos , Universidade Federal da Bahia , Salvador , BA , Brazil .</institution></aff><aff id="aff8"><label>8</label><institution content-type="orgname">Santa Casa de Misericórdia de Porto Alegre</institution><addr-line><named-content content-type="city">Porto Alegre</named-content><named-content content-type="state">RS</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Santa Casa de Misericórdia de Porto Alegre , Porto Alegre , RS , Brazil .</institution></aff><aff id="aff9"><label>9</label><institution content-type="orgname">Universidade Federal de São Paulo</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Universidade Federal de São Paulo , São Paulo , SP , Brazil .</institution></aff><aff id="aff10"><label>10</label><institution content-type="orgname">Instituto Brasileiro de Controle do Câncer</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .</institution></aff><aff id="aff11"><label>11</label><institution content-type="orgname">Hospital São Luiz</institution><addr-line><named-content content-type="city">São Paulo</named-content><named-content content-type="state">SP</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Hospital São Luiz , São Paulo , SP , Brazil .</institution></aff><aff id="aff12"><label>12</label><institution content-type="orgname">Oncobio</institution><addr-line><named-content content-type="city">Nova Lima</named-content><named-content content-type="state">MG</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Oncobio , Nova Lima , MG , Brazil .</institution></aff><aff id="aff13"><label>13</label><institution content-type="orgname">Instituto Nacional de Câncer José Alencar Gomes da Silva</institution><addr-line><named-content content-type="city">Rio de Janeiro</named-content><named-content content-type="state">RJ</named-content></addr-line><country country="BR">Brazil</country><institution content-type="original"> Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA, Rio de Janeiro , RJ , Brazil .</institution></aff><aff id="aff14"><label>14</label><institution content-type="orgname">Seattle Cancer Care Alliance</institution><addr-line><named-content content-type="city">Seattle</named-content><named-content content-type="state">WA</named-content></addr-line><country country="US">United States</country><institution content-type="original"> Seattle Cancer Care Alliance , Seattle , WA , United States .</institution></aff><author-notes><corresp id="c01">Corresponding author: Andrea Z Pereira Avenida Albert Einstein, 627/701 – Morumbi Zip code: 05652-900 – São Paulo, SP, Brazil Phone: (55 11) 3773-6590 E-mail: <email>pereira.andrea2@einstein.br</email></corresp><fn fn-type="COI-statement"><p><bold>Conflict of interest:</bold> none.</p></fn></author-notes><pub-date date-type="pub" publication-format="electronic"><day>13</day><month>3</month><year>2020</year></pub-date><pub-date date-type="collection" publication-format="electronic"><year>2020</year></pub-date><volume>18</volume><elocation-id>eAE4799</elocation-id><history><date date-type="received"><day>23</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>27</day><month>6</month><year>2019</year></date></history><permissions><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><title>ABSTRACT</title><p>The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft- <italic>versus</italic> -host disease was approved by <italic>Sociedade Brasileira de Transplante de Medula Óssea</italic> , with the participation of 26 Brazilian hematopoietic stem cell transplantation centers. It describes the main nutritional protocols in cases of Graft- <italic>versus</italic> -host disease, the main complication of hematopoietic stem cell transplantation.</p></abstract><kwd-group><kwd>Nutrition</kwd><kwd>Graft <italic>versus</italic> host disease</kwd><kwd>Hematopoietic stem cell transplantation</kwd></kwd-group><counts><fig-count count="4"></fig-count><table-count count="16"></table-count><equation-count count="0"></equation-count><ref-count count="130"></ref-count></counts></article-meta></front><body><sec><title>EMATOPOIETIC STEM CELL TRANSPLANTATION</title><p>Over the past 20 years, research on hematopoietic stem cell transplantation (HSCT) has enabled better donor selection, reduced toxicity from conditioning, reduced intensity regimens and improved supportive care, with reduced post-transplantation complications, thus increasing the survival of transplant recipients. <sup>( <xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> )</sup></p><p>Graft- <italic>versus</italic> -host disease (GVHD) is the major cause of allogeneic HSCT-related morbidity and mortality, accounting for a major impact on the quality of life of these patients. Approximately 30% to 50% of allogeneic transplant recipients have post-HSCT GVHD. <sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup> The global survival rate of patients with GVHD, particularly the chronic form, is 72% at 1 year, and 55% at 5 years. <sup>( <xref rid="B2" ref-type="bibr">2</xref> )</sup></p></sec><sec><title>PATHOPHYSIOLOGY OF GRAFT- <italic>VERSUS</italic> -HOST DISEASE</title><p>Graft- <italic>versus</italic> -host disease is caused by activation of T cells that recognize host antigens as non-self, causing an autoimmune reaction in recipient organs, such as skin, lungs, liver, gastrointestinal tract (GIT), thymus, hematopoietic system and possibly even the central nervous system. <sup>( <xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> )</sup></p><p>Severe acute GVHD (a-GVHD) is characterized by severe skin, gastrointestinal and hepatic lesions, whereas the chronic form is associated with progressive ulcerative mucosal damage, and systemic lesions to other organs, such as the skin and lungs. <sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup></p><p>Chronic GVHD (c-GVHD) has more characteristics of alloimmunity and immunodeficiency. Very similar to a-GVHD, c-GVHD is also induced by donor immune cells, but its pathophysiology is less well understood. Although T lymphocytes are considered the key factor in their development, recent data reveal that B cells also have an important role.</p><p>Classically, the development of GVHD can be divided into three phases: <sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup> the first phase consists of injury to recipient’s tissues by agents used in the aggressive conditioning regimens necessary to prevent recurrence of neoplastic diseases and graft rejection. Although other organs may be affected, with varying degrees of severity, the hematopoietic system and GIT are more susceptible to this toxicity.</p><p>The second phase in the development of GVHD consists of activation of T lymphocytes by host antigen-presenting cells, and later by donor antigen-presenting cells, that acquire effector helper T cell functions and secrete cytokines, which subsequently accelerate the immune activation. <sup>( <xref rid="B4" ref-type="bibr">4</xref> , <xref rid="B5" ref-type="bibr">5</xref> )</sup></p><p>In the third phase of GVHD pathogenesis, the immunological activation of cytotoxic effector functions of mediator cells, such as CD 81+ T cells, causes direct lesions in the characteristic GVHD target cells in organs like liver, skin and GIT. <sup>( <xref rid="B6" ref-type="bibr">6</xref> , <xref rid="B7" ref-type="bibr">7</xref> )</sup></p><p>In search of more knowledge about GVHD and how to better control it, a consensus was reached in 2005 with the formation of a working group of the National Institutes of Health (NIH). It defined that the clinical presentation, and not time, is considered the most important aspect for the diagnosis and differentiation between a-GVHD and c-GVHD. Some signs and symptoms are similar in both conditions; the differences, however, are striking and allow the definition of two distinct clinical syndromes.</p></sec><sec><title>ACUTE GRAFT <italic>VERSUS</italic> HOST-DISEASE</title><p>A-GVHD primarily affects the skin, liver, and GIT. On skin, coalescent erythematous maculopapular lesions are observed, characteristically in the plantar region and the palm. The onset of hepatic GVHD may be heralded by increased liver enzymes and signs of cholestasis on laboratory tests. Less specific gastrointestinal symptoms are diarrhea, nausea and vomiting. This variety of symptoms is widely diverse in severity. <sup>( <xref rid="B2" ref-type="bibr">2</xref> - <xref rid="B4" ref-type="bibr">4</xref> )</sup></p><p>These conditions can be extremely aggressive, leading, for example, to laceration of the intestinal mucosa and its fecal elimination associated with secondary hemorrhages. However, there often are mild conditions that require invasive and often inconclusive differential diagnosis. <sup>( <xref rid="B2" ref-type="bibr">2</xref> - <xref rid="B4" ref-type="bibr">4</xref> )</sup> For this reason, a-GVHD was staged ( <xref rid="t1" ref-type="table">Table 1</xref> ) to establish severity criteria ( <xref rid="t2" ref-type="table">Table 2</xref> ) and to standardize an evaluation method in universal academic papers.</p><p><table-wrap id="t1" orientation="portrait" position="float"><label>Table 1</label><caption><title>Graft- <italic>versus-</italic> host disease organ staging categories ( <xref rid="B2" ref-type="bibr"><sup>2</sup></xref> - <xref rid="B4" ref-type="bibr"><sup>4</sup></xref> ) </title></caption><table frame="hsides" rules="groups"><colgroup width="25%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Stage</th><th rowspan="1" colspan="1">Skin findings</th><th rowspan="1" colspan="1">Liver findings</th><th rowspan="1" colspan="1">Intestinal findings</th></tr></thead><tbody><tr><td rowspan="2" colspan="1">+</td><td align="center" rowspan="2" colspan="1">Maculopapular rash on <25% of body surface</td><td align="center" rowspan="2" colspan="1">Bilirubin: 2-3mg/dL</td><td align="center" rowspan="1" colspan="1">Persistent diarrhea</td></tr><tr><td align="center" rowspan="1" colspan="1">(500-1,00mL) and nausea</td></tr><tr><td rowspan="1" colspan="1">++</td><td align="center" rowspan="1" colspan="1">Maculopapular rash on 25%-50% of body surface</td><td align="center" rowspan="1" colspan="1">Bilirubin: 3-6mg/dL</td><td align="center" rowspan="1" colspan="1">Diarrhea (1,000-1,500mL)</td></tr><tr><td rowspan="1" colspan="1">+++</td><td align="center" rowspan="1" colspan="1">Generalized erythroderma</td><td align="center" rowspan="1" colspan="1">Bilirubin: 6-15mg/dL</td><td align="center" rowspan="1" colspan="1">Diarrhea (>1,500mL)</td></tr><tr><td rowspan="1" colspan="1">++++</td><td align="center" rowspan="1" colspan="1">Peeling and blistering</td><td align="center" rowspan="1" colspan="1">Bilirubin: >15mg/dL</td><td align="center" rowspan="1" colspan="1">Pain with or without obstruction</td></tr></tbody></table></table-wrap></p><p><table-wrap id="t2" orientation="portrait" position="float"><label>Table 2</label><caption><title>Acute Graft- <italic>versus</italic> -host disease global staging categories ( <xref rid="B2" ref-type="bibr"><sup>2</sup></xref> - <xref rid="B4" ref-type="bibr"><sup>4</sup></xref> ) </title></caption><table frame="hsides" rules="groups"><colgroup width="20%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Grade/stage</th><th rowspan="1" colspan="1">Skin</th><th rowspan="1" colspan="1">Liver</th><th rowspan="1" colspan="1">Intestine</th><th rowspan="1" colspan="1">Functional disorder</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">0 (none)</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">I (mild)</td><td align="center" rowspan="1" colspan="1">+ to ++</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">II (moderate)</td><td align="center" rowspan="1" colspan="1">+ to +++</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td></tr><tr><td rowspan="1" colspan="1">III (severe)</td><td align="center" rowspan="1" colspan="1">++ to +++</td><td align="center" rowspan="1" colspan="1">++ to +++</td><td align="center" rowspan="1" colspan="1">++ to +++</td><td align="center" rowspan="1" colspan="1">++</td></tr><tr><td rowspan="1" colspan="1">IV (life-threatening)</td><td align="center" rowspan="1" colspan="1">++ to ++++</td><td align="center" rowspan="1" colspan="1">++ to ++++</td><td align="center" rowspan="1" colspan="1">++ to ++++</td><td align="center" rowspan="1" colspan="1">+++</td></tr></tbody></table></table-wrap></p></sec><sec><title>CHRONIC GRAFT- <italic>VERSUS</italic> -HOST-DISEASE</title><p>Chronic Graft- <italic>versus</italic> -host-disease is a clinical-pathological syndrome that involves many organs and systems, closely resembling autoimmune diseases.</p><p>Efforts have been made to identify risk factors associated with increased morbidity and mortality in patients with GVHD. Identified variables included multi-organ or local involvement, poor performance status, thrombocytopenia at diagnosis, defined as platelet count below 100,000/µL, progressive onset of c-GVHD, elevated bilirubin levels, and extensive skin involvement (involvement greater than 50% of body surface). <sup>( <xref rid="B2" ref-type="bibr">2</xref> , <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>In 2005, the NIH developed a project to reach a consensus on the criteria that should be used in c-GVHD clinical studies. <sup>( <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> )</sup> The characteristics used in the diagnosis were standardized, as well as the methods for scoring the organs involved and for the global severity assessment. <sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B12" ref-type="bibr">12</xref> )</sup></p><p>These criteria, revised in 2014, are useful for a better analysis of the incidence of c-GVHD, and for assessing the severity of the organ or site involvement, isolated or combined, and the influence on transplant-related mortality (TRM). According to the NIH consensus, diagnostic signs and symptoms refer to manifestations that establish the presence of c-GVHD without the need for tests or the evidence of other organs affected ( <xref rid="t3" ref-type="table">Table 3</xref> ). Distinct signs and symptoms refer to those manifestations that are not commonly found in c-GVHD, but are insufficient to establish an accurate diagnosis of c-GVHD without further testing or the involvement of other organs. Other characteristics define rare, controversial and non-specific manifestations of c-GVHD and cannot be used to confirm the diagnosis of c-GVHD. <sup>( <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> )</sup></p><p><table-wrap id="t3" orientation="portrait" position="float"><label>Table 3</label><caption><title>Signs and symptoms related to chronic Graft- <italic>versus</italic> -host-disease ( <xref rid="B10" ref-type="bibr"><sup>10</sup></xref> , <xref rid="B11" ref-type="bibr"><sup>11</sup></xref> ) </title></caption><table frame="hsides" rules="groups"><colgroup width="20%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Organ or site</th><th rowspan="1" colspan="1">Diagnostic (sufficient to establish diagnosis of c-GVHD)</th><th rowspan="1" colspan="1">Characteristic (present in GVHD but not sufficient to establish diagnosis)</th><th rowspan="1" colspan="1">Other characteristics</th><th rowspan="1" colspan="1">Common to a-GVHD and c-GVHD</th></tr></thead><tbody><tr><td align="left" rowspan="7" valign="top" colspan="1">Skin</td><td align="center" rowspan="1" colspan="1">Poikiloderma</td><td align="center" rowspan="7" valign="top" colspan="1">Depigmentation</td><td align="center" rowspan="1" colspan="1">Depigmentation</td><td align="center" rowspan="1" colspan="1">Erythema</td></tr><tr><td align="center" rowspan="1" colspan="1">Lichen planus</td><td align="center" rowspan="1" colspan="1">Excessive or absent sweating</td><td align="center" rowspan="1" colspan="1">Maculopapular rash</td></tr><tr><td align="center" rowspan="1" colspan="1">Sclerotic changes</td><td align="center" rowspan="1" colspan="1">Ichthyosis</td><td align="center" rowspan="5" colspan="1">Pruritus</td></tr><tr><td align="center" rowspan="1" colspan="1">Morphea</td><td align="center" rowspan="2" colspan="1">Keratosis pilaris Hypopigmentation</td></tr><tr><td align="center" rowspan="3" colspan="1">Lichen sclerosus</td></tr><tr><td align="center" rowspan="1" colspan="1">Hyperpigmentation</td></tr><tr><td align="center" rowspan="1" colspan="1">Hiperpigmentação</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Nail</td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Dystrophy</td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Longitudinal grooves</td></tr><tr><td align="center" rowspan="1" colspan="1">Onycholysis</td></tr><tr><td align="center" rowspan="1" colspan="1">Pterygium unguis</td></tr><tr><td align="center" rowspan="1" colspan="1">Nail drop (usually symmetrically)</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Scalp and hair</td><td rowspan="2" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Total alopecia or alopecia areata after post-chemotherapy recovery</td><td align="center" rowspan="1" colspan="1">Thinning of hair not explainable by other causes</td><td rowspan="2" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Papulosquamous lesions</td><td align="center" rowspan="1" colspan="1">Early white hair</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Mouth</td><td align="center" rowspan="1" colspan="1">Lichen-type changes</td><td align="center" rowspan="1" colspan="1">Xerostomia</td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Gingivitis</td></tr><tr><td align="center" rowspan="1" colspan="1">Hyperkeratotic plates</td><td align="center" rowspan="1" colspan="1">Mucocele</td><td align="center" rowspan="1" colspan="1">Mucositis</td></tr><tr><td align="center" rowspan="3" colspan="1">Restriction of mouth opening by sclerosis</td><td align="center" rowspan="1" colspan="1">Mucosal atrophy</td><td align="center" rowspan="1" colspan="1">Erythema</td></tr><tr><td align="center" rowspan="1" colspan="1">Pseudomembranes</td><td align="center" rowspan="2" colspan="1">Pain</td></tr><tr><td align="center" rowspan="1" colspan="1">Ulcers</td></tr><tr><td align="left" rowspan="4" valign="top" colspan="1">Eye</td><td rowspan="4" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Dry eye and eye pain</td><td align="center" rowspan="1" colspan="1">Photophobia</td><td rowspan="4" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Healing conjunctivitis</td><td align="center" rowspan="1" colspan="1">Periorbital hyperpigmentation</td></tr><tr><td align="center" rowspan="1" colspan="1">Dry keratoconjunctivitis (Schrimer test <5mm/5 minutes)</td><td align="center" rowspan="1" colspan="1">Blepharitis</td></tr><tr><td align="center" rowspan="1" colspan="1">Keratitis punctata in confluent areas</td><td rowspan="1" colspan="1"> </td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Genitals</td><td align="center" rowspan="1" colspan="1">Lichen planus</td><td align="center" rowspan="1" colspan="1">Erosions</td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td></tr><tr><td align="center" rowspan="2" colspan="1">Vaginal stenosis</td><td align="center" rowspan="1" colspan="1">Fissures</td></tr><tr><td align="center" rowspan="1" colspan="1">Ulcers</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">GIT</td><td align="center" rowspan="1" colspan="1">Esophageal web</td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="5" colspan="1">Exogenous pancreatic insufficiency</td><td align="center" rowspan="1" colspan="1">Anorexia</td></tr><tr><td align="center" rowspan="4" colspan="1">Stricture or stenosis in the proximal third of the esophagus</td><td align="center" rowspan="1" colspan="1">Nausea</td></tr><tr><td align="center" rowspan="1" colspan="1">Vomiting</td></tr><tr><td align="center" rowspan="1" colspan="1">Diarrhea</td></tr><tr><td align="center" rowspan="1" colspan="1">Weight loss</td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Liver</td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Total bilirubin and alkaline phosphatase</td></tr><tr><td align="center" rowspan="1" colspan="1">>twice above the normal limit</td></tr><tr><td align="center" rowspan="1" colspan="1">ALT or AST > twice the upper limit</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Lungs</td><td align="left" valign="middle" rowspan="1" colspan="1">Bronchiolitis obliterans diagnosed with biopsy</td><td align="center" rowspan="1" colspan="1">Bronchiolitis obliterans diagnosed with pulmonary function test or chest computed tomography</td><td rowspan="1" colspan="1"> </td><td align="center" rowspan="1" colspan="1">BOOP</td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Muscle, fascia, joints</td><td align="center" rowspan="1" colspan="1">Fasciitis</td><td align="center" rowspan="3" colspan="1">Myositis or polymyositis</td><td align="center" rowspan="1" colspan="1">Edema</td><td rowspan="3" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Joint contractures secondary to sclerosis</td><td align="center" rowspan="1" colspan="1">Cramps</td></tr><tr><td align="center" rowspan="1" colspan="1">Joint stiffness</td><td align="center" rowspan="1" colspan="1">Arthralgia or arthritis</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Hematopoietic and immune systems</td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Thrombocytopenia</td></tr><tr><td align="center" rowspan="1" colspan="1">Eosinophilia</td></tr><tr><td align="center" rowspan="1" colspan="1">Lymphopenia</td></tr><tr><td align="center" rowspan="1" colspan="1">Hypo- or hypergammaglobulinemia</td></tr><tr><td align="center" rowspan="1" colspan="1">Autoantibodies (AIHA and ITP)</td></tr><tr><td align="left" rowspan="6" valign="top" colspan="1">Other</td><td rowspan="6" colspan="1"> </td><td rowspan="6" colspan="1"> </td><td rowspan="6" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Pleural or pericardial effusion</td></tr><tr><td align="center" rowspan="1" colspan="1">Ascites</td></tr><tr><td align="center" rowspan="1" colspan="1">Peripheral neuropathy</td></tr><tr><td align="center" rowspan="1" colspan="1">Nephrotic syndrome</td></tr><tr><td align="center" rowspan="1" colspan="1">Myasthenia gravis</td></tr><tr><td align="center" rowspan="1" colspan="1">Cardiomyopathy or cardiac conduction defects</td></tr></tbody></table><table-wrap-foot><fn id="TFN1"><p>c-GVHD: chronic Graft <italic>versus</italic> host disease; GVHD: Graft- <italic>versus</italic> -host disease; a-GVHD: acute Graft- <italic>versus</italic> -host disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BOOP: Bronchiolitis obliterans with organizing pneumonia; AIHA: Autoimmune hemolytic anemia; ITP: Immune thrombocytopenia purpura.</p></fn></table-wrap-foot></table-wrap></p><p>The consensus recommends the following criteria for diagnosis of c-GVHD: <sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup> distinction from a-GVHD; presence of at least one diagnostic clinical sign of c-GVHD, or presence of at least one distinct manifestation confirmed by a relevant biopsy, according to defined histopathological criteria, laboratory tests, or radiological images, on the same organ or in other organ; and exclusion of other possible diagnoses.</p><p>The revised NIH 2014 classification includes eight major organs for being those most affected by the disease: skin, mouth, eyes, GIT, liver, lungs, joints, and female genital tract. The organs most affected in mild c-GVHD are skin, mouth and liver. Lung involvement in c-GVHD adds to severity of the disease, according to the consensus. Therefore, lung damage is considered a severity criterion of great importance in this classification. <sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>To facilitate grading and establish standardized staging criteria for the disease, the commonly affected organs were scored and graded according to severity of the injury produced by c-GVHD. Each organ or site received a score from zero to 3, with zero representing no involvement, and 3 representing severe impairment. <sup>( <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>The global severity assessment ( <xref rid="t4" ref-type="table">Table 4</xref> ) in this consensus is based on the number of organs or sites involved and on severity of the disease in each organ. Patients are diagnosed as having mild c-GVHD when just one or two organs (except the lungs) are affected, without any clinically significant functional damage, and with a maximum score of 1 in all organs or sites. The diagnosis of moderate c-GVHD is considered when at least one organ or site presents significant clinical impairment, but without any major damage, with a maximum score of 2 in any affected organ or site, or when two, three or more organs or sites are affected, but without any clinically significant functional impairment, with a maximum score of 1 in all affected organs or sites. A score of 1 in the lungs is also considered moderate. Severe c-GVHD indicates major damage with a score of 3 in any organ or site. A score of ≥2 in the lungs is also considered severe. <sup>( <xref rid="B9" ref-type="bibr">9</xref> , <xref rid="B10" ref-type="bibr">10</xref> )</sup> All these values are recorded in a questionnaire validated by NIH and now universally used by numerous research and care centers.</p><p><table-wrap id="t4" orientation="portrait" position="float"><label>Table 4</label><caption><title>Graft- <italic>versus</italic> -host disease global severity assessment ( <xref rid="B9" ref-type="bibr"><sup>9</sup></xref> , <xref rid="B10" ref-type="bibr"><sup>10</sup></xref> ) </title></caption><table frame="hsides" rules="groups"><colgroup width="50%" span="1"><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Types of chronic GVHD</th><th align="left" rowspan="1" colspan="1">Classification criteria</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Mild c-GVHD</td><td rowspan="1" colspan="1">1 or 2 organs involved + score in the organs involved 1 + lung score 0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Moderate c-GVHD</td><td rowspan="1" colspan="1">3 or more organs involved + score 1 in each organ or At least 1 organ (except lung) with score 2 or Lung score 1</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Severe c-GVHD</td><td rowspan="1" colspan="1">At least 1 organ with score 3 OR</td></tr><tr><td rowspan="1" colspan="1">Lung score 2 or 3</td></tr><tr><td colspan="2" rowspan="1">1. On skin: The highest score will be used for the global severity assessment</td></tr><tr><td colspan="2" rowspan="1">2. In the lungs: FEV1 is used instead of the clinical score for the global severity assessment</td></tr><tr><td colspan="2" rowspan="1">3. If an abnormality of an organ is unambiguously explained by a cause not associated with GVHD, the organ score will be zero for the global severity assessment.</td></tr><tr><td colspan="2" rowspan="1">4. If an organ abnormality is attributed to multifactorial causes (GVHD plus other causes), the organ score will be used for the global severity assessment, regardless of the contributing causes (the organ score will not be disregarded)</td></tr></tbody></table><table-wrap-foot><fn id="TFN2"><p>c-GVHD: chronic Graft- <italic>versus</italic> -host disease; GVHD: Graft- <italic>versus</italic> -host disease; FEV: forced expiratory volume.</p></fn></table-wrap-foot></table-wrap></p><p>There is a growing interest in studying c-GVHD among the academic community, coupled with the recent establishment of criteria that categorize the disease based on established evidence. These are the first steps on the path for a better understanding of the pathogenesis of c-GVHD.</p></sec><sec><title>INTRODUCTION ON THE IMPORTANCE OF THE NUTRITIONAL STATUS IN GRAFT- <italic>VERSUS</italic> -HOST DISEASE</title><p>There are no clear literature data on the impact of the pre-HSCT nutritional status as a cause of higher or lower incidence of GVHD, nor on the best way to perform its assessment. <sup>( <xref rid="B13" ref-type="bibr">13</xref> - <xref rid="B16" ref-type="bibr">16</xref> )</sup> Some studies report that high rates of malnutrition <sup>( <xref rid="B17" ref-type="bibr">17</xref> )</sup> and worsening of nutritional status are associated to more severe GVHD in the GIT, mouth, and lung. <sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p><p>On the other hand, despite the heterogeneity of the studies, and although no one knows exactly by what mechanism this interference occurs, both obesity and malnutrition are associated with a higher risk of GVHD. <sup>( <xref rid="B19" ref-type="bibr">19</xref> , <xref rid="B20" ref-type="bibr">20</xref> )</sup></p><p>Recovering or improving the pre-HSCT nutritional status of patients may result in a better outcome. <sup>( <xref rid="B20" ref-type="bibr">20</xref> )</sup></p><p>However, the relation between GVHD and deficient states, such as vitamin deficits, is well known. <sup>( <xref rid="B14" ref-type="bibr">14</xref> - <xref rid="B16" ref-type="bibr">16</xref> )</sup></p><p>In the immediate post-transplant period (30 to 50 days), the nutritional needs reflect the increased caloric-protein intake due to conditioning, infections, a-GVHD, fever, and other metabolic complications, affecting mainly the protein balance, energy requirements, and micronutrient metabolism. <sup>( <xref rid="B21" ref-type="bibr">21</xref> , <xref rid="B22" ref-type="bibr">22</xref> )</sup></p><p>The nutritional status in a-GVHD or c-GVHD is affected by several symptoms, which are widely discussed later, such as prolonged hospital stay and high doses of corticosteroids, which profoundly affect the body composition with increased muscle loss, fluid retention, and increased visceral fat, impairing even more the nutritional status. <sup>( <xref rid="B18" ref-type="bibr">18</xref> , <xref rid="B23" ref-type="bibr">23</xref> - <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>In the oral, pulmonary and gastrointestinal manifestations of c-GVHD, up to 29% of patients may be malnourished due to oral mucosa pain and disease activity, among other factors. <sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup> This directly influences a reduction in patient functionality and quality of life. <sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p><p>Graft- <italic>versus</italic> -host-disease is a complex condition with significant negative effects on the nutritional status, leading to a reduction in patient quality of life and functionality. <sup>( <xref rid="B18" ref-type="bibr">18</xref> , <xref rid="B25" ref-type="bibr">25</xref> )</sup> We discuss below specific topics on nutritional status and therapy in a-GVHD and in c-GVHD.</p></sec><sec><title>MICRO- AND MACRONUTRIENTS IN GRAFT- <italic>VERSUS</italic> -HOST DISEASE</title><p>Diet therapy management depends on how GVHD manifests in the patient. Most patients start treatment with a relatively healthy diet, but this diet quickly becomes depleted. This is due to the direct toxic effects of the treatment or secondary complications, such as infections and a-GVHD itself. <sup>( <xref rid="B15" ref-type="bibr">15</xref> )</sup></p><p>Moderate to severe GVHD and the multi-drug regimens used in its prevention and treatment result in profound and prolonged immunosuppression. Despite advances in management, GVHD remains a significant problem. Patients often have high nutritional needs and present changes in carbohydrate, fat, and protein metabolism. They also find it difficult to eat for a variety of organ-dependent reasons and generally require modified diets, oral supplements, or enteral (EN) or parenteral (PNT) nutrition to prevent malnutrition. <sup>( <xref rid="B26" ref-type="bibr">26</xref> )</sup></p><sec><title>Nutrition recommendations: macronutrients</title><sec><title>Calories</title><p>Nutritional needs in patients undergoing HSCT increase due to intense catabolism. <sup>( <xref rid="B27" ref-type="bibr">27</xref> )</sup> It is suggested that energy requirements during the early phase of HSCT and GVHD are up to 130% to 150% of estimated basal energy expenditure, which amounts to 30 to 50kcal/kg body weight per day, and these increased energy requirements contribute to patients’ weight loss. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B28" ref-type="bibr">28</xref> , <xref rid="B29" ref-type="bibr">29</xref> )</sup> This chronic hypermetabolic state found in these patients is a response to inflammatory cytokines (tumor necrosis factor alpha − TNF-α; interleukins – IL−1 and 6) and changes in norepinephrine and glucagon levels. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B30" ref-type="bibr">30</xref> , <xref rid="B31" ref-type="bibr">31</xref> )</sup> Some studies show increased serum glucagon levels leading to up to a 10% increase in basal metabolism, mainly by stimulating gluconeogenesis. <sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup> Increased norepinephrine in these cases leads to increased hepatic glucose production, and also contributes to increased basal metabolism. <sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup></p><p>A cross-sectional study with 13 patients compared the energy requirements of healthy controls with those of patients with extensive c-GVHD of skin, mucocutaneous membranes, lung, eyes and liver, using indirect calorimetry, showing a slight increase in energy requirements (1.9kcal/kg/day or 133kcal in a 70kg person), and changes in fat and carbohydrate oxidation rates. <sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup></p><p>In addition, an animal model has shown an increase in glycolysis and fatty acid metabolism for adequate alloreactive T-cell function and GVHD induction. <sup>( <xref rid="B32" ref-type="bibr">32</xref> , <xref rid="B33" ref-type="bibr">33</xref> )</sup> It is also believed that GVHD treatment itself may have effects on patients’ energy metabolism, but reports on this topic are also scarce. <sup>( <xref rid="B22" ref-type="bibr">22</xref> )</sup></p><p>In this case, we recommend using 30 to 50kcal/kg body weight per day to calculate the caloric requirements in these patients.</p></sec><sec><title>Proteins and lipids</title><p>The World Health Organization (WHO) recommends 0.83g/kg weight as an acceptable protein intake, with the maximum protein synthesis capacity reached with an intake of 1.5g/kg/day. <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup> Although there are no well designed studies to support such reference, it is recommended that higher protein intake levels (about 1.8 to 2.5g/kg/day) are maintained in patients who have developed GVHD. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B29" ref-type="bibr">29</xref> )</sup> This recommendation is based on the protein loss due to exudation of the intestinal mucosa and the effect of chronic use of corticosteroids on increased protein requirements. <sup><xref rid="B29" ref-type="bibr">29</xref> , <xref rid="B34" ref-type="bibr">34</xref></sup></p><p>Lipids can be safely administered as long-chain triglycerides (LCTs) or LCT/medium-chain triglyceride mixture, which generally contribute with 30% to 40% of non-protein energy. <sup>( <xref rid="B40" ref-type="bibr">40</xref> , <xref rid="B41" ref-type="bibr">41</xref> )</sup></p></sec><sec><title>Omega 3</title><p>Omega 3 fatty acid plays a role as an immunomodulating factor. <sup>( <xref rid="B42" ref-type="bibr">42</xref> )</sup> It has been theorized that lipids could advantageously modulate GVHD by controlling cytokine production via the prostaglandin E2 pathway. Lipid manipulation is associated with glucose intolerance control. Thus, there is an increase in monounsaturated fatty acids that would replace saturated fatty acids ( <xref rid="t5" ref-type="table">Table 5</xref> ). <sup>( <xref rid="B42" ref-type="bibr">42</xref> )</sup></p><p><table-wrap id="t5" orientation="portrait" position="float"><label>Table 5</label><caption><title>Recommended nutritional supplements for hematopoietic stem cell transplant recipients with Graft- <italic>versus</italic> -host disease at Baylor University Medical Center ( <xref rid="B29" ref-type="bibr"><sup>29</sup></xref> ) </title></caption><table frame="hsides" rules="groups"><colgroup width="50%" span="1"><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Supplements</th><th align="left" rowspan="1" colspan="1">Reason for use</th></tr></thead><tbody><tr><td align="left" rowspan="2" valign="top" colspan="1">Multivitamin with minerals (minimum iron during first year after HSCT)</td><td rowspan="1" colspan="1">To ensure adequate vitamin and mineral resources</td></tr><tr><td rowspan="1" colspan="1">Metabolism and anabolism, especially if the patient has inadequate oral intake.</td></tr><tr><td rowspan="1" colspan="1">Vitamin C (500mg/twice a day)</td><td rowspan="1" colspan="1">To aid in wound healing</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Zinc (22mg zinc sulphate/once a day for 2 weeks)</td><td rowspan="1" colspan="1">To aid in wound healing</td></tr><tr><td rowspan="1" colspan="1">To replace lost amounts in chronic disarrhea</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Folic acid (1mg/day)</td><td rowspan="1" colspan="1">To meet the high requirements for red blood cell production.</td></tr><tr><td rowspan="1" colspan="1">Some medications increase the metabolism or wasting of this vitamin, and therefore it needs to be replaced.</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Calcium with vitamin D (dose depends on serum level)*</td><td rowspan="1" colspan="1">Interaction with cell levels for cytokine modification, reducing the GVHD inflammatory process</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Omega 3 (2 g/day)</td><td rowspan="1" colspan="1">Interaction with cell levels for cytokine modification, reducing the GVHD inflammatory process</td></tr></tbody></table><table-wrap-foot><fn id="TFN3"><p>* Serum level <10ng/mL-50,000UL/week; 10-30ng/mL-10,000UL/week. HSCT: Hematopoietic stem cell transplantation; GVHD: Graft <italic>versus</italic> host disease.</p></fn></table-wrap-foot></table-wrap></p></sec><sec><title>Glutamine</title><p>The use of glutamine is controversial. There appear to be some benefits of oral use in reducing mucositis and GVHD, and intravenous glutamine may reduce infections. <sup>( <xref rid="B43" ref-type="bibr">43</xref> )</sup></p><p>According to the Cochrane review, glutamine not only modulates the immune system function in the digestive tract, but it can also promote intestinal healing and reduce the severity of mucositis and GIT GVHD. <sup>( <xref rid="B44" ref-type="bibr">44</xref> )</sup> The recent guideline of the European Society for Clinical Nutrition and Metabolism (ESPEN) concludes that there is insufficient evidence to recommend glutamine supplementation to reduce treatment toxicity in patients with GIT GVHD. <sup>( <xref rid="B36" ref-type="bibr">36</xref> )</sup></p><p>Therefore, due to this inconsistency in the literature, the use of glutamine in this population is not recommended.</p></sec></sec></sec><sec><title>Nutritional recommendations: micronutrients</title><sec><title>Vitamin B12</title><p>The effects of GVHD in the stomach, reducing the intrinsic factor, and in the intestine, reducing vitamin B12 absorption, and the HSCT conditioning regimen resulting in crypt cell degeneration, are associated with decreased vitamin B12 ( <xref rid="t5" ref-type="table">Table 5</xref> ). <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p></sec><sec><title>Vitamin C</title><p>Studies show that vitamin C plays an important role in fighting mucositis in patients with GVHD. Patients with vitamin C deficiency who received treatment with 2,000mg/month of ascorbic acid had significant visual improvements in mucositis and were able to eat again <sup>( <xref rid="B45" ref-type="bibr">45</xref> )</sup> ( <xref rid="t5" ref-type="table">Table 5</xref> ).</p></sec><sec><title>Zinc</title><p>Chronic diarrhea and malabsorption caused by GVHD can lead to zinc deficiency, which is important in maintaining the sense of taste and the integrity of the gastrointestinal mucosa. <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup> In addition, zinc acts on healing and taste perception, and is important in the defense against intestinal infections due to the maintenance of the integrity of the intestinal mucosa. <sup>( <xref rid="B46" ref-type="bibr">46</xref> )</sup></p><p>Several studies recommended zinc supplementation in patients with GVHD, including one by Roberts et al., <sup>( <xref rid="B29" ref-type="bibr">29</xref> )</sup> who stated zinc supplementation is relevant for the treatment of recurrent lesions. Ripamonti et al., <sup>( <xref rid="B47" ref-type="bibr">47</xref> )</sup> suggested zinc supplementation (up to 3 doses of 45mg ZnSO <sub>4</sub> /day) is safe and effective for treating taste perception.</p><p>In addition, experimental studies have suggested the role of this element in the activation of regulatory T cells, which may be relevant for HSCT <sup>( <xref rid="B48" ref-type="bibr">48</xref> )</sup> ( <xref rid="t5" ref-type="table">Table 5</xref> ).</p></sec><sec><title>Vitamin D</title><p>Some studies have described the presence of vitamin D deficiency in patients after HSCT, its relation with the development of GVHD, and reduction of bone mineral density. <sup>( <xref rid="B49" ref-type="bibr">49</xref> )</sup> Despite its association with inadequate nutrition, vitamin D deficiency has not been characterized as a direct complication of GVHD, <sup>( <xref rid="B50" ref-type="bibr">50</xref> )</sup> but seems to play a role in its development. Sproat et al., in a retrospective study with a small number of patients (58 transplant patients between 2000 and 2009), reported a 89.7% prevalence of hypovitaminosis D, and most of these patients had GVHD (94.8%) and used corticosteroids (98.3%). <sup>( <xref rid="B51" ref-type="bibr">51</xref> )</sup> However, other studies also found the association of low serum vitamin D (<25ng/mL) with GVHD, and also with post-transplant cytomegalovirus (CMV) reactivation. <sup>( <xref rid="B52" ref-type="bibr">52</xref> , <xref rid="B53" ref-type="bibr">53</xref> )</sup></p><p>The reduction of GVHD-related effects can be explained by the apparent role of vitamin D in the immune system, regulating the function of dendritic cells, macrophages, and B and T lymphocytes. <sup>( <xref rid="B54" ref-type="bibr">54</xref> - <xref rid="B56" ref-type="bibr">56</xref> )</sup></p><p>Patients with a-GVHD treated with corticosteroids show a tendency for a greater decrease in vitamin D. Monitoring of vitamin D levels and, if necessary, treatment for correcting its deficiency, may be indicated at regular intervals before HSCT and during the follow-up of these patients. <sup>( <xref rid="B49" ref-type="bibr">49</xref> )</sup></p><p>Calcium and vitamin D replacement in combination with bisphosphonates, or supplementation with active metabolites, such as 1,25 (OH) <sub>2</sub> D3 vitamin D or 25 (OH) <sub>3</sub> vitamin D have beneficial effects on bone mass and GVHD modulation. <sup>( <xref rid="B57" ref-type="bibr">57</xref> , <xref rid="B58" ref-type="bibr">58</xref> )</sup></p><p>The study of vitamin D supplementation in HSCT is relatively recent, but already offers promising results. Serum levels should be measured in the pre-HSCT and post-HSCT periods, and the deficiency should be corrected.</p></sec><sec><title>Magnesium</title><p>The main change in metabolism in GVHD patients is hypomagnesemia, caused by calcineurin inhibitors, one of the most widely used drug classes for both prophylaxis and treatment of the disease. However, there are case reports of severe hypermagnesemia following the use of high magnesium laxative medications, probably associated with dehydration and high intestinal permeability seen in GVHD. <sup>( <xref rid="B59" ref-type="bibr">59</xref> )</sup></p></sec><sec><title>Iron</title><p>Iron overload is a common complication of HSCT due to increased iron absorption secondary to anemia and multiple transfusions. Iron overload may increase the risk of GVHD, especially the acute form, due to the tendency to cause direct liver toxicity. In addition, ferritin appears to be a poor-prognosis marker in patients with GVHD. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B60" ref-type="bibr">60</xref> )</sup> The use of non-iron multivitamins is recommended in this population. <sup>( <xref rid="B61" ref-type="bibr">61</xref> )</sup></p><p>Nutritional recommendations in patients with Graft- <italic>versus</italic> -host disease are presented in <xref rid="t6" ref-type="table">table 6</xref> .</p><p><table-wrap id="t6" orientation="portrait" position="float"><label>Table 6</label><caption><title>Nutritional recommendations in patients with Graft- <italic>versus</italic> -host disease</title></caption><table frame="hsides" rules="groups"><colgroup width="100%" span="1"><col span="1"></col></colgroup><thead><tr><th align="left" style="font-weight:normal" rowspan="1" colspan="1">Evaluate nutritional status by a specialist</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Maintain energy requirements at 30 to 50 cal/kg, and protein requirements at 1.5-2g/kg</td></tr><tr><td rowspan="1" colspan="1">Monitor weight and nutrient intake in the first year after transplant; patients with active GVHD need longer monitoring</td></tr><tr><td rowspan="1" colspan="1">Advise and monitor nutritional support specifically for patients with GVHD of the gastrointestinal tract; initiate specialized nutritional support in patients with significant gastrointestinal tract dysfunction and anorexia, who are unable to maintain adequate body weight</td></tr><tr><td rowspan="1" colspan="1">Supplement with multivitamins/minerals (no iron due to the risk of hemochromatosis); other supplements, like vitamin C, zinc, folic acid, and omega 3 may be beneficial</td></tr><tr><td rowspan="1" colspan="1">Advise the patient on nutritional aspects regarding food safety and the risk of foodborne diseases during immunosuppression</td></tr></tbody></table><table-wrap-foot><attrib>Source: Adapted from Roberts S, Thompson J. Graft-vs-host disease: nutrition therapy in a challenging condition. Nutr Clin Pract. 2005;20(4):440-50. <sup>(</sup><xref rid="B29" ref-type="bibr"><sup>29</sup></xref><sup>)</sup> GVHD: Graft <italic>versus</italic> host disease.</attrib></table-wrap-foot></table-wrap></p></sec></sec><sec><title>MOST COMMON NUTRITIONAL COMPLICATIONS IN GRAFT- <italic>VERSUS</italic> -HOST DISEASE</title><p>Due to the importance of this theme, we will try to review below the main nutritional complications of GVHD, both those caused by its development and those related to its therapy. The side effects related to nutritional aspects of the main medications used to treat GVHD are shown in <xref rid="t7" ref-type="table">table 7</xref> .</p><p><table-wrap id="t7" orientation="portrait" position="float"><label>Table 7</label><caption><title>Main medications and immunosuppressive therapies used to treat Graft- <italic>versus</italic> -host disease and their nutritional and metabolic side effects</title></caption><table frame="hsides" rules="groups"><colgroup width="33%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Medication/therapy</th><th align="left" rowspan="1" colspan="1">Mechanism of action</th><th align="left" rowspan="1" colspan="1">Nutritional and metabolic effects</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Anti-inflammatory response, inhibits IL-1, decreases IL-2 and suppresses lymphocyte proliferation</td><td rowspan="1" colspan="1">Sodium and water retention, hyperglycemia, hypercholesterolemia, increased appetite, weight gain, bone demineralization and muscular effects</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Cyclosporine/tacrolimus</td><td align="left" valign="top" rowspan="1" colspan="1">Inhibits T lymphocyte proliferation/response and alters IL-2 production</td><td rowspan="1" colspan="1">Hypertension, dyslipidemia, hyperglycemia, hypomagnesemia, hyperkalemia, nephrotoxicity, neurotoxicity, nausea, vomiting, taste changes and diarrhea</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Methotrexate</td><td align="left" valign="top" rowspan="1" colspan="1">Antimetabolite and immunosuppressive</td><td rowspan="1" colspan="1">Anorexia, nausea, vomiting, diarrhea, stomatitis, mucositis, hepatotoxicity and nephrotoxicity</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Mycophenolate mofetil</td><td rowspan="1" colspan="1">Decreases lymphocytic activation and proliferation of B and T cells; suppresses antibody formation</td><td rowspan="1" colspan="1">Nausea, vomiting, diarrhea, constipation, gastrointestinal bleeding and peripheral edema</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Sirolimus</td><td rowspan="1" colspan="1">Inhibits B and T lymphocyte proliferation</td><td rowspan="1" colspan="1">Dyslipidemia, hypertension, and peripheral edema</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Thalidomide</td><td rowspan="1" colspan="1">Immunosuppressive and anti-inflammatory properties</td><td rowspan="1" colspan="1">Neuropathy and constipation</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Antithymocyte globulin (ATG)</td><td align="left" valign="top" rowspan="1" colspan="1">Decreases circulating lymphocytes</td><td rowspan="1" colspan="1">Abdominal pain, nausea, vomiting, diarrhea, hyperkalemia, hypertension, and peripheral edema</td></tr><tr><td rowspan="1" colspan="1">Etarnecept</td><td rowspan="1" colspan="1">TNF-α antagonist</td><td rowspan="1" colspan="1">Abdominal pain and vomiting</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ursodeoxycholic acid</td><td rowspan="1" colspan="1">Replaces native human bile acids; decreases HLA antigen expression in hepatocytes</td><td rowspan="1" colspan="1">Nausea, vomiting, diarrhea and abdominal pain</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Daclizumab</td><td align="left" valign="top" rowspan="1" colspan="1">Anti-IL-2 antibody</td><td rowspan="1" colspan="1">Vomiting, edema, hypertension and hypotension</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Azathioprine</td><td rowspan="1" colspan="1">Prevents cytotoxic T and B lymphocyte proliferation by inhibiting DNA and RNA synthesis</td><td rowspan="1" colspan="1">Gastrointestinal hypersensitivity, hepatotoxicity, megaloblastic anemia and pancreatitis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hydroxychloroquine</td><td rowspan="1" colspan="1">Interferes with antigen processing and presentation, proliferation, TNF-α production and cytotoxicity</td><td align="left" valign="top" rowspan="1" colspan="1">Nausea, vomiting and diarrhea</td></tr><tr><td rowspan="1" colspan="1">Infliximab</td><td rowspan="1" colspan="1">Anti-TNF-α antibody</td><td rowspan="1" colspan="1">Abdominal pain, nausea, vomiting</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Psoralen and PUVA</td><td rowspan="1" colspan="1">Interferes with antigen presentation and pro-inflammatory cytokine production</td><td rowspan="1" colspan="1">Nausea, hepatotoxicity</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Extracorporeal photopheresis</td><td rowspan="1" colspan="1">Induces alloreactive T cell apoptosis, photoinactivation of antigen presenting cells</td><td align="left" valign="top" rowspan="1" colspan="1">Hypocalcemia (citrate use) and gastrointestinal disorders</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Cyclophosphamide</td><td rowspan="1" colspan="1">Immunosuppressive activity and blockade of cell growth by DNA metabolite binding</td><td align="left" valign="top" rowspan="1" colspan="1">Anorexia, nausea, vomiting and mucositis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Rituximab</td><td align="left" valign="top" rowspan="1" colspan="1">Anti-CD20 antibody</td><td rowspan="1" colspan="1">Abdominal pain, diarrhea, nausea, vomiting, hypertension and hyperglycemia</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Pentostatin</td><td align="left" valign="top" rowspan="1" colspan="1">DNA synthesis block</td><td rowspan="1" colspan="1">Nausea, vomiting, fatigue, diarrhea, anorexia and stomatitis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Imatinib</td><td align="left" valign="top" rowspan="1" colspan="1">PDGF-r inhibition</td><td rowspan="1" colspan="1">Nausea, fatigue, diarrhea, abdominal pain, vomiting, weight gain, hepatotoxicity, hyperglycemia and myopathy</td></tr></tbody></table><table-wrap-foot><attrib>Source: Adapted from Roberts S, Thompson J. Clinical Observations Graft-vs-Host Disease: Nutrition Therapy in a Challenging Condition. Nutr Clin Pract. 2005;20:440-50. <sup>(</sup><xref rid="B29" ref-type="bibr"><sup>29</sup></xref><sup>)</sup> IL: interleukin; TNF-α: tumor necrosis factor alpha; HLA: human leukocyte antigen; PUVA: psolaren + ultraviolet irradiation A; PDGF-r: platelet-derived growth factor receptor.</attrib></table-wrap-foot></table-wrap></p></sec><sec><title>MECHANICAL CHANGES IN THE GASTRINTESTINAL TRACT</title><p>The GIT is involved in most patients with GVHD, and any part of the digestive tract can be affected. Although rarer, mechanical and structural changes in the digestive tract deserve to be reported due to their severity and the need for early management. <sup>( <xref rid="B62" ref-type="bibr">62</xref> )</sup></p><p>Esophageal complications are rare and include ulceration, esophageal varices and vesicular lesions. Dysphagia with severe stenosis requires esophageal dilation. <sup>( <xref rid="B62" ref-type="bibr">62</xref> )</sup></p><p>One of the most serious bowel complications is intestinal perforation; however, the most common is diarrhea. <sup>( <xref rid="B63" ref-type="bibr">63</xref> )</sup></p></sec><sec><title>HANGE IN NUTRIENT ABSORPTION</title><p>The change in absorption seen in patients with GVHD may be associated with hepatic and pancreatic changes. Hepatic changes may be due to impaired excretion of bile salts and play an important role in lipid metabolism. <sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup></p><p>Pancreatic changes have already been reported in autopsies of experimental models, and are associated with involvement of GVHD; however, these changes, which may include atrophy, can also be due to some medications, such as azathioprine, cyclosporine, and corticosteroids. <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup> The main symptoms of pancreatic exocrine insufficiency are steatorrhea, fatigue, abdominal pain, weight loss, and flatulence. Such symptoms are more frequent after transplant in patients with signs of GVHD, being more frequent among more advanced degrees of the disease. <sup>( <xref rid="B65" ref-type="bibr">65</xref> , <xref rid="B66" ref-type="bibr">66</xref> )</sup></p><p>In addition to pancreatic function, GVHD in the small bowel has also been studied as a possible cause of digestive disorders in post-transplant patients. In addition to endoscopic capsule studies, a marker being tested is citrulline. The small bowel is the main source of this amino acid in our body. Previous studies in patients without GVHD showed a correlation between reduced plasma levels of citrulline and intestinal damage. <sup>( <xref rid="B67" ref-type="bibr">67</xref> , <xref rid="B68" ref-type="bibr">68</xref> )</sup> Such findings were also described among patients with intestinal GVHD. <sup>( <xref rid="B69" ref-type="bibr">69</xref> )</sup> This amino acid has also shown to be promising in predicting GVHD, <sup>( <xref rid="B70" ref-type="bibr">70</xref> )</sup> although more literature data are needed for its use in clinical practice.</p></sec><sec><title>DIARRHEA AND PROTEIN-LOSING ENTEROPATHY</title><p>Diarrhea is one of the main symptoms of low digestive tract GVHD. However, its etiology in this entity is multifactorial and may include villous atrophy, mucosal ulceration, secretory dysfunction, osmotic factors, pancreatic insufficiency, and altered intestinal transit. It is often greenish, liquid, mucous and can be voluminous. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B71" ref-type="bibr">71</xref> )</sup></p><p>Graft- <italic>versus</italic> -host-disease damage to the gastrointestinal tissue can lead to a number of problems, including dehydration, electrolyte loss, and protein-losing enteropathy. This situation is defined by an increase in alpha 1-antitrypsin (>2.2mg/g dry fecal weight) in fecal samples and occurs especially in patients with digestive tract GVHD. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B35" ref-type="bibr">35</xref> )</sup></p><p>Papadopoulou et al., studied a sample of 47 patients undergoing HSCT, 42 of them allogeneic. They found that 91% of diarrhea episodes were associated with protein-losing enteropathy, and the amount of protein lost was more severe among patients with GVHD (19.4mg/g) than among individuals with other causes of diarrhea, such as rotavirus, CMV infection or uncertain causes (6.7mg/g). <sup>( <xref rid="B35" ref-type="bibr">35</xref> )</sup></p><p>The amount of protein loss also appears to be correlated with severity of GVHD, especially among patients undergoing myeloablative conditioning. <sup>( <xref rid="B72" ref-type="bibr">72</xref> )</sup> In addition, GVHD patients tend to persistently increase the amount of protein lost in their stools, unlike what happens with individuals with other diarrheal disorders. <sup>( <xref rid="B34" ref-type="bibr">34</xref> )</sup></p></sec><sec><title>EFFECTS ON APPETITE</title><p>In addition to the effects of the conditioning regimen and the immunosuppressive and supportive medications used, the development of GVHD may, <italic>per se</italic> , have an effect on appetite. Malone et al., demonstrated higher oral ingestion among patients without GVHD or grade 1 GVHD compared with others. <sup>( <xref rid="B73" ref-type="bibr">73</xref> )</sup> Graft- <italic>versus</italic> -host disease-associated symptoms, especially of the digestive tract, are reported as causal agents of inadequate nutrition. However, this is not so easily explained. It seems that GVHD activity itself may play a role in appetite suppression. <sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p></sec><sec><title>HANGES IN CARBOHYDRATE AND LIPID METABOLISM</title><p>Glycemic control is important during the post-transplant period. Hyperglycemia not only impacts on immune function, but also causes damage to other tissues, such as endothelial dysfunction, elevation of proinflammatory cytokines, muscular and adipose catabolism. Theoretically, hyperglycemia may increase the level of cytokines and the risk of infectious diseases, which may lead to an increased risk of GVHD. On the other hand, GVHD may also, through inflammatory mechanisms, lead to a state of hyperglycemia. <sup>( <xref rid="B74" ref-type="bibr">74</xref> )</sup> In addition, corticosteroids used in the treatment of GVHD have hyperglycemia as one of the most common side effects. <sup>( <xref rid="B29" ref-type="bibr">29</xref> )</sup></p><p>Regarding dyslipidemia, several medications used to treat GVHD are related to the development of this complication ( <xref rid="t7" ref-type="table">Table 7</xref> ). However, not only immunosuppressive medications affect lipid homeostasis. Liver GVHD can lead to elevations of cholesterol and triglycerides, due to the inability of bile salts and cholesterol to be excreted in the bile duct. <sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup> In addition, nephrotic syndrome, which can be a severe complication of GVHD, can also lead to significant dyslipidemia. <sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup></p></sec><sec><title>LOSS OF LEAN BODY MASS AND MYOPATHY</title><p>Loss of lean body mass is frequent among patients with GVHD and a consequence of nutritional changes caused by it. Corticosteroid therapy significantly influences this complication. The development of c-GVHD seems to be an independent risk factor for the loss of lean body mass, and the likelihood is higher among those with extensive GVHD and those who required corticosteroids. <sup>( <xref rid="B75" ref-type="bibr">75</xref> , <xref rid="B76" ref-type="bibr">76</xref> )</sup></p></sec><sec><title>NUTRITIONAL INTERVENTION IN ACUTE AND CHRONIC GRAFT- <italic>VERSUS</italic> -HOST-DISEASE</title><p>Graft- <italic>versus</italic> -host-disease patients have difficulty ingesting food for various reasons, depending on the organ involved. They often require dietary modifications, oral supplements, and nutritional support therapy (NST) to prevent or treat malnutrition. <sup>( <xref rid="B77" ref-type="bibr">77</xref> )</sup></p><p>According to Bassim et al., <sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup> the main indications for the onset of NST are uncontrolled nausea and vomiting, voluminous diarrhea, oral and esophageal mucosa pain, dysphagia, dysgeusia, xerostomia, anorexia, early satiety and weight loss. In particular, GIT a-GVHD and oral, gastrointestinal, and pulmonary c-GVHD produce severe malnutrition and lead to impaired patient’s functional capacity and quality of life, hence the need for early onset of NST.</p><p>Nutritional therapy is of utmost importance as a treatment support to counteract the deleterious effects of GVHD and to circumvent the adverse effects of medications. <sup>( <xref rid="B15" ref-type="bibr">15</xref> , <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B77" ref-type="bibr">77</xref> , <xref rid="B78" ref-type="bibr">78</xref> )</sup></p></sec><sec><title>SYMPTOM MANAGEMENT BY NUTRITIONAL CHANGES</title><p>According to the consensus on nutrition in cancer patients of the <italic>Instituto Nacional do Câncer José de Alenca</italic> r, <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup> some nutritional interventions may be directed towards improving and controlling gastrointestinal symptoms.</p><sec><title>Early satiety</title><p>Make the patient aware of the importance of food; perform diet fractionation (from six to eight meals/day); modify dietary fiber by cooking and/or grinding to reduce satiety (unpeeled fruit, cooked vegetables, soups and liquid juices); increase the caloric and protein density of meals; do not drink fluids during meals; use lean, cooked, shredded or minced meat in small portions; avoid high-fat foods and preparations; and prefer non-carbonated drinks. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Diarrhea</title><p>Diet fractionation is important as well as reducing the volume of food per meal; evaluate the restriction of lactose, sucrose, gluten, fat, insoluble fiber, caffeine and theine; increase water and isotonic fluid intake to at least 3L/day; avoid flatulence-producing and hyperosmolar foods; and avoid extreme temperatures. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Dysphagia</title><p>Accompaniment with the speech therapist, for proper modification of the diet; advise the patient on the care of dry and hard foods, and prefer soft, easily chewed and swallowed foods; drink small volumes of fluid with meals to facilitate chewing and swallowing; and keep the headboard high while eating. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Xerostomia</title><p>Consuming at least 2L/day of water and other liquids up to 3L/day is required; stimulate the intake of more enjoyable foods; adjust food consistency according to patient acceptance; avoid consuming coffee, tea and caffeine-containing soft drinks; maintain oral hygiene and lip hydration; use lemon drops on salads and drinks; if necessary, drink fluids with meals to facilitate chewing and swallowing; suck on sugarless citrus and mint candies; season foods with herbs, avoiding excess salt and condiments; chew and suck on ice cubes made of water, coconut water and fruit juice or popsicles. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Nausea and vomiting</title><p>It is necessary to advise a fractional diet in small volumes; give preference to drier, citric, salty and cold or frozen foods; maintain oral hygiene; avoid fasting for long periods; suck on ice cubes 40 minutes before meals; avoid fried foods and fatty foods; avoid overly sweet or strong smelling foods and preparations; have meals in airy places; do not drink liquids during meals, using them in small quantities at intervals, preferably cold ( <italic>e.g</italic> . popsicle); do not lie down after meals; and use ginger for its antiemetic effect, in a brew, as a spice, or added to juices. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Anorexia</title><p>The patient should be advised about the importance of adequate food intake; fractional diet in small portions; meals with higher caloric and protein density; consume foods better tolerated and of appropriate consistency, according to patient preferences. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Odynophagia</title><p>Meal consistency should be modified according to tolerance; improve the caloric and protein density of meals; good oral hygiene; do not consume dry, hard, citric, salty, peppery and spicy foods; avoid extreme temperatures <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Oral diet</title><p>In mild oral cavity involvement, the consumption of acidic foods should be avoided; in more severe cases with esophageal stenosis, the consistency and temperature of the meals should be modified, with preference to liquid or liquefied foods, served at a moderate or room temperature. <sup>( <xref rid="B21" ref-type="bibr">21</xref> , <xref rid="B74" ref-type="bibr">74</xref> )</sup></p><p>During treatment with high doses of glucocorticoids and/or calcineurin inhibitors, proper patient orientation is important. Frequent and small-portion meals, soluble and insoluble fiber-rich diet, high-protein diet with reduced simple and high-glycemic-index carbohydrates, sodium reduction, good water intake and adequate intake of food sources of vitamin D, calcium, magnesium and zinc are recommended, and, if necessary, a supplementation of these elements. <sup>( <xref rid="B79" ref-type="bibr">79</xref> , <xref rid="B80" ref-type="bibr">80</xref> )</sup></p></sec><sec><title>Oral supplements</title><p>Regardless of the type and severity of GVHD, when the patient has a dietary intake below 70% of the energy requirements in the last 3 days, and symptoms that impair adequate nutrition, it is important to intervene with the use of high-calorie and high-protein nutritional supplements (adapted according to the phase of the restricted diet in the case of intestinal GVHD). Discontinuing oral nutritional supplementation is indicated only in the presence of hemodynamic instability, esophagitis, or severe mucositis that prevent adequate oral intake, GIT obstruction, incoercible vomiting, risk of bronchoaspiration, patient refusal, and supplemental intolerance. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec></sec><sec><title>ENTERAL NUTRITION</title><p>If the food intake is below 60% of energy requirements in the last 3 days or oral use is contraindicated, EN may be prescribed. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup> The enteral route, if tolerable and clinically possible, may be chosen for maintaining digestive function and integrity of the mucosal barrier, preventing bacterial translocation in the digestive tract. <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>According to the American Society for Parental and Enteral Nutrition, <sup>( <xref rid="B77" ref-type="bibr">77</xref> )</sup> when neutrophil and platelet counts are normal and GIT is healed, NE is safe for the transition from parenteral nutritional therapy to oral diet, or when NST is necessary, in case of GVHD, among other late complications of HSCT.</p><p>According to a systematic review by Baumgartner et al., <sup>( <xref rid="B15" ref-type="bibr">15</xref> )</sup> several studies compared EN with PNT, showing superior results for the enteral route and moderate to high tolerance to the tube, and PNT is recommended only in cases of gastrointestinal insufficiency. EN is contraindicated when there are hemodynamic instability and/or worsening of abdominal pain, abdominal distension, mucositis, diarrhea, incoercible vomiting, paralytic ileus, and intestinal bleeding. <sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p><p>There is strong evidence indicating that early introduction of EN may decrease both the incidence and severity of GIT GVHD and may be a form of prophylaxis. In addition, EN is associated with lower infection-related mortality and shorter times of neutrophil engraftment. <sup>( <xref rid="B81" ref-type="bibr">81</xref> )</sup></p></sec><sec><title>PARENTERAL DIET</title><p>Parenteral Nutrition Therapy can also be indicated for patients who have an oral diet acceptance of less than 60% to 70% of nutritional requirements for 3 consecutive days, <sup>( <xref rid="B82" ref-type="bibr">82</xref> )</sup> or in patients with energy-protein deficiency with exclusive use of EN. <sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup></p><p>American Society for Parental and Enteral Nutrition guidelines recommend oral or enteral diet, as long as possible, but in case of vomiting, incoercible diarrhea, severe mucositis, or significant malabsorption, PNT should be the preferred route. <sup>( <xref rid="B36" ref-type="bibr">36</xref> )</sup></p><p>Studies show that patients with grade III-IV GVHD receive more PNT than patients with grade I-II GVHD, and are not exempt from clinical complications related to the number of days receiving PNT. <sup>( <xref rid="B84" ref-type="bibr">84</xref> )</sup></p><p>Some precautions should be taken when prescribing and monitoring PNT. Malnourished patients at risk of feedback syndrome should receive progressive energy intake in the initial phase (first to third day), with 20% of basal energy needs. Protein may be supplied from the outset, respecting renal and liver functions. Glycemic control should be performed, maintaining blood glucose levels lower than 180mg/dL, and avoiding hypertriglyceridemia, with serum triglyceride levels below 400mg/dL. <sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup> In addition to monitoring liver function, with the measurement of AST, ALT, gamma glutamil transferase, alkaline phosphatase and bilirubin levels twice a week, the measurement of urea, creatinine, serum electrolyte (potassium, magnesium, phosphorus, calcium and sodium), total cholesterol and fractions levels should be included in routine tests. Weaning of PNT should be gradual, respecting the offer and the patient’s acceptance of oral or enteral diet. <sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup></p></sec><sec><title>NUTRITIONAL MANAGEMENT IN INTESTINAL GRAFT- <italic>VERSUS</italic> -HOST-DISEASE</title><p>The nutritional assessment of patients with this complication can be very difficult, since many of them have fluid retention related to low serum albumin levels, which masks body weight loss. In addition, the standard treatment of GIT GVHD is corticoid therapy, which has direct effects on body composition, leading to increased body fat, decreased lean mass, water and sodium retention, hypertriglyceridemia, hypercholesterolemia, sarcopenia and bone demineralization, and this may mask the nutritional status of patients. <sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>The goals of nutritional therapy in GIT GVHD are to provide adequate and individualized nutritional support to maintain or restore the patient’s nutritional status, control symptoms, reestablish intestinal mucosa integrity, satisfy the patient, and promote quality of life, whenever possible. <sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B85" ref-type="bibr">85</xref> )</sup></p></sec><sec><title>NUTRITIONAL THERAPY IN INTESTINAL GRAFT- <italic>VERSUS</italic> -HOST DISEASE</title><sec><title>Oral diet</title><p>At the National Cancer Center Japan, a study was carried out with stepped nutritional therapy with its own protocol, and it was observed that the nutritional status of patients tended to improve with this type of therapy. However, no improvement was observed in the overall severity of GIT GVHD. <sup>( <xref rid="B86" ref-type="bibr">86</xref> )</sup></p><p>At the Seattle Cancer Care Alliance, as per the physicians´ guide, nutritional therapy is also based on this type of stepped nutritional therapy, and the clinical course of the diet occurs according to the patient’s tolerance and the symptoms presented. <sup>( <xref rid="B87" ref-type="bibr">87</xref> )</sup></p><p>The use of home-made or industrialized oral supplements can take place from step 2, when food intake does not meet the recommended nutritional needs, and should follow the same characteristics of the corresponding step of the diet and the patient’s wishes.</p><p>Based on this literature, <xref rid="t8" ref-type="table">table 8</xref> shows how the patient’s nutritional therapy should be altered, according to symptoms, clinical course and tolerance. Whenever the patient does not tolerate a change in diet, the patient should go back to the previous step.</p><p><table-wrap id="t8" orientation="portrait" position="float"><label>Table 8</label><caption><title>Stepped progression of the nutritional therapy in patients with intestinal Graft- <italic>versus-</italic> host disease</title></caption><table frame="hsides" rules="groups"><colgroup width="33%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Step</th><th align="left" rowspan="1" colspan="1">Symptoms</th><th align="left" rowspan="1" colspan="1">Nutrition therapy</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">1. Bowel rest</td><td rowspan="1" colspan="1">Large volume of watery diarrhea (over 1,000mL/day); intestinal cramps; serum albumin depletion; decreased intestinal transit; bowel obstruction; nausea and vomiting</td><td align="left" valign="top" rowspan="1" colspan="1">PNT only</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">2. Introduction of oral/enteral feeding</td><td rowspan="1" colspan="1">Diarrhea volume less than 500mL/day; decreased intestinal cramps; improvement of intestinal transit time; decrease in nausea and vomiting</td><td align="left" valign="top" rowspan="1" colspan="1">PNT + oral/enteral diet with characteristics: isosmotic liquid, no residues, no lactose, no acids, and low in fat</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">3. Introduction of solid foods</td><td align="left" valign="top" rowspan="1" colspan="1">Absence or reduction of cramps and more consistent stools</td><td rowspan="1" colspan="1">Oral/enteral diet with characteristics: solid foods, without residues, without lactose, low in fat, and no gastric acids and irritants</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">4. Expansion of diet</td><td align="left" valign="top" rowspan="1" colspan="1">Absence or reduction of cramps and more consistent stools</td><td rowspan="1" colspan="1">Oral/enteral diet (if necessary, according to the individuality of the patient) with characteristics: low in fiber, lactose, acids, gastric irritants, and fat according to the tolerance of the patient</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">5. Introduction of the patient’s usual diet</td><td align="left" valign="top" rowspan="1" colspan="1">Absence of colic and stools of normal consistency</td><td rowspan="1" colspan="1">Oral diet with characteristics: gradual introduction and according to the patient’s tolerance of acidic foods, gastric irritants, fiber, lactose and fat</td></tr></tbody></table><table-wrap-foot><attrib>Source: Adapted from Fred Hutchinson Cancer Research Center. Long-term follow-up after hematopoietic stem cell transplant. Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance [Internet]. Seattle, WA; 2014 [cited 2019 June 25]. Available from: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/physician.pdf; <sup>(</sup><xref rid="B80" ref-type="bibr"><sup>80</sup></xref><sup>)</sup> Gauvreau JM, Lenssen P, Cheney CL, Aker SN, Hutchinson ML, Barale KV. Nutritional management of patients with intestinal graft- <italic>versus</italic> -host disease. J Am Diet Assoc. 1981;79(6):673-7. <sup>(</sup><xref rid="B88" ref-type="bibr"><sup>88</sup></xref><sup>)</sup> PNT: parenteral nutrition therapy.</attrib></table-wrap-foot></table-wrap></p></sec><sec><title>Parenteral diet</title><p>Patients with GIT GVHD in the acute and early phase of the disease usually present diarrhea, with stool volume >1,000mL/day, making oral or enteral nutrition insufficient to meet their minimum nutritional needs. This can last for days or weeks. Thus, the most appropriate nutritional therapy would be GIT rest with fasting and the use of parenteral nutritional therapy. <sup>( <xref rid="B28" ref-type="bibr">28</xref> )</sup></p><p>The most traditional approach in the nutritional management of GIT GVHD is the administration of PNT and the initiation of oral ingestion only after the recovery of GIT symptoms. However, due to prolonged use of PNT, damage to the intestinal mucosa occurs, inducing atrophy and further intestinal dysfunction.</p></sec><sec><title>Enteral diet</title><p>The introduction of oral or EN diet from step 2 should occur after diarrhea volume reduction to less than 500mL/day; decreased intestinal cramps; improvement of intestinal transit time; decreased nausea and vomiting. This gradual introduction should be prioritized because it assists in the maintenance of intestinal tropism, helps preserve mucosal barrier, and local and systemic immunity, and also prevents bacterial translocation. <sup>( <xref rid="B13" ref-type="bibr">13</xref> )</sup></p><p>The choice of oral, enteral or concomitant nutrition during the progressive stages of nutritional therapy is based on the symptoms and the possibility of oral feeding and in situations when oral diet is inadequate to meet nutritional needs.</p><p>Enteral, if chosen as a route of nutrition or supplementation, must follow the characteristics of each step. From step 2 on, the patient does not tolerate large volumes of oral and/or enteral diet, therefore PNT does not need to be suspended, in order to meet all the patient’s nutritional needs.</p><p>Some studies showed the use of EN in GIT GVHD, as compared to PNT, reduced infectious complications by preserving intestinal tropism, improving intestinal barrier function and thus decreasing the risk of bacterial translocation. <sup>( <xref rid="B89" ref-type="bibr">89</xref> , <xref rid="B90" ref-type="bibr">90</xref> )</sup> However, historically, transplant centers prefer PNT to EN, making it difficult to use it early or during HSCT.</p></sec></sec><sec><title>THE IMPORTANCE OF THE MICROBIOTA IN HEMATOPOETIC STEM CELL TRANSPLANTATION</title><sec><title>Intestinal microbiota</title><p>Human GIT can be populated by up to 100 trillion bacteria (for comparison, the number of cells in the human body is estimated at 10 trillion), as well as by viruses and fungi also present in considerable number and diversity, and which may be from approximately 1,000 different species in a single individual. More than 15,000 different species have already been identified in human GIT-derived samples. <sup>( <xref rid="B91" ref-type="bibr">91</xref> )</sup></p><p>Gastrointestinal tract immune system is the first line of defense against microorganisms and other ingested substances, and has evolved not only to protect against potential pathogens, but also to tolerate commensal bacteria that play a beneficial role in homeostasis, allowing symbiosis with the intestinal microbiota. The gastrointestinal immune system maintains the mucosal barrier through secretion of antimicrobial peptides and antibodies, and the commensal microbiota participates in the intestinal physiology of the host. <sup>( <xref rid="B92" ref-type="bibr">92</xref> , <xref rid="B93" ref-type="bibr">93</xref> )</sup></p><p>Intestinal exposure to bacteria is related to the recruitment of regulatory T lymphocytes (Tregs). <sup>( <xref rid="B94" ref-type="bibr">94</xref> , <xref rid="B95" ref-type="bibr">95</xref> )</sup> Tregs cells are critical for the development of an appropriate immune response to antigens within the GIT, but also influence systemic immunity. <sup>( <xref rid="B96" ref-type="bibr">96</xref> , <xref rid="B97" ref-type="bibr">97</xref> )</sup></p><p>Intestinal bacteria are responsible for the breakdown of dietary fiber and are also important for the production of a number of metabolites that function in the intestinal physiology. The best known of these metabolites are short chain fatty acids (SCFAs) such as butyrate, propionate and acetate, which serve as energy sources for intestinal epithelial cells and induce protective regulatory immune responses both locally in GIT and systemically. <sup>( <xref rid="B98" ref-type="bibr">98</xref> , <xref rid="B99" ref-type="bibr">99</xref> )</sup></p></sec><sec><title>Dysbiosis</title><p>Chemotherapy and conditioning regimens alter the composition of the intestinal microbiota, causing the reduction of <italic>Clostridium</italic> cluster XIV and bifidobacteria strains, and the increase of <italic>Enterococcus</italic> . This change in the microbiota is called dysbiosis. <sup>( <xref rid="B100" ref-type="bibr">100</xref> - <xref rid="B102" ref-type="bibr">102</xref> )</sup></p><p>A specific study with patients undergoing HSCT found increased levels of proteobacteria, including <italic>Escherichia</italic> species, and reduced levels of <italic>Firmicutes</italic> , including <italic>Blautia</italic> species, following chemotherapy. <sup>( <xref rid="B102" ref-type="bibr">102</xref> )</sup></p><p>Nonetheless, the causal relation between chemotherapy and microbiota is difficult to establish because many of the patients studied received prophylactic antibiotics concurrently with chemotherapy.</p></sec><sec><title>Intestinal microbiota and Graft- <italic>versus</italic> -host disease</title><p>The normal intestinal microbiota have great diversity and are dominated by anaerobic bacteria. <sup>( <xref rid="B103" ref-type="bibr">103</xref> )</sup> During hospitalization, many patients undergoing HSCT lose this diversity, and the changes that occur are influenced by both antimicrobial treatments and the development of GVHD. <sup>( <xref rid="B104" ref-type="bibr">104</xref> - <xref rid="B106" ref-type="bibr">106</xref> )</sup></p><p>The impact of microbiota on GVHD was first proposed in the 1970s, after demonstrating that mice kept under germ-free conditions developed less GIT GVHD. <sup>( <xref rid="B107" ref-type="bibr">107</xref> , <xref rid="B108" ref-type="bibr">108</xref> )</sup> Subsequent clinical studies showing promising results in intestinal decontamination of transplant patients <sup>( <xref rid="B109" ref-type="bibr">109</xref> , <xref rid="B110" ref-type="bibr">110</xref> )</sup> have not been confirmed in further research. <sup>( <xref rid="B111" ref-type="bibr">111</xref> , <xref rid="B112" ref-type="bibr">112</xref> )</sup></p><p>A large prospective study focusing on anaerobic bacterial decontamination showed a reduction in GVHD development, indicating that selective decontamination could have beneficial effects. <sup>( <xref rid="B113" ref-type="bibr">113</xref> )</sup></p><p>The loss of intestinal diversity observed in patients undergoing HSCT is generally associated with the loss of <italic>Clostridium</italic> species, which are known to produce short chain fatty acids from dietary fibers. <sup>( <xref rid="B114" ref-type="bibr">114</xref> )</sup></p><p>Butyrate is the preferred energy source of intestinal epithelial cells, and one study suggests that reduced amounts of butyrate are found in the intestinal epithelial cells of mice submitted to HSCT, and the addition of these fatty acids reduces intestinal lesions and the development of GVHD. <sup>( <xref rid="B115" ref-type="bibr">115</xref> )</sup></p><p>These findings are reproduced by the administration of varied species of butyrate-producing bacteria belonging to the <italic>Clostridia</italic> class, and a clinical study has shown that intestinal abundance of <italic>Blautia</italic> genus, of the <italic>Clostridia</italic> class, correlates with reduced mortality risk due to GVHD. <sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup></p><p>The administration of antibiotics to treat febrile neutropenia is probably the main factor affecting the changes in microbiota observed in the evolution of transplanted patients, and the choice of antibiotic regimen influences the incidence of GVHD. Imipenem-cilastatin and piperacillin-tazobactam administration was associated with higher GVHD-related mortality at 5-year follow-up, in a retrospective study. <sup>( <xref rid="B117" ref-type="bibr">117</xref> )</sup> This same study did not demonstrate the association between metronidazole and the previously reported GVHD reduction, <sup>( <xref rid="B113" ref-type="bibr">113</xref> )</sup> which may be due to a number of factors, including the use of different antibiotic combinations between studies, as well as cultural and geographical differences, which may influence intestinal flora.</p><p>The intestinal microbiota can not only predispose GVHD, but also act to recover and even prevent the disease. Intestinal damage caused by conditioning regimens causes increased intestinal permeability that allows bacteria to translocate through the enteric barrier. As a consequence, immunological stimulation by a series of pathogens and associated molecules, such as bacterial lipopolysaccharides and peptidoglycan, reinforces the cytokine-mediated inflammatory response, providing the ideal scenario for allogeneic T lymphocyte activation.</p><p>The degree of loss of intestinal microbiota diversity is a risk factor for transplant-related mortality (TRM), including GVHD mortality, infections and organ failure after HSCT. <sup>( <xref rid="B118" ref-type="bibr">118</xref> )</sup></p></sec></sec><sec><title>NUTRITION AND MICROBIOTA</title><p>The use of PNT reduces the amount of nutrients reaching the intestinal epithelium, and thus some of the changes in microbiota observed during HSCT may be due to insufficient nutrients in GIT to maintain a balanced flora. <sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup></p><p>The study that showed an association between <italic>Blautia</italic> reduction and GVHD also demonstrated a correlation between this finding and prolonged PNT. <sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup> These findings suggest that EN, unlike PNT, may have a beneficial effect on post-HSCT intestinal flora and perhaps accelerate patient recovery.</p><sec><title>Use of probiotics and prebiotics</title><p>Increasing attention has been paid to the potential of probiotics and prebiotics in the prevention and treatment of intestinal dysbiosis. Probiotics are nutritional supplements that contain a definite amount of viable microorganisms, the administration of which may confer benefits to the patient, <sup>( <xref rid="B119" ref-type="bibr">119</xref> )</sup> whereas prebiotics consist of indigestible food ingredients ( <italic>e.g</italic> ., indigestible fibers), which favor the growth of beneficial bacteria. <sup>( <xref rid="B119" ref-type="bibr">119</xref> )</sup></p><p>Until recently, the use of probiotics in immunosuppressed individuals was totally banned, because it was believed that as they are living bacteria, they could cause severe infectious diseases. However, this concept has been gradually modified by several studies that demonstrated, initially, their safety in this profile of patients, in addition to potential better prognostic effects.</p><p>In general, several studies showed the use of probiotics in various clinical conditions - such as inflammatory bowel diseases - is safe because they are immunosuppressed individuals, and also because it is related to the reduction of the systemic and local inflammatory response through an adequate immune response. Therefore, the indication for the use of probiotics in patients undergoing allogeneic HSCT is based on this condition. <sup>( <xref rid="B120" ref-type="bibr">120</xref> , <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>It is known that these microorganisms may inhibit the action of external pathogens; and improve the intestinal barrier function by increasing the production of mucus and peptides with bactericidal properties, improving the structure of cell junctions between enterocytes and preventing early cellular apoptosis. <sup>( <xref rid="B120" ref-type="bibr">120</xref> , <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>One of the strains that has its most proven safety is <italic>Lactobacillus plantarum</italic> (LPB). In addition to safety, it is also proven <italic>in vitro</italic> that its pre-HSCT use decreases GVHD severity and mortality. <sup>( <xref rid="B104" ref-type="bibr">104</xref> )</sup></p><p>According to Coehn et al., a retrospective analysis of medical records of 3,796 patients undergoing HSCT from 2002 to 2011, with the aim of identifying bloodstream infection by probiotic agents ( <italic>Lactobacillus, Bifidobacterium, Streptococcus thermophilus</italic> and <italic>Saccharomyces</italic> ), showed that only 0.5% (n=19) developed this condition one year after transplantation, and of the 19 patients, 74% received allogeneic HSCT, with 98% of bloodstream infection by <italic>Lactobaccilus</italic> . <sup>( <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>In 2004, Gerbitz et al., demonstrated in an experimental study in rats that the <italic>Lactobacillus rhamnosus</italic> -treated group had lower mortality than the control group, especially in the recent post-HSCT period (7 to 14 days after cell infusion), and had milder GVHD manifestations. <sup>( <xref rid="B122" ref-type="bibr">122</xref> )</sup></p><p>In 2015, Laval et al., published another <italic>in vitro</italic> study, considering both the hypothesis that intestinal cell permeability is increased in various inflammatory bowel diseases, even GVHD, and the proven theory that certain probiotic strains can increase intestinal integrity. In this study, they demonstrated that the use of <italic>Lactobacillus rhamnosus</italic> can partially restore the enterocyte barrier function and also increase the production of intestinal mucosa protective dipeptides. <sup>( <xref rid="B123" ref-type="bibr">123</xref> )</sup></p><p>In 2017, Gorshein et al., demonstrated in a study of 31 allogeneic HSCT patients who received <italic>Lactbacillus rhamnosus</italic> at a daily dose of 10 billion strains, that their use is safe and unrelated to severe infectious complications; however, no statistical difference was found in morbidity and mortality in both groups. <sup>( <xref rid="B124" ref-type="bibr">124</xref> )</sup></p><p>According to Ladas et al., the use of LPB is subjected to rigorous microbiological analysis and therefore proven to be decontaminated at the dose of 1×108 colonies offered from day -7 to day +14. In a study involving 31 children and adolescents (2 to 17 years) undergoing allogeneic HSCT with myeloablative conditioning regimen, it was safe, so that no episode of LPB bacteremia was observed, as well as no other severe complications related to the use of LPB. <sup>( <xref rid="B125" ref-type="bibr">125</xref> )</sup></p><p>Ladas et al., also reported 70% of patients did not develop a-GVHD on day +100 and none of the patients who died on day +100 developed a-GVHD. Of the 30% who developed a-GVHD, no patient had maximum severity (grade 4). <sup>( <xref rid="B125" ref-type="bibr">125</xref> )</sup></p><p>Although the use of these treatments seems promising, further clinical studies are needed to establish the safety and efficacy of these therapies. An important aspect of the efficacy of probiotic treatment lies in the ability of ingested microorganisms to survive the acidic environment of the stomach and small intestine. Many strains of lactobacilli, including those most commonly found in common dairy products, are sensitive to low gastrointestinal pH and could not be reisolated in fecal samples after administration to humans, <sup>( <xref rid="B126" ref-type="bibr">126</xref> )</sup> making it difficult to interpret their efficacy.</p><p>The use of probiotics and prebiotics in HSCT is not yet routinely recommended.</p></sec></sec><sec><title>FECAL MICROBIOTA TRANSPLANTION</title><p>Fecal microbiota transplantation (FMT) can be used to restore damaged intestinal flora. A small series of patients with refractory or corticosteroid-dependent GVHD showed promising results; <sup>( <xref rid="B127" ref-type="bibr">127</xref> )</sup> however, larger and better controlled studies are required to determine the efficacy of FMT in the treatment of GVHD.</p><p>Fecal microbiota transplantation for the treatment of resistant <italic>Clostridium difficile</italic> infections is already a well-described technique in many populations. <sup>( <xref rid="B128" ref-type="bibr">128</xref> )</sup> Its use is still modest in the context of post-transplantation patients, and one of the pioneering experiments was carried out in Brazil, without major complications. <sup>( <xref rid="B129" ref-type="bibr">129</xref> )</sup> Since then, other cases have been successfully reported using familiar donors or not, and using some methods, such as retrograde enteroscopy or ingestion of capsules that open only in the jejunum, releasing the new microbiota. <sup>( <xref rid="B130" ref-type="bibr">130</xref> )</sup></p><p>At the time of publication of this consensus, FMT for immunomodulation and GVHD treatment is promising, but should only be done within well-designed clinical studies. It is necessary to understand which components of the microbiota are desirable, as well as to know the best time to perform this type of intervention. However, its use in the treatment of <italic>Clostridium difficile</italic> infections, although lacking randomized trials and large case series in this group of patients, can be considered in special situations, since no complications have been reported so far.</p></sec><sec><title>A PRACTICAL FLOWCHART</title><p><xref ref-type="fig" rid="f01">Figures 1</xref> and <xref ref-type="fig" rid="f02">2</xref> below summarize in a practical way the nutritional protocols in GVHD.</p><p><fig id="f01" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Nutritional planning for hematopoietic stem cell transplantation</title><p>HSCT: hematopoietic stem cell transplantation; ONT: oral nutrition therapy; ENT: enteral nutrition therapy; PNT: parenteral nutrition therapy.</p></caption><graphic xlink:href="2317-6385-eins-18-eAE4799-gf01"></graphic></fig></p><p><fig id="f02" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Nutritional planning for Graft- <italic>versus</italic> -host disease of the gastrointestinal tract</title><p>GVHD: Graft- <italic>versus</italic> -host disease; GIT: gastrointestinal tract.</p></caption><graphic xlink:href="2317-6385-eins-18-eAE4799-gf02"></graphic></fig></p></sec></body><back><ref-list><title>REFERENCES</title><ref id="B1"><label>1</label><mixed-citation publication-type="other" id="B1-gen-2">1. 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xml:lang="pt"><front-stub><article-categories><subj-group subj-group-type="heading"><subject>Artigo Especial</subject></subj-group></article-categories><title-group><article-title>Consenso Brasileiro de Nutrição no Transplante de Células Tronco Hematopoiéticas: doença do enxerto contra o hospedeiro</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-3572-6405</contrib-id><name><surname>Pereira</surname><given-names>Andréa Z</given-names></name><xref ref-type="aff" rid="aff1002"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-9990-1313</contrib-id><name><surname>Vigorito</surname><given-names>Afonso Celso</given-names></name><xref ref-type="aff" rid="aff2002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9289-9727</contrib-id><name><surname>Almeida</surname><given-names>Alessandro de Moura</given-names></name><xref ref-type="aff" rid="aff3002"><sup>3</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9237-8411</contrib-id><name><surname>Candolo</surname><given-names>Alexandre de Almeida</given-names></name><xref ref-type="aff" rid="aff4002"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-1969-9363</contrib-id><name><surname>Silva</surname><given-names>Ana Carolina Leão</given-names></name><xref ref-type="aff" rid="aff5002"><sup>5</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5650-1360</contrib-id><name><surname>Brandão-Anjos</surname><given-names>Ana Elisa de Paula</given-names></name><xref ref-type="aff" rid="aff6002"><sup>6</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-7807-4550</contrib-id><name><surname>Sá</surname><given-names>Bianca Laselva de</given-names></name><xref ref-type="aff" rid="aff1002"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6511-0943</contrib-id><name><surname>Souza</surname><given-names>Catarina Lôbo Santos de</given-names></name><xref ref-type="aff" rid="aff7002"><sup>7</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-4610-8282</contrib-id><name><surname>Castro</surname><given-names>Cláudio Galvão de</given-names><suffix>Junior</suffix></name><xref ref-type="aff" rid="aff8002"><sup>8</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9862-4345</contrib-id><name><surname>Oliveira</surname><given-names>José Salvador Rodrigues de</given-names></name><xref ref-type="aff" rid="aff9002"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-7731-0061</contrib-id><name><surname>Barban</surname><given-names>Juliana Bernardo</given-names></name><xref ref-type="aff" rid="aff9002"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-5242-2561</contrib-id><name><surname>Mancilha</surname><given-names>Elaine Maria Borges</given-names></name><xref ref-type="aff" rid="aff9002"><sup>9</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-2709-4767</contrib-id><name><surname>Todaro</surname><given-names>Juliana</given-names></name><xref ref-type="aff" rid="aff1002"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-4932-3671</contrib-id><name><surname>Lopes</surname><given-names>Lilian Pinheiro</given-names></name><xref ref-type="aff" rid="aff4002"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6105-9968</contrib-id><name><surname>Macedo</surname><given-names>Maria Cristina Martins de Almeida</given-names></name><xref ref-type="aff" rid="aff10002"><sup>10</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-0061-7882</contrib-id><name><surname>Rodrigues</surname><given-names>Morgani</given-names></name><xref ref-type="aff" rid="aff1002"><sup>1</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-0062-676X</contrib-id><name><surname>Ribeiro</surname><given-names>Paulo Cesar</given-names></name><xref ref-type="aff" rid="aff5002"><sup>5</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-5445-7194</contrib-id><name><surname>Silva</surname><given-names>Roberto Luiz da</given-names></name><xref ref-type="aff" rid="aff10002"><sup>10</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-0368-4052</contrib-id><name><surname>Roberto</surname><given-names>Telma Sigolo</given-names></name><xref ref-type="aff" rid="aff11002"><sup>11</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-4455-3283</contrib-id><name><surname>Rodrigues</surname><given-names>Thays de Cássia Ruiz</given-names></name><xref ref-type="aff" rid="aff2002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-7842-2957</contrib-id><name><surname>Colturato</surname><given-names>Vergilio Antonio Rensi</given-names></name><xref ref-type="aff" rid="aff6002"><sup>6</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6790-2004</contrib-id><name><surname>Paton</surname><given-names>Eduardo José de Alencar</given-names></name><xref ref-type="aff" rid="aff12002"><sup>12</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-2816-3077</contrib-id><name><surname>Barros</surname><given-names>George Maurício Navarro</given-names></name><xref ref-type="aff" rid="aff4002"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-8331-6155</contrib-id><name><surname>Almeida</surname><given-names>Rosana Ducatti Souza</given-names></name><xref ref-type="aff" rid="aff4002"><sup>4</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-8376-7199</contrib-id><name><surname>Moreira</surname><given-names>Maria Claudia Rodrigues</given-names></name><xref ref-type="aff" rid="aff13002"><sup>13</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-1631-0911</contrib-id><name><surname>Flowers</surname><given-names>Mary Evelyn</given-names></name><xref ref-type="aff" rid="aff14002"><sup>14</sup></xref></contrib></contrib-group><aff id="aff1002"><label>1</label><country country="BR">Brasil</country><institution content-type="original">Hospital Israelita Albert Einstein, São Paulo, SP, Brasil .</institution></aff><aff id="aff2002"><label>2</label><country country="BR">Brasil</country><institution content-type="original">Universidade Estadual de Campinas, Campinas, SP, Brasil .</institution></aff><aff id="aff3002"><label>3</label><country country="BR">Brasil</country><institution content-type="original">Universidade Federal da Bahia, Salvador, BA, Brasil .</institution></aff><aff id="aff4002"><label>4</label><country country="BR">Brasil</country><institution content-type="original">Hospital de Câncer de Barretos, Barretos, SP, Brasil .</institution></aff><aff id="aff5002"><label>5</label><country country="BR">Brasil</country><institution content-type="original">Hospital Sírio-Libanês, São Paulo, SP, Brasil .</institution></aff><aff id="aff6002"><label>6</label><country country="BR">Brasil</country><institution content-type="original">Fundação Hospital Amaral Carvalho, Jaú, SP, Brasil .</institution></aff><aff id="aff7002"><label>7</label><country country="BR">Brasil</country><institution content-type="original">Complexo Hospitalar Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brasil .</institution></aff><aff id="aff8002"><label>8</label><country country="BR">Brasil</country><institution content-type="original">Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil .</institution></aff><aff id="aff9002"><label>9</label><country country="BR">Brasil</country><institution content-type="original">Universidade Federal de São Paulo, São Paulo, SP, Brasil .</institution></aff><aff id="aff10002"><label>10</label><country country="BR">Brasil</country><institution content-type="original">Instituto Brasileiro de Controle do Câncer, São Paulo, SP, Brasil .</institution></aff><aff id="aff11002"><label>11</label><country country="BR">Brasil</country><institution content-type="original">Hospital São Luiz, São Paulo, SP, Brasil .</institution></aff><aff id="aff12002"><label>12</label><country country="BR">Brasil</country><institution content-type="original">Oncobio, Nova Lima, MG, Brasil .</institution></aff><aff id="aff13002"><label>13</label><country country="BR">Brasil</country><institution content-type="original">Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA, Rio de Janeiro, RJ, Brasil .</institution></aff><aff id="aff14002"><label>14</label><country country="US">United States</country><institution content-type="original">Seattle Cancer Care Alliance, Seattle, WA, United States .</institution></aff><author-notes><corresp id="c01002"><bold>Autor correspondente:</bold> Andrea Z Pereira Avenida Albert Einstein, 627/701 – Morumbi CEP: 05652-900 – São Paulo, SP, Brasil Tel.: (11) 3773-6590 E-mail: pereira.andrea2@einstein.br</corresp><fn fn-type="COI-statement"><p><bold>Conflitos de interesse:</bold> não há.</p></fn></author-notes><abstract><title>RESUMO</title><p>O Consenso Brasileiro de Nutrição no Transplante de Células Tronco Hematopoiéticas: doença do enxerto contra o hospedeiro foi aprovado pela Sociedade Brasileira de Transplante de Medula Óssea, com a participação de 26 centros brasileiros de transplante de células-tronco hematopoiéticas. O Consenso descreve as principais condutas nutricionais em casos de doença do enxerto contra o hospedeiro, a principal complicação do transplante de células-tronco hematopoiéticas.</p></abstract><kwd-group xml:lang="pt"><kwd>Nutrição</kwd><kwd>Doença enxerto-hospedeiro</kwd><kwd>Transplante de células-tronco hematopoéticas</kwd></kwd-group></front-stub><body><sec><title>TRANSPLANTE DE CÉULAS-TRONCO HEMATOPOIÉTICAS</title><p>Nos últimos 20 anos, as pesquisas desenvolvidas no transplante de céulas-tronco hematopoiéticas (TCTH) permitiram melhor seleção de doadores, redução na toxicidade advinda do condicionamento, com desenvolvimento de regimes de intensidade reduzida e melhora no tratamento de suporte, com a diminuição das complicações pós-transplante, aumentando, dessa forma, a sobrevida dos transplantados.<sup>( <xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> )</sup></p><p>A doença do enxerto contra o hospedeiro (DECH) é a maior causa de morbimortalidade relacionada ao TCTH alogênico, sendo responsável por grande impacto na qualidade de vida desses pacientes. Aproximadamente de 30% a 50% dos transpslantados alogênicos apresentam DECH no pós-TCTH.<sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup>A sobrevida global dos pacientes que apresentam DECH, particularmente a forma crônica, é de 72% em 1 ano e de 55% em 5 anos.<sup>( <xref rid="B2" ref-type="bibr">2</xref> )</sup></p></sec><sec><title>A FISIOPATOLOGIA DA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO</title><p>A DECH é causada pela ativação das células T que reconhecem os antígenos do hospedeiro como não próprios, provocando reação do tipo autoimune em órgãos do receptor, como pele, pulmões, fígado, trato gastrintestinal (TGI), timo, sistema hematopoiético e, possivelmente, mesmo o sistema nervoso central.<sup>( <xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> )</sup></p><p>A DECH aguda (DECH-a) grave se caracteriza por intensas lesões cutâneas, gastrintestinais e hepáticas, enquanto a forma crônica está associada a danos progressivos do tipo ulcerativos em mucosas e lesões sistêmicas em outros órgãos, como a pele e os pulmões.<sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup></p><p>A DECH crônica (DECH-c) apresenta mais características de aloimunidade e imunodeficiência. Muito semelhante à DECH-a, a DECH-c também é induzida por células imunes do doador, mas sua fisiopatologia é menos compreendida. Apesar dos linfócitos T serem considerados o fator-chave em seu desenvolvimento, dados recentes revelam que as células B também apresentam importante papel.</p><p>Classicamente, o desenvolvimento da DECH pode ser dividido em três fases:<sup>( <xref rid="B3" ref-type="bibr">3</xref> )</sup>a primeira fase consiste na lesão dos tecidos do receptor pelos agentes utilizados nos regimes de condicionamento agressivos necessários para prevenir a recidiva das doenças neoplásicas e a rejeição do enxerto. Embora outros órgãos possam ser comprometidos em graus variados de gravidade, o sistema hematopoiético e o TGI são mais suscetíveis a esta toxicidade.</p><p>A segunda fase do desenvolvimento da DECH consiste na ativação de linfócitos T por células apresentadoras de antígenos do hospedeiro e, posteriormente, do doador, que adquirem funções de células T <italic>helper</italic> efetoras e secretam citocinas que, subsequentemente, aceleram a ativação imunológica.<sup>( <xref rid="B4" ref-type="bibr">4</xref> , <xref rid="B5" ref-type="bibr">5</xref> )</sup></p><p>Na terceira fase da patogenia da DECH, a ativação imunológica de funções citotóxicas efetoras de células mediadoras, como as células T CD 81+, provoca lesões diretas das células-alvo características da DECH em órgãos como o fígado, a pele e o TGI.<sup>( <xref rid="B6" ref-type="bibr">6</xref> , <xref rid="B7" ref-type="bibr">7</xref> )</sup></p><p>Em busca de maior conhecimento sobre a DECH e as maneiras de melhor controlá-la, no ano de 2005 foi estabelecido um consenso com a formação de um grupo de trabalho da <italic>National Institutes of Health</italic> (NIH), sendo definido que a apresentação clínica, não o tempo, é considerada o mais importante para o diagnóstico e para a diferenciação entre a DECH-c e a DECH-a. Alguns sinais e sintomas mostram-se similares em ambas; as diferenças, entretanto, são pungentes e permitem a delimitação de duas síndromes clínicas distintas.</p></sec><sec><title>DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO AGUDA</title><p>A DECH-a afeta primordialmente a pele, o fígado e o TGI. Na pele, são vistas lesões maculopapulares eritematosas coalescentes, que podem estar caracteristicamente na região plantar e na palma das mãos. O início da DECH hepática pode ocorrer pelo aumento das enzimas hepáticas e por sinais de colestase em exames laboratoriais. Os sintomas gastrintestinais mais inespecíficos são diarreia, náuseas e vômitos. Essa variedade de sintomas é amplamente diversa em gravidade.<sup>( <xref rid="B2" ref-type="bibr">2</xref> - <xref rid="B4" ref-type="bibr">4</xref> )</sup></p><p>Os quadros podem ser extremamente agressivos, levando, por exemplo, à laceração da mucosa intestinal e sua eliminação fecal associada a hemorragias secundárias. Porém, muitas vezes, pode se apresentar com quadros leves, que necessitam de um diagnóstico diferencial invasivo e, muitas vezes, inconclusivo.<sup>( <xref rid="B2" ref-type="bibr">2</xref> - <xref rid="B4" ref-type="bibr">4</xref> )</sup>Por este motivo, a DECH-a foi estadiada ( <xref rid="t1002" ref-type="table">Tabela 1</xref> ) para se estabelecerem critérios de gravidade ( <xref rid="t2002" ref-type="table">Tabela 2</xref> ) e para padronizar uma maneira de avaliação em trabalhos acadêmicos universais.</p><p><table-wrap id="t1002" orientation="portrait" position="float"><label>Tabela 1</label><caption><title>Estadiamento da doença do enxerto contra o hospedeiro aguda por órgão ( <xref rid="B2" ref-type="bibr"><sup>2</sup></xref> - <xref rid="B4" ref-type="bibr"><sup>4</sup></xref> )</title></caption><table frame="hsides" rules="groups"><colgroup width="25%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Estágio</th><th rowspan="1" colspan="1">Achados cutâneos</th><th rowspan="1" colspan="1">Achados hepáticos</th><th rowspan="1" colspan="1">Achados intestinais</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">Exantema maculopapular em <25% da superfície corporal</td><td align="center" rowspan="1" colspan="1">Bilirrubina: 2-3mg/dL</td><td align="center" rowspan="1" colspan="1">Diarreia (500-1.000mL) persistente e náuseas</td></tr><tr><td rowspan="1" colspan="1">++</td><td align="center" rowspan="1" colspan="1">Exantema maculopapular em 25%-50% da superfície corporal</td><td align="center" rowspan="1" colspan="1">Bilirrubina: 3-6mg/dL</td><td align="center" rowspan="1" colspan="1">Diarreia (1.000-1.500mL)</td></tr><tr><td rowspan="1" colspan="1">+++</td><td align="center" rowspan="1" colspan="1">Eritrodermia generalizada</td><td align="center" rowspan="1" colspan="1">Bilirrubina: 6-15mg/dL</td><td align="center" rowspan="1" colspan="1">Diarreia >1.500mL)</td></tr><tr><td rowspan="1" colspan="1">++++</td><td align="center" rowspan="1" colspan="1">Descamação e bolhas</td><td align="center" rowspan="1" colspan="1">Bilirrubina: >15mg/dL</td><td align="center" rowspan="1" colspan="1">Dor com ou sem obstrução</td></tr></tbody></table></table-wrap></p><p><table-wrap id="t2002" orientation="portrait" position="float"><label>Tabela 2</label><caption><title>Graduação global da doença do enxerto contra o hospedeiro aguda ( <xref rid="B2" ref-type="bibr"><sup>2</sup></xref> - <xref rid="B4" ref-type="bibr"><sup>4</sup></xref> )</title></caption><table frame="hsides" rules="groups"><colgroup width="20%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Grau/estágio</th><th rowspan="1" colspan="1">Pele</th><th rowspan="1" colspan="1">Fígado</th><th rowspan="1" colspan="1">Intestino</th><th rowspan="1" colspan="1">Distúrbio funcional</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">0 (nenhum)</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">I (leve)</td><td align="center" rowspan="1" colspan="1">+ a ++</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td rowspan="1" colspan="1">II (moderado)</td><td align="center" rowspan="1" colspan="1">+ a +++</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td><td align="center" rowspan="1" colspan="1">+</td></tr><tr><td rowspan="1" colspan="1">III (grave)</td><td align="center" rowspan="1" colspan="1">++ a +++</td><td align="center" rowspan="1" colspan="1">++ a +++</td><td align="center" rowspan="1" colspan="1">++ a +++</td><td align="center" rowspan="1" colspan="1">++</td></tr><tr><td rowspan="1" colspan="1">IV (com risco de morte)</td><td align="center" rowspan="1" colspan="1">++ a ++++</td><td align="center" rowspan="1" colspan="1">++ a ++++</td><td align="center" rowspan="1" colspan="1">++ a ++++</td><td align="center" rowspan="1" colspan="1">+++</td></tr></tbody></table></table-wrap></p></sec><sec><title>DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO CRÔNICA</title><p>A DECH-c é uma síndrome clínico-patológica que envolve vários órgãos e sistemas, assemelhando-se muito às doenças autoimunes.</p><p>Esforços foram feitos no sentido de identificar os fatores de risco associados a um aumento da morbimortalidade nos pacientes com DECH-c. As variáveis identificadas incluíram envolvimento de múltiplos órgãos ou locais, piora da <italic>performance status</italic> , plaquetopenia no momento do diagnóstico, definida como contagem de plaquetas menor do que 100.000/µL, aparecimento progressivo da DECH-c, bilirrubinas elevadas e envolvimento extenso de pele (acometimento maior de 50% da superfície corpórea).<sup>( <xref rid="B2" ref-type="bibr">2</xref> , <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>Em 2005, o NIH desenvolveu um projeto para consenso dos critérios que devem ser utilizados em estudos clínicos da DECH-c.<sup>( <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> )</sup>Foram padronizadas as características utilizadas no diagnóstico, além de serem propostos meios para a pontuação dos órgãos envolvidos e avaliação global da gravidade.<sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B12" ref-type="bibr">12</xref> )</sup></p><p>Estes critérios, revistos em 2014, são úteis para melhor análise da incidência da DECH-c, além de possibilitarem avaliar a gravidade do comprometimento de um órgão ou local, isolado ou combinado, e a influência na mortalidade relacionada ao transplante (MRT). Pelo consenso do NIH, sinais e sintomas diagnósticos se referem a manifestações que estabelecem a presença de DECH-c sem a necessidade de testes ou evidências de outros órgãos acometidos ( <xref rid="t3002" ref-type="table">Tabela 3</xref> ). Sinais e sintomas distintos se referem àquelas manifestações que não são comumente encontradas na DECH-c, mas são insuficientes para estabelecer diagnóstico preciso de DECH-c sem outros testes ou envolvimento de outros órgãos. Outras características definem manifestações raras, controversas e não específicas de DECH-c e não podem ser utilizadas para firmar o diagnóstico de DECH-c.<sup>( <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> )</sup></p><p><table-wrap id="t3002" orientation="portrait" position="float"><label>Tabela 3</label><caption><title>Sinais e sintomas relacionados à doença do enxerto contra o hospedeiro crônica ( <xref rid="B10" ref-type="bibr"><sup>10</sup></xref> , <xref rid="B11" ref-type="bibr"><sup>11</sup></xref> )</title></caption><table frame="hsides" rules="groups"><colgroup width="20%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Órgão ou sítio</th><th rowspan="1" colspan="1">Diagnóstico (suficiente para estabelecer o diagnóstico de DECH-c)</th><th rowspan="1" colspan="1">Característico (presente na DECH, mas isoladamente é insuficiente para estabelecer o diagnóstico)</th><th rowspan="1" colspan="1">Outras características</th><th rowspan="1" colspan="1">Comuns à DECH-a e à DECH-c</th></tr></thead><tbody><tr><td align="left" rowspan="6" valign="top" colspan="1">Pele</td><td align="center" rowspan="1" colspan="1">Poiquiloderma</td><td align="center" rowspan="6" colspan="1">Despigmentação</td><td align="center" rowspan="1" colspan="1">Despigmentação</td><td align="center" rowspan="1" colspan="1">Eritema</td></tr><tr><td align="center" rowspan="1" colspan="1">Líquen plano</td><td align="center" rowspan="1" colspan="1">Excesso ou falta de suor</td><td align="center" rowspan="1" colspan="1"><italic>Rash</italic> Maculopapular</td></tr><tr><td align="center" rowspan="1" colspan="1">Alterações escleróticas</td><td align="center" rowspan="1" colspan="1">Ictose</td><td align="center" rowspan="4" colspan="1">Prurido</td></tr><tr><td align="center" rowspan="1" colspan="1">Morfeia</td><td align="center" rowspan="1" colspan="1">Queratose pilar</td></tr><tr><td align="center" rowspan="2" colspan="1">Líquen esclerosante</td><td align="center" rowspan="1" colspan="1">Hipopigmentação</td></tr><tr><td align="center" rowspan="1" colspan="1">Hiperpigmentação</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Unha</td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Distrofia</td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Sulcos longitudinais</td></tr><tr><td align="center" rowspan="1" colspan="1">Onicolise</td></tr><tr><td align="center" rowspan="1" colspan="1"><italic>Pterygium unguis</italic></td></tr><tr><td align="center" rowspan="1" colspan="1">Queda das unhas (geralmente simetricamente)</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Couro cabeludo e pelos</td><td rowspan="2" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Alopecia total ou alopecia areata após a recuperação pós-quimioterapia</td><td align="center" rowspan="1" colspan="1">Afinamento dos pelos não explicável por outras causas</td><td rowspan="2" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Lesões papuloescamosas</td><td align="center" rowspan="1" colspan="1">Pelos brancos precocemente</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Boca</td><td align="center" rowspan="1" colspan="1">Alterações tipo líquen</td><td align="center" rowspan="1" colspan="1">Xerostomia</td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Gengivite</td></tr><tr><td align="center" rowspan="1" colspan="1">Placas hiperqueratóticas</td><td align="center" rowspan="1" colspan="1">Mucocele</td><td align="center" rowspan="1" colspan="1">Mucosite</td></tr><tr><td align="center" rowspan="3" colspan="1">Restrição da abertura da boca por esclerose</td><td align="center" rowspan="1" colspan="1">Atrofia da mucosa</td><td align="center" rowspan="1" colspan="1">Eritema</td></tr><tr><td align="center" rowspan="1" colspan="1">Pseudomembranas</td><td align="center" rowspan="2" colspan="1">Dor</td></tr><tr><td align="center" rowspan="1" colspan="1">Úlceras</td></tr><tr><td align="left" rowspan="4" valign="top" colspan="1">Olho</td><td rowspan="4" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Secura e dor nos olhos</td><td align="center" rowspan="2" colspan="1">Fotofobia</td><td rowspan="4" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Conjuntivite cicatricial</td></tr><tr><td align="center" rowspan="1" colspan="1">Ceratoconjuntivite seca (teste de Schrimer <5mm/5 minutos)</td><td align="center" rowspan="1" colspan="1">Hiperpigmentação periorbital</td></tr><tr><td align="center" rowspan="1" colspan="1">Ceratopatia punctata em áreas confluentes</td><td align="center" rowspan="1" colspan="1">Blefarite</td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Genitais</td><td align="center" rowspan="1" colspan="1">Líquen plano</td><td align="center" rowspan="1" colspan="1">Erosões</td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td></tr><tr><td align="center" rowspan="2" colspan="1">Estenose vaginal</td><td align="center" rowspan="1" colspan="1">Fissuras</td></tr><tr><td align="center" rowspan="1" colspan="1">Úlceras</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">TGI</td><td align="center" rowspan="1" colspan="1"><italic>Esophageal web</italic></td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="5" colspan="1">Insuficiência pancreática exógena</td><td align="center" rowspan="1" colspan="1">Anorexia</td></tr><tr><td align="center" rowspan="4" colspan="1">Constrição ou estenose no terço proximal do esôfago</td><td align="center" rowspan="1" colspan="1">Náusea</td></tr><tr><td align="center" rowspan="1" colspan="1">Vômitos</td></tr><tr><td align="center" rowspan="1" colspan="1">Diarreia</td></tr><tr><td align="center" rowspan="1" colspan="1">Perda de peso</td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Fígado</td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td><td rowspan="3" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Bilirrubina total e fosfatase alcalina ></td></tr><tr><td align="center" rowspan="1" colspan="1">2 vezes acima do limite normal</td></tr><tr><td align="center" rowspan="1" colspan="1">ALT ou AST >2 vezes limite superior</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Pulmão</td><td align="center" rowspan="1" colspan="1">Bronquiolite obliterante diagnosticada com biópsia</td><td align="center" rowspan="1" colspan="1">Bronquiolite obliterante diagnosticada com Prova de função pulmonar ou Tomografia Computadorizada de Tórax</td><td rowspan="1" colspan="1"> </td><td align="center" rowspan="1" colspan="1">BOOP</td></tr><tr><td align="left" rowspan="3" valign="top" colspan="1">Músculo, fascia, articulações</td><td align="center" rowspan="1" colspan="1">Fasciíte</td><td align="center" rowspan="3" colspan="1">Miosite ou polimiosite</td><td align="center" rowspan="1" colspan="1">Edema</td><td rowspan="3" colspan="1"> </td></tr><tr><td align="center" rowspan="1" colspan="1">Contraturas articulares secundárias à esclerose</td><td align="center" rowspan="1" colspan="1">Cãibras</td></tr><tr><td align="center" rowspan="1" colspan="1">Rigidez articular</td><td align="center" rowspan="1" colspan="1">Artralgia ou artrite</td></tr><tr><td align="left" rowspan="5" valign="top" colspan="1">Hematopoiético e imunológico</td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td><td rowspan="5" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Trombocitopenia</td></tr><tr><td align="center" rowspan="1" colspan="1">Eosinofilia</td></tr><tr><td align="center" rowspan="1" colspan="1">Linfopenia</td></tr><tr><td align="center" rowspan="1" colspan="1">Hipo ou hipergamaglobulinemia</td></tr><tr><td align="center" rowspan="1" colspan="1">Autoanticorpos (AHAI e PTI)</td></tr><tr><td align="left" rowspan="6" valign="top" colspan="1">Outros</td><td rowspan="6" colspan="1"> </td><td rowspan="6" colspan="1"> </td><td rowspan="6" colspan="1"> </td><td align="center" rowspan="1" colspan="1">Derrame pleural ou pericárdico</td></tr><tr><td align="center" rowspan="1" colspan="1">Ascite</td></tr><tr><td align="center" rowspan="1" colspan="1">Neuropatia periférica</td></tr><tr><td align="center" rowspan="1" colspan="1">Síndrome nefrótica</td></tr><tr><td align="center" rowspan="1" colspan="1">Miastenia grave</td></tr><tr><td align="center" rowspan="1" colspan="1">Cardiomiopatia ou defeitos de condução cardíaca</td></tr></tbody></table><table-wrap-foot><fn id="TFN1002"><p>DECH-c: doença do enxerto contra o hospedeiro crônica; DECH: doença do enxerto contra o hospedeiro; DECH-a: doença do enxerto contra o hospedeiro aguda; ALT: alanina aminotransferase; AST: aspartato aminotransferase; BOOP: Bronquiolite obliterante com pneumonia em organização; AHAI: anemia hemolítica autoimune; PTI: púrpura trombocitopênica imunológica.</p></fn></table-wrap-foot></table-wrap></p><p>O consenso recomenda os seguintes critérios para o diagnóstico da DECH-c:<sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup>distinção de DECH-a; presença de pelo menos um sinal clínico diagnóstico da DECH-c, ou presença de pelo menos uma manifestação distinta confirmada por biópsia pertinente de acordo com critérios histopatológicos definidos, testes laboratoriais, ou imagens radiológicas, no mesmo ou em outro órgão; e exclusão de outros diagnósticos possíveis.</p><p>A classificação revisada do NIH 2014 inclui oito órgãos como principais, por serem aqueles mais acometidos pela doença: pele, boca, olhos, TGI, fígado, pulmão, articulações e trato genital feminino. Os mais acometidos na DECH-c leve são pele, boca e fígado. Envolvimento do pulmão na DECH-c acrescenta por si só maior gravidade à doença, segundo o consenso, e, por isso, o dano pulmonar é um critério de gravidade considerado de grande importância nessa classificação.<sup>( <xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>Para facilitar a graduação e estabelecer critérios padronizados de estágios da doença, os órgãos comumente afetados receberam pontuações e escalas de gravidade do dano produzido pela DECH-c. Cada órgão ou local recebeu pontuação de zero a 3, com zero representando nenhum envolvimento e 3, comprometimentos graves.<sup>( <xref rid="B9" ref-type="bibr">9</xref> )</sup></p><p>A avaliação global da gravidade ( <xref rid="t4002" ref-type="table">Tabela 4</xref> ) nesse consenso é baseada no número de órgãos ou locais envolvidos e no grau de acometimento de cada órgão afetado. Os pacientes são considerados com diagnóstico de DECH-c leve quando apenas um ou dois órgãos (exceto os pulmões) forem afetados, sem dano funcional clinicamente significante, com pontuação máxima de 1 em todos os órgãos ou locais. O diagnóstico de DECH-c moderado é considerado quando pelo menos um órgão ou local apresentar comprometimento clínico significante, porém sem dano maior, com pontuação máxima de 2 em qualquer órgão ou local afetado, ou dois, três ou mais órgãos ou locais forem acometidos, porém sem prejuízo funcional clinicamente significante, com pontuação máxima de 1 em todos os órgãos ou locais afetados. Pontuação de 1 nos pulmões também é considerada moderada. DECH-c grave indica dano maior com a pontuação de 3 em qualquer órgão ou local. Pontuação ≥2 nos pulmões é considerada grave.<sup>( <xref rid="B9" ref-type="bibr">9</xref> , <xref rid="B10" ref-type="bibr">10</xref> )</sup>Estes valores são todos registrados em questionário validado pelo NIH e atualmente utilizado universalmente por inúmeros centros de pesquisa e assistência.</p><p><table-wrap id="t4002" orientation="portrait" position="float"><label>Tabela 4</label><caption><title>Avaliação global de gravidade da doença do enxerto contra o hospedeiro crônica ( <xref rid="B9" ref-type="bibr"><sup>9</sup></xref> , <xref rid="B10" ref-type="bibr"><sup>10</sup></xref> )</title></caption><table frame="hsides" rules="groups"><colgroup width="50%" span="1"><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Tipos DECH crônica</th><th rowspan="1" colspan="1">Critérios para classificação</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">DECH-c leve</td><td rowspan="1" colspan="1">1 ou 2 órgãos envolvidos +p ontuação nos órgãos envolvidos 1 + pontuação do pulmão 0</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">DECH-c moderada</td><td rowspan="1" colspan="1">3 ou mais órgãos envolvidos + pontuação 1 em cada órgão ou Pelo menos 1 órgão (exceto pulmão) com pontuação 2 ou Pontuação do pulmão 1</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">DECH-c grave</td><td rowspan="1" colspan="1">Pelo menos 1 órgão com pontuação 3 ou</td></tr><tr><td rowspan="1" colspan="1">Pontuação do pulmão 2 ou 3</td></tr><tr><td colspan="2" rowspan="1">1. Na pele: a pontuação maior será usada para o cálculo da gravidade global</td></tr><tr><td colspan="2" rowspan="1">2. No pulmão: VEF1 é usado no lugar da pontuação clínica para o cálculo da gravidade global</td></tr><tr><td colspan="2" rowspan="1">3. Se uma anormalidade de um órgão é inequivocamente explicada por uma causa não associada à DECH, a pontuação deste órgão será zero para o cálculo da gravidade global</td></tr><tr><td colspan="2" rowspan="1">4. Se uma anormalidade de um órgão é atribuída a causas multifatoriais (DECH mais outras causas), a pontuação do órgão será usada para o cálculo da gravidade global independentemente das causas contribuintes (a pontuação do órgão não será desconsiderada)</td></tr></tbody></table><table-wrap-foot><fn id="TFN2002"><p>DECH-c: doença do enxerto contra o hospedeiro crônica; DECH: doença do enxerto contra o hospedeiro; VEF: volume expiratório forçado.</p></fn></table-wrap-foot></table-wrap></p><p>O estudo da DECH-c inspira crescente interesse na comunidade acadêmica, agregado ao fato do estabelecimento recente de critérios que categorizaram a doença, baseados em evidências sedimentadas; foi iniciado o caminho para um maior entendimento da patogênese da DECH-c.</p></sec><sec><title>INTRODUÇÃO SOBRE A IMPORTÂNCIA DO ESTADO NUTRICIONAL NA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO</title><p>Não existem dados de literatura claros sobre a interferência do estado nutricional prévio ao TCTH como causa de maior ou menor incidência de DECH, assim como sobre qual seria a melhor forma de realizar sua avaliação.<sup>( <xref rid="B13" ref-type="bibr">13</xref> - <xref rid="B16" ref-type="bibr">16</xref> )</sup>Alguns trabalhos relatam que taxas elevadas de desnutrição<sup>( <xref rid="B17" ref-type="bibr">17</xref> )</sup>e piora do estado nutricional associam-se a maior gravidade da DECH de TGI, de boca e de pulmão.<sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p><p>Por outro lado, apesar da heterogeneidade dos estudos e de não se saber exatamente por meio de qual mecanismo se dá a interferência, tanto a obesidade quanto a desnutrição estão associadas a um maior risco para desenvolvimento de DECH.<sup>( <xref rid="B19" ref-type="bibr">19</xref> , <xref rid="B20" ref-type="bibr">20</xref> )</sup></p><p>Recuperar ou melhorar o estado nutricional dos pacientes pré-TCHT poderia trazer consequências melhores ao desfecho.<sup>( <xref rid="B20" ref-type="bibr">20</xref> )</sup></p><p>Entretanto, é conhecida a relação da DECH com os estados carenciais, como os défices vitamínicos.<sup>( <xref rid="B14" ref-type="bibr">14</xref> - <xref rid="B16" ref-type="bibr">16</xref> )</sup></p><p>No período pós-transplante imediato (30 a 50 dias), as necessidades nutricionais refletem o aumento do aporte calórico-proteico em razão de condicionamento, infecções, DECH-a, febre e outras complicações metabólicas, afetando, principalmente, o balanço de proteínas, as necessidades energéticas e o metabolismo de micronutrientes.<sup>( <xref rid="B21" ref-type="bibr">21</xref> , <xref rid="B22" ref-type="bibr">22</xref> )</sup></p><p>O estado nutricional na DECH-a ou na DECH-c é afetado por vários sintomas, que são amplamente discutidos posteriormente, como internações prolongadas e altas doses de corticosteroides, afetando profundamente a composição corporal com maior perda de massa muscular, retenção de líquido e aumento da gordura visceral, atingindo ainda mais o estado nutricional.<sup>( <xref rid="B18" ref-type="bibr">18</xref> , <xref rid="B23" ref-type="bibr">23</xref> - <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>Na DECH-c, nas manifestações orais, pulmonares e gastrintestinais, podemos encontrar até 29% de pacientes desnutridos em decorrência de dor na mucosa oral e atividade da doença, entre outros fatores.<sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup>Isso influi diretamente na redução da funcionalidade e da qualidade de vida dos pacientes.<sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p><p>A DECH é uma condição complexa com efeitos significativos sobre a piora do estado nutricional, ocasionando redução da qualidade de vida e da funcionalidade dos pacientes.<sup>( <xref rid="B18" ref-type="bibr">18</xref> , <xref rid="B25" ref-type="bibr">25</xref> )</sup>Discutiremos, a seguir, tópicos específicos do estado e da terapia nutricional na DECH-a e na DECH-c.</p></sec><sec><title>MICRO E MACRONUTRIENTES NA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO</title><p>A conduta dietoterápica depende da forma que a DECH se manifesta no paciente. A maioria dos pacientes inicia o tratamento com dieta relativamente saudável, mas rapidamente ocorre depleção dessa dieta. Isso se dá devido aos efeitos tóxicos diretos do tratamento ou às complicações secundárias, como as infecções e a própria DECH-a.<sup>( <xref rid="B15" ref-type="bibr">15</xref> )</sup></p><p>A DECH moderada a grave e os regimes multifarmácias utilizados em sua prevenção e tratamento resultam em imunossupressão profunda e prolongada. Apesar dos avanços no manejo, a DECH continua problema significativo. Os pacientes frequentemente têm as necessidades nutricionais elevadas e alterações no metabolismo de carboidratos, gorduras e proteínas. Apresentam, ainda, dificuldade para comer por uma variedade de razões dependentes do envolvimento de órgãos e em geral requerem dietas modificadas, suplementos orais ou nutrição enteral (NE) ou parenteral (TNP) para prevenir a desnutrição.<sup>( <xref rid="B26" ref-type="bibr">26</xref> )</sup></p><sec><title>Recomendações nutricionais: macronutrientes</title><sec><title>Calorias</title><p>As necessidades nutricionais em pacientes submetidos ao TCTH aumentam devido ao catabolismo intenso.<sup>( <xref rid="B27" ref-type="bibr">27</xref> )</sup>É sugerido que as necessidades de energia durante a fase inicial do TCTH e da DECH sejam de até 130% a 150% do gasto estimado de energia basal, o que corresponde a 30 a 50kcal/kg de peso corporal por dia, e esse aumento da necessidade energética contribuiria para a perda ponderal desses pacientes.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B28" ref-type="bibr">28</xref> , <xref rid="B29" ref-type="bibr">29</xref> )</sup>Esse estado hipermetabólico crônico encontrado nesses pacientes é uma resposta às citocinas inflamatórias (fator de necrose tumoral alfa − TNF-α; interleucinas - IL − 1 e 6) e às alterações no níveis de norepinefrina e glucagon.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B30" ref-type="bibr">30</xref> , <xref rid="B31" ref-type="bibr">31</xref> )</sup>Estudos mostram aumento dos níveis séricos de glucagon ocasionando aumento de até 10% do metabolismo basal, principalmente pelo estímulo a gliconeogênese.<sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup>O aumento da norepinefrina nesses casos resulta em elevação da produção hepática de glicose, e também contribui para o aumento de metabolismo basal.<sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup></p><p>Um estudo transversal com 13 pacientes comparou o requerimento energético por calorimetria indireta entre controles saudáveis e pacientes que apresentavam DECH-c extensa de pele, membranas mucocutâneas, pulmão, olhos e fígado, mostrando que houve pequeno aumento no requerimento de energia (1,9kcal/kg/dia ou 133kcal em uma pessoa de 70kg) e nas alterações das taxas de oxidação de gorduras e carboidratos.<sup>( <xref rid="B30" ref-type="bibr">30</xref> )</sup></p><p>Além disso, foi demonstrado, em modelo animal, aumento da glicólise e do metabolismo de ácidos graxos para adequada função de células T alorreativas e indução da DECH.<sup>( <xref rid="B32" ref-type="bibr">32</xref> , <xref rid="B33" ref-type="bibr">33</xref> )</sup>Acredita-se, ainda, que o próprio tratamento da DECH possa ter efeitos no metabolismo energético dos pacientes, mas também são escassos os relatos sobre esse tópico.<sup>( <xref rid="B22" ref-type="bibr">22</xref> )</sup></p><p>Nesse caso, recomendamos o uso de 30 a 50kcal/kg de peso corporal por dia para cálculo das necessidades calóricas nesses pacientes.</p></sec><sec><title>Proteínas e lipídios</title><p>A Organização Mundial de Saúde (OMS) recomenda como aceitável valor de ingestão proteica de 0,83g/kg de peso, sendo a capacidade máxima de síntese proteica atingida com ingestão de 1,5g/kg/dia.<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup>Embora não existam estudos bem desenhados para embasarem tal recomendação, existe recomendação de manutenção de níveis mais elevados de ingestão proteica (cerca de 1,8 a 2,5g/kg/dia) nos casos de pacientes que desenvolveram DECH.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B29" ref-type="bibr">29</xref> )</sup>Tal recomendação baseia-se no fato da perda proteica por exsudação da mucosa intestinal e pelo efeito do uso crônico de corticoides no aumento da necessidade proteica.<sup>( <xref rid="B29" ref-type="bibr">29</xref> , <xref rid="B34" ref-type="bibr">34</xref> - <xref rid="B40" ref-type="bibr">40</xref> )</sup></p><p>Os lipídios podem ser administrados com segurança como triacilgliceróis de cadeia longa (LCTs) ou LCT/mistura de triacilgliceróis de cadeia média, que geralmente contribuem com 30% a 40% de energia não proteica.<sup>( <xref rid="B40" ref-type="bibr">40</xref> , <xref rid="B41" ref-type="bibr">41</xref> )</sup></p></sec><sec><title>Ômega 3</title><p>O ácido graxo ômega 3 desempenha papel como fator imunomodulador.<sup>( <xref rid="B42" ref-type="bibr">42</xref> )</sup>Foi teorizado que os lipídios poderiam modular vantajosamente a DECH, controlando a produção de citocinas por meio da via da prostaglandina E2. A manipulação de lipídio está associada ao controle da intolerância a glicose. Desse modo, temos aumento dos ácidos graxos monoinsaturados que substituiriam os ácidos graxos saturados ( <xref rid="t5002" ref-type="table">Tabela 5</xref> ).<sup>( <xref rid="B42" ref-type="bibr">42</xref> )</sup></p><p><table-wrap id="t5002" orientation="portrait" position="float"><label>Tabela 5</label><caption><title>Suplementos nutricionais recomendados para receptores de transplante de células-tronco hematopoiéticas com doença do enxerto contra o hospedeiro no <italic>Baylor University Medical Center</italic> ( <xref rid="B29" ref-type="bibr"><sup>29</sup></xref> )</title></caption><table frame="hsides" rules="groups"><colgroup width="50%" span="1"><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Suplementos</th><th align="left" rowspan="1" colspan="1">Motivo do consumo</th></tr></thead><tbody><tr><td align="left" rowspan="2" valign="top" colspan="1">Multivitamínico com minerais (com mínimo de ferro para o primeiro ano após o TCTH)</td><td rowspan="1" colspan="1">Para assegurar recursos adequados de vitaminas e minerais</td></tr><tr><td rowspan="1" colspan="1">Metabolismo e anabolismo, especialmente se o paciente estiver com ingestão oral inadequada</td></tr><tr><td rowspan="1" colspan="1">Vitamina C (500mg/ 2vezes/dia)</td><td rowspan="1" colspan="1">Para ajudar na cicatrização de feridas</td></tr><tr><td rowspan="2" colspan="1">Zinco (22mg de sulfato de zinco/ 1 vez/ dia, durante 2 semanas)</td><td rowspan="1" colspan="1">Ajuda na cicatrização de feridas</td></tr><tr><td rowspan="1" colspan="1">Para repor as quantidades perdidas na diarreia crônica</td></tr><tr><td align="left" rowspan="2" valign="top" colspan="1">Ácido fólico (١mg/dia)</td><td rowspan="1" colspan="1">Para satisfazer as elevadas necessidades de produção de hemácias</td></tr><tr><td rowspan="1" colspan="1">Certos medicamentos aumentam o metabolismo ou desperdício dessa vitamina e, portanto, precisa ser reposta</td></tr><tr><td rowspan="1" colspan="1">Cálcio com vitamina D (dose depende do nível sérico)*</td><td rowspan="1" colspan="1">Para minimizar a desmineralização óssea com uso de esteroides crônicos.</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ômega 3 (2 g/dia)</td><td rowspan="1" colspan="1">Interação com os níveis celulares para modificação das citocinas, reduzindo o processo inflamatório da DECH</td></tr></tbody></table><table-wrap-foot><fn id="TFN3002"><p>* Nível sérico <10ng/mL-50.000UL/semana; 10-30ng/mL-10.000UL/semana. TCTH: Transplante de células-tronco hematopoiéticas; DECH: doença do enxerto contra o hospedeiro.</p></fn></table-wrap-foot></table-wrap></p></sec><sec><title>Glutamina</title><p>A utilização da glutamina é controversa. Parece haver alguns benefícios de seu uso oral na redução da mucosite e da DECH, enquanto a glutamina endovenosa pode reduzir as infecções.<sup>( <xref rid="B43" ref-type="bibr">43</xref> )</sup></p><p>Segundo a revisão Cochrane, a glutamina não só modula a função do sistema imunológico no trato digestivo, mas também pode promover a cicatrização intestinal e reduzir a gravidade da mucosite e também da DECH-TGI.<sup>( <xref rid="B44" ref-type="bibr">44</xref> )</sup>Já a recente diretriz da <italic>European Society for Clinical Nutrition and Metabolism</italic> (ESPEN) conclui que não há evidências suficientes para recomendação da suplementação com glutamina para redução de toxicidade ao tratamento em pacientes com DECH-TGI.<sup>( <xref rid="B36" ref-type="bibr">36</xref> )</sup></p><p>Então, devido a essa inconsistência da literatura, não se recomenda o uso de glutamina nessa população.</p></sec></sec></sec><sec><title>Recomendações nutricionais: micronutrientes</title><sec><title>Vitamina B12</title><p>Os efeitos da DECH no estômago, reduzindo o fator intrínseco, e no intestino, reduzindo a absorção de vitamina B12, e o regime de condicionamento do TCTH, resultando na degeneração das células de cripta, associam-se à diminuição dessa vitamina ( <xref rid="t5002" ref-type="table">Tabela 5</xref> ).<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p></sec><sec><title>Vitamina C</title><p>Estudos mostram que a vitamina C tem importante papel no combate de mucosite em pacientes com DECH. Pacientes com deficiência em vitamina C que receberam tratamento com 2.000mg/mês de ácido ascórbico apresentaram significantes melhorias visuais na mucosite e conseguiram voltar a comer<sup>( <xref rid="B45" ref-type="bibr">45</xref> )</sup>( <xref rid="t5002" ref-type="table">Tabela 5</xref> ).</p></sec><sec><title>Zinco</title><p>A diarreia crônica e a malabsorção ocasionadas pela DECH podem levar a uma deficiência de zinco, que é importante na manutenção do paladar e da integridade da mucosa gastrintestinal.<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup>Além disso, o zinco atua na cicatrização e na percepção do sabor, e é importante defesa contra as infecções intestinais, devido à manutenção da integridade da mucosa intestinal.<sup>( <xref rid="B46" ref-type="bibr">46</xref> )</sup></p><p>Diversos estudos recomendam sua suplementação em pacientes com DECH, como Roberts et al.,<sup>( <xref rid="B29" ref-type="bibr">29</xref> )</sup>que recomendam que a suplementação de zinco é interessante para o tratamento de lesões recorrentes. Ripamonti et al.,<sup>( <xref rid="B47" ref-type="bibr">47</xref> )</sup>sugerem que a suplementação (até 3 doses/dia de 45mg ZnSO<sub>4</sub>) é segura e efetiva para tratamento da percepção do sabor.</p><p>Além disso, estudos experimentais têm sugerido papel desse elemento na ativação de células T regulatórias, podendo ser interessante para o TCTH<sup>( <xref rid="B48" ref-type="bibr">48</xref> )</sup>( <xref rid="t5002" ref-type="table">Tabela 5</xref> ).</p></sec><sec><title>Vitamina D</title><p>Alguns estudos já descreveram a presença de deficiência de vitamina D em pacientes após o TCTH e sua relação com o desenvolvimento da DECH e com a redução da densidade mineral óssea.<sup>( <xref rid="B49" ref-type="bibr">49</xref> )</sup>A despeito de sua associação com uma nutrição inadequada, a deficiência de vitamina D não tem sido caracterizada como complicação direta do desenvolvimento da DECH,<sup>( <xref rid="B50" ref-type="bibr">50</xref> )</sup>mas parece ter papel em seu desenvolvimento. Sproat et al., em estudo retrospectivo com número reduzido de pacientes (58 pacientes transplantados entre 2000 e 2009), relataram prevalência de hipovitaminose D de 89,7%, e a maioria destes pacientes tiveram DECH (94,8%) e fizeram uso de corticosteroides (98,3%).<sup>( <xref rid="B51" ref-type="bibr">51</xref> )</sup>Contudo, outros estudos também observaram essa associação de baixos níveis séricos de vitamina D (<25ng/mL) e DECH, além de reativação de citomegalovírus (CMV) pós-transplante.<sup>( <xref rid="B52" ref-type="bibr">52</xref> , <xref rid="B53" ref-type="bibr">53</xref> )</sup></p><p>A redução dos efeitos da DECH pode ser explicada pelo aparente papel da vitamina D no sistema imunológico, regulando o funcionamento de células dendríticas, macrófagos e linfócitos B e T.<sup>( <xref rid="B54" ref-type="bibr">54</xref> - <xref rid="B56" ref-type="bibr">56</xref> )</sup></p><p>Os pacientes com DECH-a tratados com corticosteroides revelam tendência para maior diminuição da vitamina D. O monitoramento de seus níveis e, se necessário, o tratamento para sua correção, podem ser indicados em intervalos regulares antes do TCTH e durante o seguimento destes pacientes.<sup>( <xref rid="B49" ref-type="bibr">49</xref> )</sup></p><p>A reposição de cálcio e vitamina D em combinação com bifosfonatos, ou a suplementação com metabólitos ativos como 1,25 (OH)<sub>2</sub>D3 vitamina D ou 25 (OH)<sub>3</sub>vitamina D trazem efeitos benéficos para a massa óssea e a modulação da DECH.<sup>( <xref rid="B57" ref-type="bibr">57</xref> , <xref rid="B58" ref-type="bibr">58</xref> )</sup></p><p>O estudo da suplementação de vitamina D no TCTH é relativamente recente, mas já oferece resultados promissores. A dosagem de seu nível sérico deveria ser realizada no pré-TCTH e no pós-TCTH, e a deficiência deve ser corrigida.</p></sec><sec><title>Magnésio</title><p>A principal alteração do metabolismo nos pacientes com DECH é a hipomagnesemia, causada pelos inibidores de calcineurina, uma das classes de medicações mais utilizadas, tanto na profilaxia quanto no tratamento da doença. Contudo, há relatos de caso em que houve hipermagnesemia severa após o uso de medicações laxantes, com alta concentração de magnésio, provavelmente associadas à desidratação e à alta permeabilidade intestinal vista na DECH.<sup>( <xref rid="B59" ref-type="bibr">59</xref> )</sup></p></sec><sec><title>Ferro</title><p>A sobrecarga de ferro é uma complicação comum dos TCTH, devido ao aumento de absorção de ferro secundária à anemia e às múltiplas transfusões. A sobrecarga de ferro pode aumentar o risco de DECH, sobretudo aguda, pela tendência a causar toxicidade hepática direta. Além disso, a ferritina parece ser marcador de pior prognóstico em pacientes com DECH.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B60" ref-type="bibr">60</xref> )</sup>Recomenda-se o uso de multivitamínicos que não contenham ferro nessa população.<sup>( <xref rid="B61" ref-type="bibr">61</xref> )</sup></p><p>As recomendações nutricionais em pacientes com doença do enxerto contra o hospedeiro são apresentadas no <xref rid="t6002" ref-type="table">tabela 6</xref> .</p><p><table-wrap id="t6002" orientation="portrait" position="float"><label>Tabela 6</label><caption><title>Recomendações nutricionais em pacientes com doença do enxerto contra o hospedeiro</title></caption><table frame="hsides" rules="groups"><colgroup width="100%" span="1"><col span="1"></col></colgroup><thead><tr><th align="left" style="font-weight:normal" rowspan="1" colspan="1">Avaliar o estado nutricional por especialista</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Manter as necessidades calóricas em 30 a 50kcal/kg e proteicas em 1,5-2g/kg</td></tr><tr><td rowspan="1" colspan="1">Monitorar o peso e a ingestão de nutrientes no primeiro ano após o transplante; pacientes com DECH ativa necessitam de monitoramento mais longo</td></tr><tr><td rowspan="1" colspan="1">Aconselhar e monitorar o suporte nutricional especificamente para os pacientes com DECH do trato gastrintestinal; iniciar o apoio nutricional especializado em pacientes com disfunção significativa do trato gastrintestinal e anorexia, que são incapazes de manter o peso corporal adequado</td></tr><tr><td rowspan="1" colspan="1">Suplementar com multivitamínicos/minerais (sem ferro, devido ao risco de hemocromatose); outros suplementos, como vitamina C, zinco, ácido fólico e ômega 3, podem ser benéficos</td></tr><tr><td rowspan="1" colspan="1">Aconselhar aspectos nutricionais referentes à segurança alimentar e orientar o risco de transmissão de doenças por alimentos durante a imunossupressão</td></tr></tbody></table><table-wrap-foot><attrib>Fonte: Adaptado de Roberts S, Thompson J. Graft-vs-host disease: nutrition therapy in a challenging condition. Nutr Clin Pract. 2005;20(4):440-50.<sup>(</sup><xref rid="B29" ref-type="bibr"><sup>29</sup></xref><sup>)</sup>DECH: com doença do enxerto contra o hospedeiro.</attrib></table-wrap-foot></table-wrap></p></sec></sec><sec><title>COMPLICAÇÕES NUTRICIONAIS MAIS COMUNS NA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO</title><p>Devido à importância desse tema, tentaremos revisar a seguir as principais complicações nutricionais da DECH, tanto causadas por seu desenvolvimento quanto relacionadas à sua terapia. Os efeitos colaterais relacionados a aspectos nutricionais das principais medicações utilizadas para tratamento da DECH estão demonstrados na <xref rid="t7002" ref-type="table">tabela 7</xref> .</p><p><table-wrap id="t7002" orientation="portrait" position="float"><label>Tabela 7</label><caption><title>Principais medicações e terapias imunossupressoras utilizadas no tratamento da doença do enxerto contra o hospedeiro e seus efeitos colaterais nutricionais e metabólicos</title></caption><table frame="hsides" rules="groups"><colgroup width="33%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Medicação/terapia</th><th align="left" rowspan="1" colspan="1">Mecanismo de ação</th><th align="left" rowspan="1" colspan="1">Efeitos nutricionais e metabólicos</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Corticoides</td><td rowspan="1" colspan="1">Resposta anti-inflamatória, inibe IL-1, diminui IL-2 e suprime a proliferação de linfócitos</td><td rowspan="1" colspan="1">Retenção de sódio e água, hiperglicemia, hipercolesterolemia, aumento de apetite, ganho de peso, desmineralização óssea e efeitos musculares</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ciclosporina/tacrolimus</td><td align="left" valign="top" rowspan="1" colspan="1">Inibe proliferação/resposta de linfócitos T e altera produção de IL-2</td><td rowspan="1" colspan="1">Hipertensão, dislipidemia, hiperglicemia, hipomagnesemia, hipercalemia, nefrotoxicidade, neurotoxicidade, náuseas, vômitos, alterações do paladar e diarreia</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Metotrexato</td><td align="left" valign="top" rowspan="1" colspan="1">Antimetabólico e imunossupressor</td><td rowspan="1" colspan="1">Anorexia, náuseas, vômitos, diarreia, estomatite, mucosite, hepatotoxicidade e nefrotoxicidade</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Micofenolato de mofetila</td><td rowspan="1" colspan="1">Diminui a ativação linfocítica e a proliferação de células B e T; suprime a formação de anticorpos</td><td align="left" valign="top" rowspan="1" colspan="1">Náuseas, vômitos, diarreia, constipação, sangramento gastrintestinal e edema periférico</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Sirolimus</td><td rowspan="1" colspan="1">Inibe a proliferação de linfócitos B e T</td><td rowspan="1" colspan="1">Dislipidemia, hipertensão e edema periférico</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Talidomida</td><td rowspan="1" colspan="1">Propriedades imunossupressoras e anti-inflamatórias</td><td align="left" valign="top" rowspan="1" colspan="1">Neuropatia e constipação</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Globulina antitimócito (ATG)</td><td rowspan="1" colspan="1">Diminuição dos linfócitos circulantes</td><td rowspan="1" colspan="1">Dor abdominal, náuseas, vômitos, diarreia, hipercalemia, hipertensão e edema periférico</td></tr><tr><td rowspan="1" colspan="1">Etarnecept</td><td rowspan="1" colspan="1">Antagonista do TNF-α</td><td rowspan="1" colspan="1">Dor abdominal e vômitos</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ácido ursodesoxicólico</td><td rowspan="1" colspan="1">Substitui ácidos biliares nativos humanos; diminui a expressão de antígenos de HLA nos hepatócitos</td><td align="left" valign="top" rowspan="1" colspan="1">Náuseas, vômitos, diarreia e dor abdominal</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Daclizumabe</td><td rowspan="1" colspan="1">Anticorpo anti-IL-2</td><td rowspan="1" colspan="1">Vômitos, edema, hipertensão e hipotensão</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Azatioprina</td><td rowspan="1" colspan="1">Previne a proliferação citotóxica de linfócitos T e B por inibir a síntese de DNA e RNA</td><td align="left" valign="top" rowspan="1" colspan="1">Hipersensibilidade gastrintestinal, hepatotoxicidade, anemia megaloblástica e pancreatite</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hidroxicloroquina</td><td rowspan="1" colspan="1">Interfere no processamento de antígenos e na apresentação, proliferação, produção de TNF-α e citotoxicidade</td><td align="left" valign="top" rowspan="1" colspan="1">Náuseas, vômitos e diarreia</td></tr><tr><td rowspan="1" colspan="1">Infliximabe</td><td rowspan="1" colspan="1">Anticorpo anti-TNF-alfa.</td><td rowspan="1" colspan="1">Dor abdominal, náuseas, vômitos</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Psoralen e PUVA</td><td rowspan="1" colspan="1">Interfere na apresentação de antígenos e na produção de citocinas pró-inflamatórias</td><td align="left" valign="top" rowspan="1" colspan="1">Náuseas e hepatotoxicidade</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Fotoaférese extracorpórea</td><td rowspan="1" colspan="1">Induz apoptose de células T alorreativas, fotoinativação de células apresentadoras de antígenos</td><td align="left" valign="top" rowspan="1" colspan="1">Hipocalcemia (uso de citrato) e transtornos gastrintestinais</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ciclofosfamida</td><td rowspan="1" colspan="1">Atividade imunossupressora e bloqueio de crescimento celular por ligação de metabólitos ao DNA</td><td align="left" valign="top" rowspan="1" colspan="1">Anorexia, náuseas, vômitos e mucosite</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Rituximabe</td><td align="left" valign="top" rowspan="1" colspan="1">Anticorpo anti-CD20</td><td rowspan="1" colspan="1">Dor abdominal, diarreia, náuseas, vômitos, hipertensão e hiperglicemia</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Pentostatin</td><td align="left" valign="top" rowspan="1" colspan="1">Bloqueio da síntese de DNA</td><td rowspan="1" colspan="1">Náuseas, vômitos, fadiga, diarreia, anorexia e estomatite</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Imatinibe</td><td align="left" valign="top" rowspan="1" colspan="1">Inibição do PDGF-r</td><td rowspan="1" colspan="1">Náuseas, fadiga, diarreia, dor abdominal, vômito, ganho de peso, hepatotoxicidade, hiperglicemia e miopatia</td></tr></tbody></table><table-wrap-foot><attrib>Fonte: Adaptado de Roberts S, Thompson J. Clinical Observations Graft- vs -Host Disease : Nutrition Therapy in a Challenging Condition. Nutr Clin Pract. 2005;20:440-50.<sup>(</sup><xref rid="B29" ref-type="bibr"><sup>29</sup></xref><sup>)</sup>IL: interleucina; TNF-α: fator de necrose tumoral alfa; HLA: antígeno humano leucocitário; PUVA: psolaren + irradiação ultravioleta A; PDGF-r: receptor do fator de crescimento derivado de plaquetas.</attrib></table-wrap-foot></table-wrap></p></sec><sec><title>ALTERAÇÕES MECÂNICAS NO TRATO GASTRINTESTINAL</title><p>O TGI é envolvido na maioria dos pacientes com DECH, podendo acometer qualquer parte do tubo digestivo. Embora sejam mais raras, as alterações mecânicas e estruturais do trato digestivo merecem ser relatadas, devido à sua gravidade e à necessidade de abordagem precoce.<sup>( <xref rid="B62" ref-type="bibr">62</xref> )</sup></p><p>As complicações esofágicas são raras e incluem ulceração, varizes esofágicas e doença vesiculoide. As disfagias com severa estenose requerem dilatação esofágica.<sup>( <xref rid="B62" ref-type="bibr">62</xref> )</sup></p><p>Uma das complicações mais graves do intestino é a perfuração intestinal; no entanto, a mais frequente é a diarreia.<sup>( <xref rid="B63" ref-type="bibr">63</xref> )</sup></p></sec><sec><title>ALTERAÇÃO NA ABSORÇÃO DE NUTRIENTES</title><p>A alteração da absorção vista em pacientes com DECH pode estar associada a alterações hepáticas e pancreáticas. As alterações hepáticas podem ser decorrentes da excreção prejudicada de sais biliares, tendo importante papel no metabolismo lipídico.<sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup></p><p>As alterações pancreáticas já foram relatadas em autópsias de modelos experimentais, sendo associadas por acometimento da DECH; contudo, estas alterações, que podem incluir atrofia, também podem ser decorrentes de medicações como azatioprina, ciclosporina e corticoides.<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup>Os principais sintomas da insuficiência exócrina pancreática são esteatorreia, fadiga, dor abdominal, perda ponderal e flatulência. Tais sintomas estão mais frequentes no pós-transplante em pacientes com sinais de DECH, sendo mais frequentes entre graus mais avançados da doença.<sup>( <xref rid="B65" ref-type="bibr">65</xref> , <xref rid="B66" ref-type="bibr">66</xref> )</sup></p><p>Além da função pancreática, a DECH em intestino delgado também tem sido estudada como possível causa de alteração digestiva em pacientes pós-transplante. Além dos estudos endoscópicos por cápsula, um marcador que vem sendo testado é a citrulina. O intestino delgado é a principal fonte deste aminoácido em nosso organismo. Estudos prévios em pacientes sem DECH demonstraram correlação entre os níveis plasmáticos reduzidos de citrulina e dano intestinal.<sup>( <xref rid="B67" ref-type="bibr">67</xref> , <xref rid="B68" ref-type="bibr">68</xref> )</sup>Tais achados foram também descritos entre pacientes com DECH intestinal.<sup>( <xref rid="B69" ref-type="bibr">69</xref> )</sup>Esse aminoácido tem demonstrado ser promissor, ainda, na predição do desenvolvimento de DECH,<sup>( <xref rid="B70" ref-type="bibr">70</xref> )</sup>embora necessite de mais dados na literatura para seu uso na prática clínica.</p></sec><sec><title>DIARREIA E ENTEROPATIA PERDEDORA DE PROTEÍNAS</title><p>A diarreia é um dos principais sintomas da DECH de trato digestivo baixo. Contudo, sua etiologia nesta entidade é multifatorial, podendo incluir atrofia vilosa, ulceração de mucosa, disfunção secretória, fatores osmóticos, insuficiência pancreática e alteração do trânsito intestinal. Ela é frequentemente esverdeada, líquida, mucoide e pode ser de grande quantidade.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B71" ref-type="bibr">71</xref> )</sup></p><p>O dano do tecido gastrintestinal provocado pela DECH pode levar a diversos problemas, incluindo desidratação, perda de eletrólitos e enteropatia perdedora de proteínas. Tal situação é definida pelo aumento da alfa 1-antitripsina (>2,2mg/g de peso fecal seco) em amostras fecais e ocorre, especialmente, em pacientes com DECH de trato digestivo.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B35" ref-type="bibr">35</xref> )</sup></p><p>Papadopoulou et al., estudaram amostra de 47 pacientes submetidos ao TCTH, sendo 42 destes alogênicos. Eles encontraram que 91% dos episódios de diarreia estavam associados à enteropatia perdedora de proteína, e a quantidade de proteína perdida era mais severa entre pacientes com DECH (19,4mg/g) do que entre pacientes com outras causas de diarreia, como rotavírus, infecção por CMV ou causas incertas (6,7mg/g).<sup>( <xref rid="B35" ref-type="bibr">35</xref> )</sup></p><p>A quantidade de perda proteica também parece estar correlacionada com a gravidade da DECH, principalmente entre pacientes submetidos a condicionamentos mieloablativos.<sup>( <xref rid="B72" ref-type="bibr">72</xref> )</sup>Além disso, os pacientes com DECH costumam apresentar elevação persistente da quantidade de proteína perdida nas fezes, diferentemente do que acontece com indivíduos com outros transtornos diarreicos.<sup>( <xref rid="B34" ref-type="bibr">34</xref> )</sup></p></sec><sec><title>EFEITOS SOBRE APETITE</title><p>Além dos efeitos do regime de condicionamento e das medicações imunossupressoras e de suporte utilizadas, o desenvolvimento da DECH pode, por si só, ter efeito sobre o apetite. Malone et al., demonstraram maior ingestão oral entre pacientes sem DECH ou com DECH-a grau 1 comparado com os demais.<sup>( <xref rid="B73" ref-type="bibr">73</xref> )</sup>Os sintomas associados à DECH, sobretudo do trato digestivo, são relacionados como agentes causais da nutrição inadequada. No entanto, isso não é tão facilmente explicado. Parece que a própria atividade da DECH pode ter papel sobre a supressão do apetite.<sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup></p></sec><sec><title>ALTERAÇÕES NO METABOLISMO DE CARBOIDRATO E LIPÍDIOS</title><p>O controle glicêmico é importante durante o período pós-transplante. Hiperglicemia causa não somente impacto na função imune, mas também causa prejuízos em outros tecidos, como disfunção endotelial, elevação das citocinas pró-inflamatorias, catabolismos muscular e adiposo. Teoricamente, a hiperglicemia pode aumentar o nível de citocinas e o risco de doenças infecciosas, o que pode levar a um risco aumentado de DECH. Por outro lado, a DECH pode também, por meio de mecanismos inflamatórios, levar a um estado de hiperglicemia.<sup>( <xref rid="B74" ref-type="bibr">74</xref> )</sup>Além disso, os corticosteroides utilizados no tratamento da DECH possuem hiperglicemia como um dos efeitos colaterais mais comuns.<sup>( <xref rid="B29" ref-type="bibr">29</xref> )</sup></p><p>Com relação à dislipidemia, diversas medicações utilizadas no tratamento da DECH estão relacionadas ao desenvolvimento desta complicação ( <xref rid="t7002" ref-type="table">Tabela 7</xref> ). Contudo, não apenas as medicações imunossupressoras afetam a homestase lipídica. A DECH do fígado pode levar a elevações de colesterol e triglicerídeos, pela inabilidade dos sais biliares e colesterol serem excretados pelo duto biliar.<sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup>Ademais, a síndrome nefrótica, que pode ser uma complicação grave da DECH, também pode levar à dislipidemia significante.<sup>( <xref rid="B64" ref-type="bibr">64</xref> )</sup></p></sec><sec><title>PERDA DE MASSA MAGRA E MIOPATIA</title><p>A perda de massa magra é frequente entre pacientes com DECH e consequência das alterações nutricionais por ela ocasionadas. A terapia com corticosteroide influencia de forma significativa nessa complicação. O desenvolvimento de DECH-c parece ser fator de risco independente para a perda de massa corpórea magra, sendo maior a probabilidade entre aqueles com DECH extensa e naqueles que necessitaram de uso de corticosteroides.<sup>( <xref rid="B75" ref-type="bibr">75</xref> , <xref rid="B76" ref-type="bibr">76</xref> )</sup></p></sec><sec><title>INTERVENÇÃO NUTRICIONAL NA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO AGUDA E CRÔNICA</title><p>Os pacientes com DECH têm dificuldade para ingerir alimentos por várias razões, dependendo do órgão envolvido. Frequentemente, necessitam de modificações na dieta, suplementos orais e terapia de suporte nutricional (TSN), para prevenir ou tratar a desnutrição.<sup>( <xref rid="B77" ref-type="bibr">77</xref> )</sup></p><p>Segundo Bassim et al.,<sup>( <xref rid="B18" ref-type="bibr">18</xref> )</sup>as principais indicações para o início da TSN são náuseas e vômitos não controlados, diarreia volumosa, dor na mucosa oral e esofágica, disfagia, disgeusia, xerostomia, anorexia, saciedade precoce e perda de peso. Em especial, a DECH-a de TGI e a DECH-c oral, gastrintestinal e pulmonar produzem desnutrição grave e levam a um comprometimento da capacidade funcional e da qualidade de vida dos pacientes, daí a necessidade do início precoce de TSN.</p><p>A terapia nutricional é de extrema importância como suporte ao tratamento para combater os efeitos deletérios da DECH e contornar os efeitos adversos dos medicamentos.<sup>( <xref rid="B15" ref-type="bibr">15</xref> , <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B77" ref-type="bibr">77</xref> , <xref rid="B78" ref-type="bibr">78</xref> )</sup></p></sec><sec><title>MANEJO DE SINTOMAS POR MODIFICAÇÕES NUTRICIONAIS</title><p>De acordo com o Consenso de Nutrição Oncológica do Instituto Nacional do Câncer José de Alencar,<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup>algumas intervenções nutricionais podem ser orientadas para melhorar e controlar os sintomas gastrintestinais.</p><sec><title>Saciedade precoce</title><p>Conscientizar o paciente da importância da alimentação; realizar fracionamento da dieta (de seis a oito refeições/dia); modificar as fibras da dieta por meio de cocção e/ou trituração, para reduzir a saciedade (frutas sem casca, legumes e verduras cozidos, sopas e sucos liquidificados); aumentar a densidade calórica e proteica das refeições; não ingerir líquidos durante as refeições; utilizar carnes magras, cozidas, picadas, desfiadas ou moídas em porções reduzidas; evitar alimentos e preparações ricos em gorduras; e preferir bebidas não gaseificadas.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Diarreia</title><p>O fracionamento da dieta é importante, bem como reduzir o volume de alimentos por refeição; avaliar a restrição de lactose, sacarose, glúten, gordura, fibras insolúveis, cafeína e teína; aumentar a ingestão hídrica e de líquidos isotônicos para, no mínimo, 3L/dia; evitar alimentos flatulentos e hiperosmolares; e evitar temperaturas extremas.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Disfagia</title><p>Acompanhamento com o fonoaudiólogo, para adequada modificação da dieta; orientar o paciente quanto a cuidados com alimentos secos e duros, e preferir alimentos pastosos, de fácil mastigação e deglutição; ingerir pequenos volumes de líquidos junto às refeições, para facilitar a mastigação e a deglutição; e manter a cabeceira elevada para alimentar-se.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Xerostomia</title><p>O consumo de, no mínimo, 2L/dia de água e líquidos em geral até 3L/dia é necessário; estimular a ingestão de alimentos mais prazerosos; adequar a consistência dos alimentos conforme a aceitação do paciente; evitar o consumo de café, chá e refrigerantes que contenham cafeína; manter higiene oral e hidratação labial; utilizar gotas de limão nas saladas e bebidas; se necessário, ingerir líquidos junto às refeições, para facilitar a mastigação e a deglutição; uso de balas cítricas e mentoladas sem açúcar; temperar os alimentos com ervas aromáticas, evitando sal e condimentos em excesso; mastigar e chupar gelo feito de água, água de coco e suco de frutas ou picolés.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Náuseas e vômitos</title><p>É necessário orientar uma alimentação fracionada em pequenos volumes; dar preferência a alimentos mais secos, cítricos, salgados e frios ou gelados; manter a higiene oral; não realizar jejuns prolongados; chupar gelo 40 minutos antes das refeições; não comer frituras e alimentos gordurosos; evitar alimentos e preparações que exalem odor forte e de sabor muito doce; procurar realizar as refeições em locais arejados; não ingerir líquidos durante as refeições, utilizando-os em pequenas quantidades nos intervalos, preferencialmente gelados (por exemplo, picolé); não deitar logo após as refeições; e utilizar gengibre pelo seu efeito antiemético, por meio de infusão, como tempero ou adicionado a sucos.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Anorexia</title><p>O paciente deve ser orientado acerca da importância de uma ingestão alimentar adequada; fracionamento da dieta e volume reduzido; maior densidade calórica e proteica das refeições; consumir alimentos com melhor tolerância e consistência, conforme preferências do paciente.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Odinofagia</title><p>A consistência da dieta deve ser modificada conforme a tolerância; melhorar a densidade calórica e proteica das refeições; boa higiene oral; não consumir alimentos secos, duros, cítricos, salgados, picantes e condimentados; evitar temperaturas extremas.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec><sec><title>Dieta oral</title><p>Nos envolvimentos leves da cavidade oral, deve-se evitar o consumo de alimentos ácidos; em casos mais graves com estenose de esôfago, a consistência e a temperatura da dieta devem ser modificadas, dando preferência para forma líquida ou liquidificada, servidas em temperatura moderada ou ambiente.<sup>( <xref rid="B21" ref-type="bibr">21</xref> , <xref rid="B74" ref-type="bibr">74</xref> )</sup></p><p>Durante o tratamento com altas doses de glicocorticoides e/ou inibidores de calcineurina é importante a orientação adequada ao paciente. São recomendadas refeições frequentes e fracionadas, alimentação rica em fibras solúveis e insolúveis, dieta hiperproteica, com redução de carboidratos simples e de alto índice glicêmico, redução de sódio, boa ingestão hídrica e consumo adequado de alimentos-fontes de vitamina D, cálcio, magnésio, zinco e, se necessário, a suplementação destes elementos.<sup>( <xref rid="B79" ref-type="bibr">79</xref> , <xref rid="B80" ref-type="bibr">80</xref> )</sup></p></sec><sec><title>Suplementos orais</title><p>Independentemente do tipo e do grau da DECH, quando o paciente apresenta ingestão alimentar abaixo de 70% das necessidades energéticas nos últimos 3 dias e sintomas que prejudiquem a alimentação adequada é importante intervir com o uso de suplementos nutricionais hipercalóricos e hiperproteicos (adaptados de acordo com a liberação e a fase da dieta restrita, no caso de DECH intestinal). A suspensão do suplemento nutricional via oral é indicada somente na presença de instabilidade hemodinâmica, esofagite ou mucosite grave que impeçam a ingestão oral adequada, obstrução do TGI, vômitos incoercíveis, risco de broncoaspiração, recusa do paciente e intolerância ao suplemento.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p></sec></sec><sec><title>NUTRIÇÃO ENTERAL</title><p>Caso a ingestão alimentar esteja abaixo de 60% das necessidades energéticas nos últimos 3 dias ou a via oral estiver contraindicada, a NE pode ser prescrita.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup>A via enteral, se tolerável e clinicamente possível, pode ser escolhida por manter a função digestiva e a integridade da barreira mucosa, prevenindo a translocação bacteriana no trato digestivo.<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>De acordo com a <italic>American Society for Parental and Enteral Nutrition</italic> ,<sup>( <xref rid="B77" ref-type="bibr">77</xref> )</sup>quando a contagem de neutrófilos e a de plaquetas estão dentro da normalidade e o TGI está cicatrizado, a NE é segura para transição da terapia nutricional parenteral para dieta oral ou quando há necessidade de TSN no caso de DECH, entre outras complicações tardias do TCTH.</p><p>Segundo revisão sistemática realizada por Baumgartner et al.,<sup>( <xref rid="B15" ref-type="bibr">15</xref> )</sup>vários estudos têm comparado a NE com TNP, mostrando resultados superiores para a via enteral e moderada a alta tolerância à sonda, sendo a TNP recomendada somente em casos de insuficiência gastrintestinal. A NE é contraindicada na presença de instabilidade hemodinâmica e/ou piora da dor abdominal, distensão abdominal, mucosite, diarreia, vômitos incoercíveis, íleo paralítico e sangramento intestinal.<sup>( <xref rid="B21" ref-type="bibr">21</xref> )</sup></p><p>Existem fortes evidências indicando que a introdução precoce de NE pode diminuir tanto a incidência quanto a gravidade da DECH-TGI, podendo ser uma forma de profilaxia. Além disso, a NE está associada a uma menor mortalidade relacionada a infecções e a períodos mais curtos de enxertia de neutrófilos.<sup>( <xref rid="B81" ref-type="bibr">81</xref> )</sup></p></sec><sec><title>DIETA PARENTERAL</title><p>A TNP também pode ser indicada para pacientes que apresentam aceitação da dieta oral inferior a 60% a 70% das necessidades nutricionais por 3 dias consecutivos,<sup>( <xref rid="B82" ref-type="bibr">82</xref> )</sup>ou, ainda, em pacientes com défice energético-proteico, com uso exclusivo de NE.<sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup></p><p>As diretrizes da ESPEN recomendam dieta oral ou enteral, desde que sejam possíveis, mas, no caso de vômitos, diarreia incoercível, mucosite grave ou má absorção importante, a TNP deve ser a via preferencial.<sup>( <xref rid="B36" ref-type="bibr">36</xref> )</sup></p><p>Estudos demonstram que pacientes com DECH graus III-IV recebem mais TNP que pacientes com DECH graus I-II, não estando isentos de apresentarem complicações clínicas, relacionadas com a progressão do número de dias que recebem a TNP.<sup>( <xref rid="B84" ref-type="bibr">84</xref> )</sup></p><p>É importante salientar alguns cuidados com a prescrição e o acompanhamento da TNP. Pacientes desnutridos, com risco de síndrome de realimentação, devem receber aporte energético progressivo, na fase inicial (primeiro ao terceiro dia), com 20% das necessidades energéticas basais. A oferta proteica pode ser oferecida desde o início, respeitando as funções renais e hepáticas. O controle glicêmico deve ser realizado respeitando níveis de glicemia menores que 180mg/dL e com a prevenção de hipertrigliceridemia, mantendo nível sérico inferior a 400mg/dL.<sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup>Além do acompanhamento da função hepática, com dosagem de AST, ALT, gama glutamil transferase, fosfatase alcalina e bilirrubina duas vezes por semana, devem ser incluídos nos exames de rotina ureia, creatinina, dosagem sérica de eletrólitos (potássio, magnésio, fósforo, cálcio e sódio), colesterol total e frações. O desmame da TNP deve ser gradativo, respeitando a oferta e a aceitação da dieta oral ou enteral pelo paciente.<sup>( <xref rid="B83" ref-type="bibr">83</xref> )</sup></p><sec><title>Manejo nutricional na doença do enxerto contra o hospedeiro intestinal</title><p>A avaliação nutricional dos pacientes acometidos por essa complicação pode ser muito difícil, visto que muitos apresentam retenção de líquidos relacionados a baixos níveis de albumina sérica, o que mascara a perda de peso corporal. Além disso, o tratamento padrão da DECH-TGI é corticoterapia, que tem efeitos diretos na composição corporal, levando a aumento da gordura corporal, diminuição da massa magra, retenção hídrica e de sódio, hipertrigliceridemia, hipercolesterolemia, sarcopenia e desmineralização óssea, podendo mascarar o estado nutricional dos pacientes.<sup>( <xref rid="B25" ref-type="bibr">25</xref> )</sup></p><p>Os objetivos da terapia nutricional na DECH-TGI são fornecer o suporte nutricional adequado e individualizado para manter ou recuperar o estado nutricional do paciente, controlar os sintomas, reestabelecer a integridade da mucosa intestinal, satisfazer o paciente e lhe promover qualidade de vida, sempre que possível.<sup>( <xref rid="B25" ref-type="bibr">25</xref> , <xref rid="B85" ref-type="bibr">85</xref> )</sup></p></sec></sec><sec><title>TERAPIA NUTRICIONAL NA DOENÇA DO ENXERTO CONTRA O HOSPEDEIRO INTESTINAL</title><sec><title>Dieta oral</title><p>No <italic>National Cancer Center Japan</italic> , realizou-se um estudo com a terapia nutricional escalonada com protocolo próprio, tendo sido observado que o estado nutricional dos pacientes tende a melhorar com esse tipo de terapia; porém, não foi observada melhora na evolução do grau da DECH-TGI.<sup>( <xref rid="B86" ref-type="bibr">86</xref> )</sup></p><p>No <italic>Seattle Cancer Care Alliance</italic> , de acordo com o guia para médicos, a terapia nutricional também é baseada nesse tipo de terapia nutricional escalonada, e a evolução da dieta do paciente ocorre de acordo com sua tolerância e sintomas apresentados.<sup>( <xref rid="B87" ref-type="bibr">87</xref> )</sup></p><p>O uso de suplementos orais artesanais ou industrializados pode se dar a partir da etapa 2, quando a ingestão alimentar não atingir as necessidades nutricionais recomendadas, devendo seguir as mesmas características da dieta da etapa correspondente e a vontade do paciente.</p><p>Baseado nessa literatura segue a <xref rid="t8002" ref-type="table">tabela 8</xref> , na qual a terapia nutricional do paciente deve alterada de acordo com os sintomas, a evolução clínica e sua tolerância; se, ao passar para uma etapa subsequente, o paciente não tolerar a alteração da dieta, esta deve ser regredida para a etapa anterior.</p><p><table-wrap id="t8002" orientation="portrait" position="float"><label>Tabela 8</label><caption><title>Progressão escalonada da terapia nutricional de pacientes acometidos por doença do enxerto contra o hospedeiro intestinal</title></caption><table frame="hsides" rules="groups"><colgroup width="33%" span="1"><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th align="left" rowspan="1" colspan="1">Etapa</th><th align="left" rowspan="1" colspan="1">Sintomas</th><th align="left" rowspan="1" colspan="1">Terapia nutricional</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">1. Repouso intestinal</td><td rowspan="1" colspan="1">Grande volume de diarreia aquosa (acima de 1.000mL/dia); cólicas intestinais; depleção da albumina sérica; diminuição do trânsito intestinal; obstrução intestinal; náuseas e vômito</td><td align="left" valign="top" rowspan="1" colspan="1">Somente TNP</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">2. Introdução de alimentação oral/enteral</td><td rowspan="1" colspan="1">Volume de diarreia menor que 500mL/dia; diminuição das cólicas intestinais; melhora do tempo de trânsito intestinal; diminuição das náuseas e vômitos</td><td align="left" valign="top" rowspan="1" colspan="1">TNP + dieta oral/enteral com características: líquida isosmótica, sem resíduos, sem lactose, sem ácidos e hipogordurosa</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">3. Introdução de alimentos sólidos</td><td align="left" valign="top" rowspan="1" colspan="1">Ausência ou diminuição das cólicas e fezes mais consistentes</td><td rowspan="1" colspan="1">Dieta oral/enteral com características: alimentos sólidos, sem resíduos, sem lactose, hipogordurosa e sem ácidos e irritantes gástricos</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">4. Expansão da dieta</td><td align="left" valign="top" rowspan="1" colspan="1">Ausência ou diminuição das cólicas e fezes mais consistentes</td><td rowspan="1" colspan="1">Dieta oral/enteral (se necessário, de acordo com a individualidade do paciente) com características: pobre em fibras, lactose, ácidos, irritantes gástricos e gordura de acordo com tolerância do paciente</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">5. Introdução da dieta habitual do paciente</td><td align="left" valign="top" rowspan="1" colspan="1">Ausência de cólicas e fezes em consistência normal</td><td rowspan="1" colspan="1">Dieta oral com características: introdução gradual e de acordo com a tolerância do paciente de alimentos ácidos, irritantes gástricos, com fibras, lactose e gordura</td></tr></tbody></table><table-wrap-foot><attrib>Fonte: Adaptado de Fred Hutchinson Cancer Research Center. Long-term follow-up after hematopoietic stem cell transplant. Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance [Internet]. Seattle, WA; 2014 [citado 25 Jun 2019]. Disponível em: https://www.fredhutch.org/content/dam/public/Treatment-Suport/Long-Term-Follow-Up/physician.pdf;<sup>(</sup><xref rid="B80" ref-type="bibr"><sup>80</sup></xref><sup>)</sup>Gauvreau JM, Lenssen P, Cheney CL, Aker SN, Hutchinson ML, Barale KV. Nutritional management of patients with intestinal graft- <italic>versus</italic> -host disease. J Am Diet Assoc. 1981;79(6):673-7.<sup>(</sup><xref rid="B88" ref-type="bibr"><sup>88</sup></xref><sup>)</sup>TNP: terapia de nutrição parenteral.</attrib></table-wrap-foot></table-wrap></p></sec><sec><title>Dieta parenteral</title><p>Os pacientes com DECH-TGI na fase aguda e inicial da doença geralmente apresentam volume de diarreia >1.000mL/dia, inviabilizando a nutrição por via oral ou enteral, suficiente para suprir suas necessidades nutricionais mínimas. Isso pode durar dias ou semanas. Desse modo, a terapia nutricional mais indicada seria o repouso do TGI com jejum e uso da terapia nutricional por via parenteral.<sup>( <xref rid="B28" ref-type="bibr">28</xref> )</sup></p><p>A abordagem mais tradicional no manejo nutricional na DECH-TGI tem sido a administração de TNP e o início da ingestão oral após a recuperação dos sintomas do TGI. Porém, devido ao tempo prolongado de uso da TNP, ocorrem danos à mucosa intestinal, induzindo a atrofia e mais disfunções intestinais.</p></sec><sec><title>Dieta enteral</title><p>A introdução da dieta oral ou NE a partir da etapa 2 deve acontecer após redução do volume de diarreia para menos que 500mL/dia; diminuição das cólicas intestinais; melhora do tempo de trânsito intestinal; diminuição das náuseas e vômitos. Essa introdução gradativa deve ser priorizada, pois auxilia na manutenção do trofismo intestinal, ajudando a preservar a barreira mucosa, e a imunidade local e sistêmica, e, também, a evitar translocação bacteriana.<sup>( <xref rid="B13" ref-type="bibr">13</xref> )</sup></p><p>A escolha pela via oral, enteral ou concomitante durante as etapas de evolução da terapia nutricional se dá de acordo com os sintomas, a possibilidade de alimentação por via oral e nas situações em que a dieta oral for inadequada para alcançar as necessidades nutricionais.</p><p>A NE, se escolhida como via de nutrição ou de suplementação, deve seguir as características de cada etapa. A partir da etapa 2, o paciente não tolera grandes volumes de dieta oral e/ou enteral, de forma que a TNP não precisa ser suspensa, a fim de suprir todas as necessidades nutricionais do paciente.</p><p>Estudos mostram que o uso de NE na DECH-TGI, em comparação ao uso da TNP, por preservar o trofismo intestinal, melhorar a função da barreira do intestino e, assim, diminuir o risco de translocação bacteriana, reduz as complicações infecciosas.<sup>( <xref rid="B89" ref-type="bibr">89</xref> , <xref rid="B90" ref-type="bibr">90</xref> )</sup>Porém, historicamente, os centros de transplante preferem a TNP à NE, dificultando seu uso precoce ou durante o TCTH.</p></sec></sec><sec><title>A IMPORTÂNCIA DA MICROBIOTA NO TRANSPLANTE DE CÉULAS-TRONCO HEMATOPOIÉTICAS</title><sec><title>Microbiota intestinal</title><p>O TGI humano pode ser povoado por até 100 trilhões de bactérias (para comparação, o número de células no corpo humano é estimado em 10 trilhões), além de vírus e fungos presentes também em considerável número e diversidade, e que podem pertencer a aproximadamente mil espécies diferentes em um único indivíduo; já foram identificadas mais de 15 mil espécies diferentes em amostras derivadas de TGI humanos.<sup>( <xref rid="B91" ref-type="bibr">91</xref> )</sup></p><p>O sistema imunológico do TGI é a primeira linha de defesa contra microrganismos e outras substâncias ingeridas, e evoluiu não apenas para a proteção contra potenciais patógenos, mas, também, para tolerar bactérias comensais que possuem um papel benéfico na homeostase, permitindo simbiose com a microbiota intestinal. O sistema imunológico gastrintestinal mantém a barreira mucosa por meio da secreção de peptídeos e anticorpos antimicrobianos, e a microbiota comensal participa da fisiologia intestinal do hospedeiro.<sup>( <xref rid="B92" ref-type="bibr">92</xref> , <xref rid="B93" ref-type="bibr">93</xref> )</sup></p><p>A exposição intestinal a bactérias está relacionada ao recrutamento de linfócitos T regulatórios (Tregs).<sup>( <xref rid="B94" ref-type="bibr">94</xref> , <xref rid="B95" ref-type="bibr">95</xref> )</sup>As células Tregs são fundamentais para o desenvolvimento de uma resposta imunológica apropriada a antígenos dentro do TGI, mas também influenciam na imunidade sistêmica.<sup>( <xref rid="B96" ref-type="bibr">96</xref> , <xref rid="B97" ref-type="bibr">97</xref> )</sup></p><p>As bactérias intestinais são responsáveis pela quebra de fibras da dieta, sendo também importantes para a produção de uma série de metabólitos com funções na fisiologia intestinal. Os mais bem conhecidos destes metabólitos são os ácidos graxos de cadeias curtas (SCFAs - <italic>short chain fatty acids</italic> ), como o butirato, o propionato e o acetato, que servem como fontes de energia para as células epiteliais intestinais e induzem respostas imunológicas regulatórias de proteção tanto localmente no TGI quanto sistemicamente.<sup>( <xref rid="B98" ref-type="bibr">98</xref> , <xref rid="B99" ref-type="bibr">99</xref> )</sup></p></sec><sec><title>Disbiose</title><p>A quimioterapia e os regimes de condicionamento alteram a composição da microbiota intestinal, provocando a redução de <italic>Clostridium clusters</italic> XIV e bifidobactérias, e o aumento de <italic>Enterococcus</italic> . Essa alteração da microbiota é chamada disbiose.<sup>( <xref rid="B100" ref-type="bibr">100</xref> - <xref rid="B102" ref-type="bibr">102</xref> )</sup></p><p>Um estudo específico com pacientes submetidos ao TCTH encontrou níveis aumentados de proteobactérias, incluindo espécies de <italic>Escherichia</italic> e redução dos níveis de <italic>Firmicutes</italic> , incluindo espécies de <italic>Blautia</italic> após a quimioterapia.<sup>( <xref rid="B102" ref-type="bibr">102</xref> )</sup></p><p>Entretanto, a relação causal entre quimioterapia e microbiota é difícil de ser estabelecida, pois muitos dos pacientes estudados receberam antibióticos profiláticos concomitantemente com a quimioterapia.</p></sec><sec><title>Microbiota intestinal e doença do enxerto contra o hospedeiro</title><p>A microbiota intestinal normal apresenta grande diversidade e é dominada por bactérias anaeróbias.<sup>( <xref rid="B103" ref-type="bibr">103</xref> )</sup>Durante a internação, muitos pacientes submetidos ao TCTH perdem esta diversidade, e as mudanças que ocorrem são influenciadas tanto pelos tratamentos antimicrobianos quanto pelo desenvolvimento de DECH.<sup>( <xref rid="B104" ref-type="bibr">104</xref> - <xref rid="B106" ref-type="bibr">106</xref> )</sup></p><p>O impacto da microbiota sobre a DECH foi inicialmente proposto nos anos 1970, após demonstração de que camundongos mantidos em condições livres de germes desenvolviam menos DECH de TGI.<sup>( <xref rid="B107" ref-type="bibr">107</xref> , <xref rid="B108" ref-type="bibr">108</xref> )</sup>Estudos clínicos subsequentes que evidenciaram resultados promissores na descontaminação intestinal de pacientes transplantados<sup>( <xref rid="B109" ref-type="bibr">109</xref> , <xref rid="B110" ref-type="bibr">110</xref> )</sup>não foram confirmados em pesquisas posteriores.<sup>( <xref rid="B111" ref-type="bibr">111</xref> , <xref rid="B112" ref-type="bibr">112</xref> )</sup></p><p>Amplo estudo prospectivo focando a descontaminação de bactérias anaeróbicas evidenciou redução no desenvolvimento de DECH, indicando que a descontaminação seletiva poderia ter efeitos benéficos.<sup>( <xref rid="B113" ref-type="bibr">113</xref> )</sup></p><p>A perda da diversidade intestinal observada em pacientes submetidos ao TCTH é geralmente associada à perda de espécies de <italic>Clostridium</italic> , que reconhecidamente produzem ácidos graxos de cadeia curta a partir das fibras da dieta.<sup>( <xref rid="B114" ref-type="bibr">114</xref> )</sup></p><p>O butirato é a fonte de energia preferencial das células epiteliais intestinais, e um estudo sugere que quantidades reduzidas de butirato são encontradas nas células epiteliais intestinais de camundongos submetidos ao TCTH, e a adição destes ácidos graxos reduz as lesões intestinais e o desenvolvimento de DECH.<sup>( <xref rid="B115" ref-type="bibr">115</xref> )</sup></p><p>Estes achados são reproduzidos pela administração de espécies variadas de bactérias produtoras de butirato pertencentes à classe <italic>Clostridia</italic> , e estudo clínico demonstrou que a abundância intestinal de bactérias do gênero <italic>Blautia</italic> , da classe <italic>Clostridia</italic> , correlaciona-se com risco reduzido de mortalidade devido à DECH.<sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup></p><p>A administração de antibióticos para tratamento da neutropenia febril é, provavelmente, o principal fator que afeta as mudanças da microbiota observadas na evolução dos pacientes transplantados, e a escolha do regime de antibioticoterapia utilizado influencia na incidência de DECH. A administração de imipenem-cilastatina e piperacilina-tazobactam foi associada a maior mortalidade relacionada à DECH em 5 anos de seguimento, em um estudo retrospectivo.<sup>( <xref rid="B117" ref-type="bibr">117</xref> )</sup>Este mesmo estudo não demonstrou a associação entre metronidazol e redução de DECH reportado anteriormente,<sup>( <xref rid="B113" ref-type="bibr">113</xref> )</sup>o que pode ser devido a inúmeros fatores, incluindo o uso de combinações diferentes de antibióticos entre os estudos, bem como diferenças culturais e geográficas, que podem influenciar na flora intestinal.</p><p>A microbiota intestinal pode não apenas predispor a DECH, mas também atuar na recuperação e até na prevenção da doença. Os danos intestinais causados pelos regimes de condicionamento provocam aumento na permeabilidade intestinal que permite a translocação de bactérias por meio da barreira entérica. Como consequência, a estimulação imunológica por uma série de patógenos e moléculas associadas, como os lipopolissacarídeos e o peptidoglicano bacterianos, reforça a resposta inflamatória mediada por citocinas, propiciando o cenário ideal para a ativação alogênica dos linfócitos T.</p><p>O grau de perda da diversidade da microbiota intestinal é um fator de risco para a mortalidade relacionada ao transplante (MRT), incluindo a mortalidade por DECH, infecções e falências orgânicas após TCTH.<sup>( <xref rid="B118" ref-type="bibr">118</xref> )</sup></p></sec></sec><sec><title>NUTRIÇÃO A MICROBIOTA</title><p>O uso de TNP reduz o montante de nutrientes que alcança o epitélio intestinal, e, dessa maneira, algumas das alterações na microbiota observada durante o TCTH podem decorrer da quantidade insuficiente de nutrientes no TGI para manter uma flora equilibrada.<sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup></p><p>O estudo que evidenciou associação entre a redução de <italic>Blautia</italic> e a DECH também mostrou correlação entre este achado e prolongada TNP.<sup>( <xref rid="B116" ref-type="bibr">116</xref> )</sup>Estes achados sugerem que NE, ao contrário da TNP, pode exercer efeito benéfico na flora intestinal pós-TCTH e, talvez, acelerar a recuperação do paciente.</p><sec><title>Uso de probióticos e prebióticos</title><p>Uma atenção crescente tem sido dada ao potencial de probióticos e prebióticos na prevenção e no tratamento da disbiose intestinal. Os probióticos são suplementos nutricionais que contêm quantidade definida de microrganismos viáveis, cuja administração pode conferir benefícios ao paciente,<sup>( <xref rid="B119" ref-type="bibr">119</xref> )</sup>enquanto os prebióticos consistem em ingredientes alimentares não digeríveis (por exemplo, fibras não digeríveis), que favorecem o crescimento de bactérias benéficas.<sup>( <xref rid="B119" ref-type="bibr">119</xref> )</sup></p><p>Até pouco tempo atrás, o uso de probióticos em indivíduos imunossuprimidos era totalmente proscrito, pois se acreditava que os mesmos, por serem bactérias vivas, poderiam causar doenças infecciosas graves. Porém, esse conceito vem sendo gradualmente modificado por vários estudos que demonstram, inicialmente, sua segurança nesse perfil de pacientes, além de potenciais efeitos de melhor prognóstico.</p><p>De maneira geral, vários estudos demonstram que o uso de probióticos em diversas condições clínicas - como nas doenças inflamatórias intestinais - é seguro pelo fato de serem indivíduos imunossuprimidos e também por estar relacionado à redução da resposta inflamatória sistêmica e local, por meio de adequada resposta imune; portanto, a indicação para o uso de probióticos em pacientes submetidos ao TCTH alogênico baseia-se nesta condição.<sup>( <xref rid="B120" ref-type="bibr">120</xref> , <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>Sabe-se que estes microrganismos podem inibir a atuação de patógenos externos; e melhoram a função de barreira intestinal, aumentando a produção de muco e de peptídeos com propriedades bactericidas, melhorando a estrutura das junções celulares entre os enterócitos e prevenindo apoptose celular precoce.<sup>( <xref rid="B120" ref-type="bibr">120</xref> , <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>Uma das cepas que mais tem sua segurança comprovada é o <italic>Lactobacillus plantarum</italic> (LPB). Além da segurança, também comprova-se <italic>in vitro</italic> que seu uso pré-TCTH diminui gravidade e mortalidade por DECH.<sup>( <xref rid="B104" ref-type="bibr">104</xref> )</sup></p><p>Segundo Coehn et al., a análise retrospectiva de prontuários de 3.796 pacientes submetidos ao TCTH no período de 2002 a 2011, com o intuito de identificar infecção de corrente sanguínea por agentes probióticos ( <italic>Lactobacillus, Bifidobacterium, Streptococcus thermophilus</italic> e <italic>Saccharomyces</italic> ), evidenciou que apenas 0,5% (n=19) desenvolveu esta condição 1 ano após o transplante, sendo que, dos 19 doentes, 74% receberem TCTH alogênico, sendo 98% de infecção de corrente sanguínea por <italic>Lactobaccilus</italic> .<sup>( <xref rid="B121" ref-type="bibr">121</xref> )</sup></p><p>Em 2004, Gerbitz et al., demonstraram em estudo experimental em ratos que o grupo tratado com <italic>Lactobacillus rhamnosus</italic> teve menor mortalidade que o grupo controle, principalmente no pós-TCTH recente (7 a 14 dias após infusão das células), além de apresentar manifestações mais brandas da DECH.<sup>( <xref rid="B122" ref-type="bibr">122</xref> )</sup></p><p>Em 2015, Laval et al., publicaram outro estudo <italic>in vitro</italic> , considerando tanto a hipótese de que a permeabilidade das células intestinais está aumentada em várias doenças inflamatórias intestinais e inclusive na DECH, quanto a já comprovada teoria de que determinadas cepas probióticas podem aumentar a integridade intestinal. Nesse estudo, demonstram que o uso de <italic>Lactobacillus rhamnosus</italic> pode restaurar parcialmente a função de barreira dos enterócitos e também aumentar a produção de dipeptídeos protetores da mucosa intestinal.<sup>( <xref rid="B123" ref-type="bibr">123</xref> )</sup></p><p>Em 2017, Gorshein et al., demonstraram, em estudo com 31 pacientes submetidos a TCTH alogênico que receberam <italic>Lactbacillus rhamnosus</italic> na dose diária de 10 bilhões de cepas, que seu uso é seguro e sem correlação com complicações infecciosas graves; porém, não foi evidenciada diferença estatística na morbimortalidade em ambos os grupos.<sup>( <xref rid="B124" ref-type="bibr">124</xref> )</sup></p><p>Segundo Ladas et al., o uso de LPB é submetido à rigorosa análise microbiológica e, por isso, comprovadamente descontaminado, na dose de 1×108 colônias ofertada do dia -7 até o dia +14. Em estudo envolvendo 31 crianças e adolescentes (2 a 17 anos) submetidos ao TCTH alogênico com regime de condicionamento mieloablativo mostrou-se seguro, de forma que não foi observado episódio de bacteremia por LPB, bem como nenhuma outra complicação grave relacionada ao uso do LPB.<sup>( <xref rid="B125" ref-type="bibr">125</xref> )</sup></p><p>Ainda segundo Ladas et al., 70% dos pacientes não desenvolveram DECH-a no d+100 e nenhum dos pacientes que vieram a óbito no d+100 desenvolveu DECH-a. Dos 30% que desenvolveram DECH-a, nenhum paciente apresentou gravidade máxima (grau 4).<sup>( <xref rid="B125" ref-type="bibr">125</xref> )</sup></p><p>Embora o uso destes tratamentos pareça promissor, são necessários mais estudos clínicos para estabelecer a segurança e a eficácia dessas terapias. Um importante aspecto na eficácia do tratamento probiótico reside na capacidade de os microrganismos ingeridos sobreviverem ao ambiente ácido do estômago e do intestino delgado. Muitas cepas de lactobacilos, incluindo os mais comumente presentes em laticínios comuns, são sensíveis ao baixo pH gastrintestinal e não puderam ser reisolados em amostras fecais após administração em humanos,<sup>( <xref rid="B126" ref-type="bibr">126</xref> )</sup>dificultando a interpretação de sua eficácia.</p><p>O uso de probióticos e prebióticos no TCTH ainda não é recomendado de forma rotineira.</p></sec></sec><sec><title>TRANSPLANTE DE MICROBIOTA FECAL</title><p>O transplante de microbiota fecal (TMF) pode ser utilizado para restaurar uma flora intestinal danificada. Um estudo com pequena série de pacientes com DECH refratária ou dependente de corticosteroides apresentou resultados promissores;<sup>( <xref rid="B127" ref-type="bibr">127</xref> )</sup>no entanto, estudos maiores e mais bem controlados são necessários para determinar a eficácia do TMF no tratamento da DECH.</p><p>O TMF para o tratamento de infecções por <italic>Clostridium difficile</italic> resistentes já é uma técnica bem descrita em diversas populações.<sup>( <xref rid="B128" ref-type="bibr">128</xref> )</sup>Seu uso ainda é modesto no contexto de pacientes pós-transplante, e uma das experiências pioneiras foi feita no Brasil, sem que houvesse maiores complicações.<sup>( <xref rid="B129" ref-type="bibr">129</xref> )</sup>Desde então, outros casos já foram relatados com sucesso, utilizando doadores familiares ou não, e usando alguns métodos, como enteroscopia retrógrada ou a ingestão de cápsulas que se abrem somente no jejuno, liberando a nova microbiota.<sup>( <xref rid="B130" ref-type="bibr">130</xref> )</sup></p><p>No momento da publicação deste consenso, o TMF para fins de imunomodulação e tratamento da DECH é algo promissor, mas que só deve ser feito dentro de estudos clínicos bem delineados. É necessário entender quais componentes da microbiota são desejáveis, assim como saber qual seria o melhor momento de realizar esse tipo de intervenção. Já seu uso no tratamento de infecções por <italic>Clostridium difficile</italic> , embora careça de ensaios randomizados e grandes séries de casos nesse grupo de pacientes, pode ser considerado em situações especiais, já que, até o momento, não foram relatadas complicações.</p></sec><sec><title>UM ORGANOGRAMA PRÁTICO</title><p>Abaixo as <xref ref-type="fig" rid="f01002">figuras 1</xref> e <xref ref-type="fig" rid="f02002">2</xref> resumem de modo prático as condutas nutricionais na DECH.</p><p><fig id="f01002" orientation="portrait" position="float"><label>Figura 1</label><caption><title>Planejamento nutricional ao transplante de celulas-tronco hematopoiéticas</title><p>TCTH: transplante de celulas-tronco hematopoiéticas; TNO: terapia de nutrição oral; TNE: terapia de nutrição enteral; TNP: terapia de nutrição parenteral.</p></caption><graphic xlink:href="2317-6385-eins-18-eAE4799-gf01-pt"></graphic></fig></p><p><fig id="f02002" orientation="portrait" position="float"><label>Figura 2</label><caption><title>Planejamento nutricional da doença do enxerto contra o hospedeiro do trato gastrintestinal</title><p>DECH: doença do enxerto contra o hospedeiro; TGI: trato gastrintestinal.</p></caption><graphic xlink:href="2317-6385-eins-18-eAE4799-gf02-pt"></graphic></fig></p></sec></body></sub-article></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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