Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- <i>versus</i> -host disease

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:
pereira.andrea2@einstein.br

Conflict of interest: none.

Hospital Israelita Albert Einstein , São Paulo , SP , Brazil .

Universidade Estadual de Campinas , Campinas , SP , Brazil .

Universidade Federal da Bahia , Salvador , BA , Brazil .

Hospital de Câncer de Barretos, Barretos , SP , Brazil .

Hospital Sírio-Libanês , São Paulo , SP , Brazil .

Fundação Hospital Amaral Carvalho , Jaú , SP , Brazil .

Complexo Hospitalar Universitário Professor Edgard Santos , Universidade Federal da Bahia , Salvador , BA , Brazil .

Santa Casa de Misericórdia de Porto Alegre , Porto Alegre , RS , Brazil .

Universidade Federal de São Paulo , São Paulo , SP , Brazil .

Instituto Brasileiro de Controle do Câncer , São Paulo , SP , Brazil .

Hospital São Luiz , São Paulo , SP , Brazil .

Oncobio , Nova Lima , MG , Brazil .

Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA, Rio de Janeiro , RJ , Brazil .

Seattle Cancer Care Alliance , Seattle , WA , United States .

Stage	Skin findings	Liver findings	Intestinal findings
+	Maculopapular rash on <25% of body surface	Bilirubin: 2-3mg/dL	Persistent diarrhea
+	Maculopapular rash on <25% of body surface	Bilirubin: 2-3mg/dL	(500-1,00mL) and nausea
++	Maculopapular rash on 25%-50% of body surface	Bilirubin: 3-6mg/dL	Diarrhea (1,000-1,500mL)
+++	Generalized erythroderma	Bilirubin: 6-15mg/dL	Diarrhea (>1,500mL)
++++	Peeling and blistering	Bilirubin: >15mg/dL	Pain with or without obstruction

Grade/stage	Skin	Liver	Intestine	Functional disorder
0 (none)	0	0	0	0
I (mild)	+ to ++	0	0	0
II (moderate)	+ to +++	+	+	+
III (severe)	++ to +++	++ to +++	++ to +++	++
IV (life-threatening)	++ to ++++	++ to ++++	++ to ++++	+++

Organ or site	Diagnostic (sufficient to establish diagnosis of c-GVHD)	Characteristic (present in GVHD but not sufficient to establish diagnosis)	Other characteristics	Common to a-GVHD and c-GVHD
Skin	Poikiloderma	Depigmentation	Depigmentation	Erythema
	Lichen planus		Excessive or absent sweating	Maculopapular rash
	Sclerotic changes		Ichthyosis	Pruritus
	Morphea		Keratosis pilaris Hypopigmentation
	Lichen sclerosus		Keratosis pilaris Hypopigmentation
			Hyperpigmentation
			Hiperpigmentação
Nail		Dystrophy
		Longitudinal grooves
		Onycholysis
		Pterygium unguis
		Nail drop (usually symmetrically)
Scalp and hair		Total alopecia or alopecia areata after post-chemotherapy recovery	Thinning of hair not explainable by other causes
Scalp and hair		Papulosquamous lesions	Early white hair
Mouth	Lichen-type changes	Xerostomia		Gingivitis
	Hyperkeratotic plates	Mucocele		Mucositis
	Restriction of mouth opening by sclerosis	Mucosal atrophy		Erythema
		Pseudomembranes		Pain
		Ulcers		Pain
Eye		Dry eye and eye pain	Photophobia
		Healing conjunctivitis	Periorbital hyperpigmentation
		Dry keratoconjunctivitis (Schrimer test <5mm/5 minutes)	Blepharitis
		Keratitis punctata in confluent areas
Genitals	Lichen planus	Erosions
	Vaginal stenosis	Fissures
	Vaginal stenosis	Ulcers
GIT	Esophageal web		Exogenous pancreatic insufficiency	Anorexia
	Stricture or stenosis in the proximal third of the esophagus			Nausea
				Vomiting
				Diarrhea
				Weight loss
Liver				Total bilirubin and alkaline phosphatase
				>twice above the normal limit
				ALT or AST > twice the upper limit
Lungs	Bronchiolitis obliterans diagnosed with biopsy	Bronchiolitis obliterans diagnosed with pulmonary function test or chest computed tomography		BOOP
Muscle, fascia, joints	Fasciitis	Myositis or polymyositis	Edema
	Joint contractures secondary to sclerosis		Cramps
	Joint stiffness		Arthralgia or arthritis
Hematopoietic and immune systems				Thrombocytopenia
				Eosinophilia
				Lymphopenia
				Hypo- or hypergammaglobulinemia
				Autoantibodies (AIHA and ITP)
Other				Pleural or pericardial effusion
				Ascites
				Peripheral neuropathy
				Nephrotic syndrome
				Myasthenia gravis
				Cardiomyopathy or cardiac conduction defects

Types of chronic GVHD	Classification criteria
Mild c-GVHD	1 or 2 organs involved + score in the organs involved 1 + lung score 0
Moderate c-GVHD	3 or more organs involved + score 1 in each organ or At least 1 organ (except lung) with score 2 or Lung score 1
Severe c-GVHD	At least 1 organ with score 3 OR
Severe c-GVHD	Lung score 2 or 3
1. On skin: The highest score will be used for the global severity assessment
2. In the lungs: FEV1 is used instead of the clinical score for the global severity assessment
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.
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)

Supplements	Reason for use
Multivitamin with minerals (minimum iron during first year after HSCT)	To ensure adequate vitamin and mineral resources
	Metabolism and anabolism, especially if the patient has inadequate oral intake.
Vitamin C (500mg/twice a day)	To aid in wound healing
Zinc (22mg zinc sulphate/once a day for 2 weeks)	To aid in wound healing
Zinc (22mg zinc sulphate/once a day for 2 weeks)	To replace lost amounts in chronic disarrhea
Folic acid (1mg/day)	To meet the high requirements for red blood cell production.
Folic acid (1mg/day)	Some medications increase the metabolism or wasting of this vitamin, and therefore it needs to be replaced.
Calcium with vitamin D (dose depends on serum level)*	Interaction with cell levels for cytokine modification, reducing the GVHD inflammatory process
Omega 3 (2 g/day)	Interaction with cell levels for cytokine modification, reducing the GVHD inflammatory process

Evaluate nutritional status by a specialist
Maintain energy requirements at 30 to 50 cal/kg, and protein requirements at 1.5-2g/kg
Monitor weight and nutrient intake in the first year after transplant; patients with active GVHD need longer monitoring
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
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
Advise the patient on nutritional aspects regarding food safety and the risk of foodborne diseases during immunosuppression

Medication/therapy	Mechanism of action	Nutritional and metabolic effects
Corticosteroids	Anti-inflammatory response, inhibits IL-1, decreases IL-2 and suppresses lymphocyte proliferation	Sodium and water retention, hyperglycemia, hypercholesterolemia, increased appetite, weight gain, bone demineralization and muscular effects
Cyclosporine/tacrolimus	Inhibits T lymphocyte proliferation/response and alters IL-2 production	Hypertension, dyslipidemia, hyperglycemia, hypomagnesemia, hyperkalemia, nephrotoxicity, neurotoxicity, nausea, vomiting, taste changes and diarrhea
Methotrexate	Antimetabolite and immunosuppressive	Anorexia, nausea, vomiting, diarrhea, stomatitis, mucositis, hepatotoxicity and nephrotoxicity
Mycophenolate mofetil	Decreases lymphocytic activation and proliferation of B and T cells; suppresses antibody formation	Nausea, vomiting, diarrhea, constipation, gastrointestinal bleeding and peripheral edema
Sirolimus	Inhibits B and T lymphocyte proliferation	Dyslipidemia, hypertension, and peripheral edema
Thalidomide	Immunosuppressive and anti-inflammatory properties	Neuropathy and constipation
Antithymocyte globulin (ATG)	Decreases circulating lymphocytes	Abdominal pain, nausea, vomiting, diarrhea, hyperkalemia, hypertension, and peripheral edema
Etarnecept	TNF-α antagonist	Abdominal pain and vomiting
Ursodeoxycholic acid	Replaces native human bile acids; decreases HLA antigen expression in hepatocytes	Nausea, vomiting, diarrhea and abdominal pain
Daclizumab	Anti-IL-2 antibody	Vomiting, edema, hypertension and hypotension
Azathioprine	Prevents cytotoxic T and B lymphocyte proliferation by inhibiting DNA and RNA synthesis	Gastrointestinal hypersensitivity, hepatotoxicity, megaloblastic anemia and pancreatitis
Hydroxychloroquine	Interferes with antigen processing and presentation, proliferation, TNF-α production and cytotoxicity	Nausea, vomiting and diarrhea
Infliximab	Anti-TNF-α antibody	Abdominal pain, nausea, vomiting
Psoralen and PUVA	Interferes with antigen presentation and pro-inflammatory cytokine production	Nausea, hepatotoxicity
Extracorporeal photopheresis	Induces alloreactive T cell apoptosis, photoinactivation of antigen presenting cells	Hypocalcemia (citrate use) and gastrointestinal disorders
Cyclophosphamide	Immunosuppressive activity and blockade of cell growth by DNA metabolite binding	Anorexia, nausea, vomiting and mucositis
Rituximab	Anti-CD20 antibody	Abdominal pain, diarrhea, nausea, vomiting, hypertension and hyperglycemia
Pentostatin	DNA synthesis block	Nausea, vomiting, fatigue, diarrhea, anorexia and stomatitis
Imatinib	PDGF-r inhibition	Nausea, fatigue, diarrhea, abdominal pain, vomiting, weight gain, hepatotoxicity, hyperglycemia and myopathy

Step	Symptoms	Nutrition therapy
1. Bowel rest	Large volume of watery diarrhea (over 1,000mL/day); intestinal cramps; serum albumin depletion; decreased intestinal transit; bowel obstruction; nausea and vomiting	PNT only
2. Introduction of oral/enteral feeding	Diarrhea volume less than 500mL/day; decreased intestinal cramps; improvement of intestinal transit time; decrease in nausea and vomiting	PNT + oral/enteral diet with characteristics: isosmotic liquid, no residues, no lactose, no acids, and low in fat
3. Introduction of solid foods	Absence or reduction of cramps and more consistent stools	Oral/enteral diet with characteristics: solid foods, without residues, without lactose, low in fat, and no gastric acids and irritants
4. Expansion of diet	Absence or reduction of cramps and more consistent stools	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
5. Introduction of the patient’s usual diet	Absence of colic and stools of normal consistency	Oral diet with characteristics: gradual introduction and according to the patient’s tolerance of acidic foods, gastric irritants, fiber, lactose and fat

[TFN1] c-GVHD: chronic Graft versus host disease; GVHD: Graft- versus -host disease; a-GVHD: acute Graft- versus -host disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BOOP: Bronchiolitis obliterans with organizing pneumonia; AIHA: Autoimmune hemolytic anemia; ITP: Immune thrombocytopenia purpura.

Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease

ABSTRACT