Children with severe acute malnutrition: New diagnostic and treatment strategies - Thesis (complete)

Children with severe acute malnutrition

New diagnostic and treatment strategies

Bartels, R.H.

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2018

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Bartels, R. H. (2018). Children with severe acute malnutrition: New diagnostic and treatment

strategies.

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Children with severe acute malnutrition:

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Children with severe acute malnutrition:

new diagnostic and treatment strategies

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op donderdag 29 maart 2018, te 10.00 uur

door

Rosalie Henriëtte Bartels

geboren te Amsterdam

Promotor(es):

Prof. dr. M. Boele van Hensbroek AMC-Universiteit van Amsterdam

Copromotor(es):

Dr. W.P. Voskuijl

AMC- Universiteit van Amsterdam

Dr. R.H.J. Bandsma

University of Toronto

Overige leden:

Prof. dr. H.S.A. Heymans

AMC- Universiteit van Amsterdam

Prof. dr. J.B. van Goudoever

AMC- Universiteit van Amsterdam

Prof. dr. M.J. Manary

Washington University

Prof. dr. T. Ahmed

University of Queensland

Dr. B.G.P. Koot

AMC-Universiteit van Amsterdam

Dr. P.F. van Rheenen

Rijksuniversiteit Groningen

the hunger

we cannot

possess

more

than

this:

Peace

in a garden

of

our own.

Chapter 1

General Introduction and Outline of the Thesis

9

Chapter 2

The relation between malnutrition and the exocrine pancreas:

a systematic review

23

Chapter 3

Both exocrine pancreatic insufficiency and signs of pancreatic

inflammation are highly prevalent in children with complicated

severe acute malnutrition: an observational study

85

Chapter 4

Pancreatic enzyme replacement therapy in children with severe

acute malnutrition: A randomized controlled trial

101

Chapter 5

Hypoallergenic and anti-inflammatory feeds in children with

complicated severe acute malnutrition: an open randomized

controlled 3-arm intervention trial in Malawi

123

Chapter 6

The clinical use of longitudinal bio-electrical impedance

analysis in children with severe acute malnutrition

155

Chapter 7

Summary, General Discussion and Conclusions

179

Appendices

Nederlandse Samenvatting

195

Abbreviations

211

Contributing Authors

213

Acknowledgements

216

Chapter 1

General Introduction and

Outline of the Thesis

1

CHIlDHOOD MORTAlITy In THe WORlD

Every day, 15000 children under the age of 5 years (under-5) died in 2016.(1) Eighty

per-cent of these deaths occur among children living in sub-Saharan Africa or Southern Asia

(Figure 1), (1) Furthermore, more than half of these deaths could be prevented when

access to simple, affordable interventions were available.(2) In 2015, the 17 Sustainable

Development Goals (SDGs), otherwise known as the Global Goals, were formulated with

the aim to: ”end poverty, protect the planet and ensure that all people enjoy peace and

prosperity”.(3) The third goal (“good health and well-being”) aims to: “end preventable

deaths of newborns and children under-5, with all countries aiming to reduce neonatal

mortality to at least as low as 12 per 1,000 live births and under-5 mortality to at least as

low as 25 per 1,000 live births” by 2030.

Childhood Undernutrition in the World

Nearly half (45%) of worldwide deaths in children under-5 is attributable directly or

in-directly to poor nutrition.(3,4) It was estimated in 2016 that on a Global scale 52 million

children under-5 were wasted (a child who’s weight is too low for his or her height) of

which , 17 million were severely wasted (Figure 2).(5) As a consequence, two of the

targets of the second SDG goal (‘zero hunger’) are to: “end hunger and ensure access by

all people, in particular the poor and people in vulnerable situations, including infants, to

safe, nutritious and sufficient food all year round” and to: “end all forms of malnutrition,

including achieving, by 2025, the internationally agreed targets on stunting and wasting

in children under 5 years of age, and address the nutritional needs of adolescent girls,

pregnant and lactating women and older persons” by 2030.(3) It is important that these

goals have been formulated, but it is also important to realize that up to date healthy

and sufficient nutrition has been a neglected area of global health and development,

accounting for less than only 1 percent of global foreign aid. This is largely due to the

underlying and often hidden role malnutrition plays in childhood illnesses and deaths.

(6) As a consequence, in order to reduce under-5 mortality, it is of great importance

to better understand malnutrition and its causes in order to develop better preventive,

diagnostic and treatment strategies.

DeFInInG SeVeRe ACUTe MAlnUTRITIOn

Different concepts and gradings of undernutrition are in use, but the World Health

Or-ganization (WHO) has defined severe acute malnutrition (SAM), which is used by most

researchers and clinicians, as any of the following (Figure 3):(7)

- Non-edematous SAM/marasmus: a weight for height (W/H) below -3 standard

devia-tion (SD), OR a mid-upper arm circumference (MUAC) of less than 115 mm

- Edematous SAM/kwashiorkor: the presence of bilateral nutritional edema

- Marasmic kwashiorkor: a combination of the two above

TReATMenT AnD PROGnOSIS OF CHIlDRen WITH SeVeRe ACUTe

MAlnUTRITIOn

Children with SAM are normally treated as outpatients, and receive WHO recommended

rehabilitation feeds outside a hospital setting.(8) However, when they have clinical

complications such as signs of severe or systemic illness and/or poor appetite, they are

considered children with

complicated SAM and require inpatient treatment.(8) Despite

adherence to WHO and National treatment protocols the case fatality rate in children

with SAM, and especially those with complicated SAM, is still unacceptably high (up to

1

35%).(3,4,9–12) In addition, mortality remains high after hospital discharge, which may

also indicate deficits in the effectiveness of current long term management.(13,14) The

above figures indicate the urgency to better understand the malnutrition ‘syndrome’

in order to improve the current SAM management and being able to identify the SAM

children who are at risk of clinical deterioration and death at an early stage.

SeVeRe ACUTe MAlnUTRITIOn AnD THe exOCRIne PAnCReAS

The pathophysiology of children with SAM is complex, multifactorial and it results in

many different physiological abnormalities (Figure 4).(11)

One of the problems children with SAM often suffer from is severe diarrhea, which greatly

increases mortality.(11,15–17) This diarrhea may be caused by: infections, intestinal

epithelial dysfunction relating to malabsorption, impaired digestion or a combination of

the above.(18,19)

The exocrine pancreas plays a significant role in nutrient digestion by secreting enzymes

(e.g. amylase, lipase, trypsinogen, etc.) that digest all macronutrients: fat, protein and

carbohydrates.(20) Exocrine pancreatic insufficiency (EPI) is defined as a lack of digestive

enzyme production, which can lead to impaired weight gain and growth due to protein

and lipid malabsorption.(21) Its main clinical symptom is steatorrhea (the presence of

excess fat in feces), caused by the inability to digest fat.(20,22) EPI is a known common

complication of conditions such as Cystic Fibrosis (CF), Shwachman-Diamond syndrome,

and HIV.(23–25) In children with CF, pancreatic function is an important predictor of

long-term survival.(26) In high income countries it is standard clinical practice to start

pancreatic enzyme replacement therapy (PERT) in patients suffering from EPI with the

aim of restoring nutritional status by improved digestion.(21,27) It is not well known if

EPI may also be of benefit for children suffering from SAM in low-income countries.

SeVeRe ACUTe MAlnUTRITIOn AnD GUT InFlAMMATIOn

Children with SAM have intestinal pathology that is thought to result from a

combina-tion of increased exposure to microbial pathogens and poor nutricombina-tion. (11,18,28–30) A

significant feature of this so called ‘enteropathy’ is gut inflammation that persists despite

management. (31,32) The inflammation has similarities to that which occurs in non-IgE

mediated food allergy (hereafter “food allergy”; e.g. due to cow’s milk protein) and

Crohn’s disease, which raises the intriguing possibility that treatments which reduce gut

Severe malnutrition can affect several organ systems. The functional impairments in these systems have been characterized, but the underlying mechanisms have not been fully elucidated. Source: Bhutta et al.(11)

1

inflammation in food allergy and Crohn’s disease may also benefit children with SAM.

(33–35) In food allergy, the intestinal inflammation responds well when the causal

anti-gen, if known, is excluded from the diet (e.g. cow’s milk protein) or, when the concerning

antigen is not known, a hypoallergenic, elemental feed composed of single amino acids

is proven to be effective both clinically and in reducing the intestinal inflammation.(35) In

pediatric Crohn’s disease, first-line therapy consists of exclusive enteral nutrition, where

either an elemental formula or polymeric formula is given for 6-8 weeks, while all other

foods are excluded.(35–38) In limited previous research, hypoallergenic and elemental

feeds were well tolerated in children with malnutrition, but evidence of benefit was

limited.(39,40) If the gut inflammation in children with SAM would respond to existing

treatments already being used in high income countries, this could mean a big step

forward in the management of this problem that currently has not been resolved and

contributes greatly to the high mortality rates of children with SAM.

SeVeRe ACUTe MAlnUTRITIOn AnD BIO-eleCTRICAl IMPeDAnCe AnAlySIS

Children with SAM are diagnosed, as described above, by measuring W/H and MUAC, and

by physical examination to identify bilateral nutritional edema. These ‘anthropometric’

measurements do not provide any information on body composition (the proportion of

fat mass and fat-free mass in the body). Altered body composition (in malnutrition: loss

of fat-free mass) is linked to poor clinical outcome, and can be estimated by bio-electrical

impedance analysis (BIA).(41) Over the past two decades, bioelectrical impedance

analy-sis (BIA) has proven to be a non-invasive and inexpensive method for estimating body

composition, and is widely used in various clinical situations both in adults as well as

children.(41–45) Body composition is not quantified directly by BIA but is calculated

from body reactance and resistance measured by changes that occur in a small

alternat-ing electrical current, as it passes through the body.(46,47) Reactance arises from cell

membranes, and resistance from extra- and intracellular fluid, and their combination is

called ‘impedance’.(43) It provides a reliable estimate of total body water and fat free

mass in healthy individuals, but requires population and disease-specific equations.(48)

Although prediction equations have been recently developed for children, they have not

been validated for the African pediatric population, let alone for malnourished children.

(49–51)

With differing phenotypes and hydration status in SAM (i.e. non-edematous SAM versus

edematous SAM), knowing how BIA changes with nutritional rehabilitation in children

with or without edematous severe acute malnutrition (SAM) during nutritional

reha-bilitation might help the clinician. In addition to this it would help to know if BIA adds a

prognostic value to clinical outcome when combined with ‘classic’ anthropometry.

SeVeRe ACUTe MAlnUTRITIOn In MAlAWI

Malawi is a landlocked, small country in southeast Africa with an esti mated populati on of

18 million people (Figure 5).(52) It is amongst the world’s least developed countries, with a

gross domesti c product per capita of $301. The economy is mostly based on agriculture, and

foreign aid. There is a high prevalence of HIV (1 million people), 24000 adults and children

die of AIDS annually and life expectancy is low (males: 57 years, females: 60 years).(53,54)

Under-5 mortality rate in Malawi has dropped over the past 20 years, but remains among

the highest in Africa with 55.1 per 1000 live births.(55) In Malawi malnutriti on is also a

major contributor to under-5 mortality. Around 46 percent of children under fi ve are

stunted; 21 percent are underweight; and four percent are wasted.(56) The Malawian

gov-ernment has put tackling the malnutriti on problem high on their agenda. As a consequence

the ‘Malawi guidelines’ on treatment of malnutriti on have been recently revised.(57) In

these guidelines, community based management is encouraged, but complicated cases

and children with complicated SAM should be treated in an inpati ent setti ng on, so called,

Nutriti onal Rehabilitati on Units (NRU), as is similar to the management of children with

complicated SAM in other low income countries. The largest NRU of Malawi is ‘Moyo’ NRU

in the pediatric department of Queen Elizabeth Central Hospital in Blantyre.Moyo NRU,

with a yearly admission rate of around 750 SAM children, is where the observati onal and

interventi on studies in this thesis (Chapters 3-6) have been conducted between 2013-2017.

Figure 5. Malawi.

1

OUTlIne OF THe THeSIS

This thesis outlines the improvement of diagnosis and management of children with

complicated SAM through improved insight into the malnutrition ‘syndrome’ and through

exploring new strategies.

Chapters 2-4: assessing the prevalence and treatment of EPI in children with SAM.

In

Chapter 2, a systematic review, we systematically synthesize current evidence

con-cerning the relation between EPI and malnutrition in children.

In

Chapter 3 we describe the results of an observational study to assess pancreatic

func-tion in children with SAM. We aim to assess whether pancreatic funcfunc-tion: 1) is impaired

in children with severe acute malnutrition (SAM), 2) is different between edematous

versus non-edematous malnutrition, and 3) improves by nutritional rehabilitation.

In

Chapter 4 we perform a randomized controlled trial to assess the benefits of

pancre-atic enzyme replacement therapy in children with complicated SAM. We look at weight

gain, pancreatic function and clinical outcome after 28 days of pancreatic replacement

therapy.

Chapter 5 and 6: Gut inflammation and BIA:

In

Chapter 5 we evaluate whether therapeutic feeds that are effective in treating

intesti-nal inflammation in food allergy and Crohn’s disease may also benefit children with SAM.

With an open randomized controlled 3-arm intervention trial we evaluate the efficacy,

tolerability and safety of a hypoallergenic and an anti-inflammatory therapeutic formula

in children with complicated SAM.

In

Chapter 6 our focus is on the diagnostic and prognostic value of BIA in children with

SAM. We aim to assess if bio-electrical impedance parameters: 1) change with nutritional

rehabilitation in children with or without edematous SAM; 2) add a prognostic value to

clinical outcome when combined to classic anthropometry.

REFEREnCES

1. United Nations Inter-agency Group for Child Mortality, Estimation (UN IGME). Levels & Trends in Child Mortality: Report 2017, Estimates Developed by the UN Inter-agency Group for Child Mortality Estima-tion.2017. Available from: https://www.unicef.org/publications/files/Child_Mortality_Report_2017. pdf. Accessed December 3, 2017.

2. WHO | Children: reducing mortality [Internet]. World Health Organization; 2017. Available from: http:// www.who.int/mediacentre/factsheets/fs178/en/. Accessed December 3, 2017.

3. UN. Sustainable Development Goals [Internet]. Available from: http://www.un.org/sustainabledevel-opment/. Accessed December 3, 2017.

4. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al. Maternal and child undernutri-tion and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427–51. 5. UNICEF-WHO-The World Bank. Levels and trends in child malnutrition, Joint Child Malnutrition

Estimates, Key findings of the 2017 edition [Internet]. 2017. Available from: https://data.unicef.org/ wp-content/uploads/2017/06/JME-2017_brochure_June-25.pdf. Accessed December 3, 2017. 6. Nutrition - Bill & Melinda Gates Foundation [Internet]. [cited 2017 Nov 2]. Available from: https://www.

gatesfoundation.org/What-We-Do/Global-Development/Nutrition. Accessed December 3, 2017. 7. WHO. WHO child growth standards and the identification of severe acute malnutrition in infants and

children. WHO. World Health Organization; 2009.

8. WHO. Guideline: Updates on the management of severe acute malnutrition in infants and children. World Health Organization. Geneva: World Health Organization; 2013.

9. Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, et al. Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet. 2008;371(9620):1305–7.

10. Bartels RH, Bourdon C, Potani I, Mhango B, van den Brink DA, Mponda JS, et al. Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial. J Pediatr. 2017;190:85–92.e2.

11. Bhutta ZA, Berkley JA, Bandsma RHJ, Kerac M, Trehan I, Briend A. Severe childhood malnutrition. Nat Rev Dis Prim. 2017;3:17067.

12. Rytter MJ, Babirekere-Iriso E, Namusoke H, Christensen VB, Michaelsen KF, Ritz C, et al. Risk factors for death in children during inpatient treatment of severe acute malnutrition: a prospective cohort study. Am J Clin Nutr. 2017;105(2):494–502.

13. Kerac M, Bunn J, Chagaluka G, Bahwere P, Tomkins A, Collins S, et al. Follow-up of post-discharge growth and mortality after treatment for severe acute malnutrition (FuSAM study): a prospective cohort study. PLoS One. 2014;9(6):e96030.

14. Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, et al. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. Lancet Glob Heal. 2016;4(7):e464-73.

15. Bhutta ZA, Ghishan F, Lindley K, Memon IA, Mittal S, Rhoads JM. Persistent and chronic diarrhea and malabsorption: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39 Suppl 2:S711-6.

16. Irena AH, Mwambazi M, Mulenga V. Diarrhea is a major killer of children with severe acute malnutrition admitted to inpatient set-up in Lusaka, Zambia. Nutr J. 2011;10:110.

17. Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, et al. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One. 2012;7(6):e38321.

1

18. Attia S, Versloot CJ, Voskuijl W, van Vliet SJ, Di Giovanni V, Zhang L, et al. Mortality in children with com-plicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study. Am J Clin Nutr. 2016;104(5):1441–9.

19. Bandsma RHJ, Spoelstra MN, Mari A, Mendel M, van Rheenen PF, Senga E, et al. Impaired Glucose Absorption in Children with Severe Malnutrition. J Pediatr. 2011;158(2):282–287.e1.

20. Taylor CJ, Chen K, Horvath K, Hughes D, Lowe ME, Mehta D, et al. ESPGHAN and NASPGHAN Report on the Assessment of Exocrine Pancreatic Function and Pancreatitis in Children. J Pediatr Gastroenterol Nutr. 2015;61(1):144–53.

21. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy. 2007;27(6):910–20.

22. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19(42):7258–66.

23. Nousia-Arvanitakis S. Cystic fibrosis and the pancreas: recent scientific advances. J Clin Gastroenterol. 1999;29(2):138–42.

24. Shwachman H, Diamond LK, Oski FA, Khaw KT. The Syndrome of Pancreatic Insufficiency and Bone Marrow Dysfunction. J Pediatr. 1964;65:645–63.

25. Carroccio A, Fontana M, Spagnuolo MI, Zuin G, Montalto G, Canani RB, et al. Pancreatic dysfunction and its association with fat malabsorption in HIV infected children. Gut. 1998;43(4):558–63.

26. Cohen JR, Schall JI, Ittenbach RF, Zemel BS, Stallings VA. Fecal elastase: pancreatic status verifica-tion and influence on nutriverifica-tional status in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2005;40(4):438–44.

27. Taylor JR, Gardner TB, Waljee AK, Dimagno MJ, Schoenfeld PS. Systematic review: efficacy and safety of pancreatic enzyme supplements for exocrine pancreatic insufficiency. Aliment Pharmacol Ther. 2010;31(1):57–72.

28. Campbell DI, Murch SH, Elia M, Sullivan PB, Sanyang MS, Jobarteh B, et al. Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel func-tion. Pediatr Res. 2003;54(3):306–11.

29. Prendergast A, Kelly P. Enteropathies in the developing world: neglected effects on global health. Am J Trop Med Hyg [Internet]. 2012;86(5):756–63.

30. Amadi B, Besa E, Zyambo K, Kaonga P, Louis-Auguste J, Chandwe K, et al. Impaired Barrier Function and Autoantibody Generation in Malnutrition Enteropathy in Zambia. EBioMedicine. 2017;22:191–9. 31. Sullivan PB, Lunn PG, Northrop-Clewes C, Crowe PT, Marsh MN, Neale G. Persistent diarrhea and

malnutrition--the impact of treatment on small bowel structure and permeability. J Pediatr Gastroen-terol Nutr. 1992;14(2):208–15.

32. Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, et al. Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med. 2014;12:133.

33. Crittenden RG, Bennett LE. Cow’s milk allergy: a complex disorder. J Am Coll Nutr. 2005;24(6 Suppl):582S–91S.

34. Caubet J-C, Szajewska H, Shamir R, Nowak-Wegrzyn A. Non-IgE-mediated gastrointestinal food allergies in children. Pediatr Allergy Immunol. 2017;28(1):6–17.

35. Hartman C, Eliakim R, Shamir R. Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroenterol. 2009;15(21):2570–8.

36. Ludvigsson JF, Krantz M, Bodin L, Stenhammar L, Lindquist B. Elemental versus polymeric en-teral nutrition in paediatric Crohn’s disease: a multicentre randomized controlled trial. Acta Paediatr. 2004;93(3):327–35.

37. Dziechciarz P, Horvath A, Shamir R, Szajewska H. Meta-analysis: Enteral nutrition in active Crohn’s disease in children. Aliment Pharmacol Ther. 2007;26(6):795–806.

38. Mayberry JF, Lobo A, Ford AC, Thomas A. NICE clinical guideline (CG152): the management of Crohn’s disease in adults, children and young people. Aliment Pharmacol Ther. 2013;37(2):195–203. 39. Amadi B, Mwiya M, Chomba E, Thomson M, Chintu C, Kelly P, et al. Improved nutritional recovery

on an elemental diet in Zambian children with persistent diarrhoea and malnutrition. J Trop Pediatr. 2005;51(1):5–10.

40. Eichenberger JR, Hadorn B, Schmidt BJ. A semi-elemental diet with low osmolarity and high content of hydrolyzed lactalbumin in the treatment of acute diarrhea in malnourished children. Arq Gastroenterol. 1984;21(3):130–5.

41. Girma T, Hother Nielsen A-L, Kæstel P, Abdissa A, Michaelsen KF, Friis H, et al. Biochemical and anthro-pometric correlates of bio-electrical impedance parameters in severely malnourished children: A cross-sectional study. Clin Nutr [Internet]. 2017; Available from: http://linkinghub.elsevier.com/retrieve/pii/ S0261561417300675. Accessed December 3, 2017.

42. Bioelectrical Impedance Analysis in Body Composition Measurement. Proceedings of a National Insti-tutes of Health Technology Assessment Conference. Bethesda, Maryland, December 12-14, 1994. Am J Clin Nutr. 1996 Sep;64:387S–532S. Available from:

43. Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gómez JM, et al. Bioelectrical impedance analysis--part I: review of principles and methods. Clin Nutr. 2004;23(5):1226–43.

44. Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Manuel Gómez J, et al. Bioelectrical imped-ance analysis-part II: utilization in clinical practice. Clin Nutr. 2004;23(6):1430–53.

45. Kushner RF, Schoeller DA. Estimation of total body water by bioelectrical impedance analysis. Am J Clin Nutr. 1986;44(3):417–24.

46. Foster KR, Lukaski HC. Whole-body impedance--what does it measure? Am J Clin Nutr. 1996;64(3 Suppl):388S–396S.

47. Baumgartner RN, Chumlea WC, Roche AF. Bioelectric impedance phase angle and body composition. Am J Clin Nutr. 1988;48(1):16–23.

48. Girma T, Kæstel P, Workeneh N, Mølgaard C, Eaton S, Andersen GS, et al. Bioimpedance index for measurement of total body water in severely malnourished children: Assessing the effect of nutritional oedema. Clin Nutr. 2016;35(3):713–7.

49. Nagano M, Suita S, Yamanouchi T. The validity of bioelectrical impedance phase angle for nutritional assessment in children. J Pediatr Surg. 2000;35(7):1035–9.

50. Llames L, Baldomero V, Iglesias ML, Rodota LP. [Values of the phase angle by bioelectrical impedance; nutritional status and prognostic value]. Nutr Hosp.2013;28(2):286–95.

51. Tanabe RF, de Azevedo ZMA, Fonseca VM, Peixoto MVM, dos Anjos LA, Gaspar-Elsas MIC, et al. Distribu-tion of bioelectrical impedance vector values in multi-ethnic infants and pre-school children. Clin Nutr. 2012;31(1):144–8.

52. Malawi [Internet]. Available from: https://en.wikipedia.org/wiki/Malawi. Accessed December 3, 2017. 53. UN. UNAIDS Data 2017 [Internet]. Available from:

http://www.unaids.org/en/regionscountries/coun-tries/malawi. Accessed December 3, 2017.

54. WHO. WHO | Malawi. WHO [Internet]. 2017; Available from: http://www.who.int/countries/mwi/en/. Accessed December 3, 2017.

55. WHO | Under-five mortality [Internet]. WHO. World Health Organization; 2017. Available from: http:// www.who.int/gho/child_health/mortality/mortality_under_five/en/. Accessed December 3, 2017. 56. UNICEF Malawi - The children - The Situation of Women and Children [Internet]. Available from: https://

1

57. Ministry of Health (MOH). Guidelines for Community-Based Management of Acute Malnutrition. 2nd Edition. Lilongwe, Malawi; 2016.

58. World Health Organization. Hospital care for children. Guidelines for the management of common illnesses with limited resources [Internet]. World Health Organization. 2013. Available from: http:// apps.who.int/iris/bitstream/10665/81170/1/9789241548373_eng.pdf?ua=1. Accessed December 5, 2017.

Chapter 2

The relation between malnutrition and the

exocrine pancreas: a systematic review

Rosalie H. Bartels*, Deborah A. van den Brink*, Robert H. Bandsma, Michael Boele van Hensbroek, Merit M. Tabbers, Wieger P. Voskuijl

*These authors contributed equally

ABSTRACT

Objective: The relation between malnutrition and exocrine pancreatic insufficiency (EPI)

has been described previously, but it is unclear if malnutrition leads to EPI or vice versa.

We systematically synthesized current evidence evaluating the association between

malnutrition and EPI in children.

Methods: Pubmed, Embase, and Cochrane databases were searched from inception

until February 2017

. We included cohort or case- controlled studies in children

report-ing on prevalence or incidence of EPI and malnutrition. Data generation was performed

independently by 2 authors. Quality was assessed by using quality assessment tools from

the National Heart, Lung, and Blood Institute.

Results: Nineteen studies were divided into 2 groups: 10 studies showing EPI leading to

malnutrition, and 9 studies showing malnutrition leading to EPI. Due to heterogeneity

in design, definitions and outcome measures, pooling of results was impossible. Quality

was good in 4/19 studies. Pancreatic insufficiency was linked to decreased nutritional

status in 8/10 articles although this link was not specified properly in most articles. In

malnourished children, improvement was seen in pancreatic function in 7/9 articles after

nutritional rehabilitation. The link between the two was not further specified.

Heteroge-neity exists with respect to definitions, outcome measures and study design.

Conclusions: There is sufficient evidence for an association between EPI and

malnutri-tion. We could not confirm whether there is a correlation or causality between EPI or

malnutrition. It was therefore not possible to draw firm conclusions from this systematic

review on underlying pathophysiological mechanisms between EPI and malnutrition.

More observational clinical trials are crucially needed.

2

InTRODUCTIOn

Undernutrition is a global problem, it contributes to approximately 45% of all deaths in

children less than 5 years of age while severe malnutrition is a co-morbidity in 7.8% of all

under 5 deaths in children.(1–3)

Malnutrition has been defined in many different ways over the past few decades and

encompasses both undernutrition and overweight.(1) In this review we will discuss

undernutrition only. The current definition of undernutrition is a weight for height (W/H)

≤-2 standard deviations (SD) and severe malnutrition is defined as a W/H <-3 SD and/or a

mid-upper arm circumference (MUAC) of <11.5cm according to the World Health

Orga-nization (WHO).(4) Severe acute malnutrition (SAM) includes two different phenotypical

forms: non-edematous SAM (severe wasting or ‘marasmus’) or edematous SAM, which

is nutritionally induced bilateral edema (kwashiorkor).

Since mortality in SAM remains very high better understanding of the pathophysiology of

SAM is needed in order to improve management.

Severe diarrhea is common in children with SAM, contributes to mortality (5,6) and is not

only caused by infections and intestinal epithelial dysfunction relating to malabsorption,

but also by impaired pancreatic digestion.(7,8) The exocrine pancreas plays a key role

in nutrient digestion by secreting digestive enzymes (i.e. amylase, lipase, and trypsin)

digesting all macronutrients: fat, protein and carbohydrates.(9) Exocrine pancreatic

insufficiency (EPI) is the inability to digest nutrients due to severe reduction of digestive

enzymes. Its main clinical symptom is steatorrhea caused by the inability to digest fat.

(9,10) Pancreatic function can be assessed by direct and indirect methods.(9) Direct

methods are more invasive and include stimulation of the pancreas by secretin, followed

by pancreatic duct intubation, collection and measurement of the secreted enzymes.

In-direct tests measure pancreatic enzymes in serum (e.g. Serum immunoreactive

trypsino-gen (IRT), lipase, and amylase), in stool (Fecal elastase-1 (FE-1) and fecal chymotrypsin

(CMT)) or by using breath analysis.(9) It is current clinical practice to measure pancreatic

function by FE-1 in stool.(9)

EPI exists in conditions such as cystic fibrosis (CF), Shwachman-Diamond syndrome (SDS),

and chronic pancreatitis (CP)(10–13) and can lead to nutrient malabsorption,

undernu-trition, poor growth and mortality.(14) However, in contrast, several older studies mostly

performed between 1940 and 1980, have reported that malnutrition in its turn can lead

to EPI.(15–26) We have recently confirmed these findings and showed a very high

preva-lence of EPI in Malawian children with SAM (93%).(27) However, it is still not clear how

exactly, the relationship between malnutrition and the exocrine pancreas is. More insight

into the pathophysiology underlying SAM might aid in lowering the huge malnutrition

related mortality. Therefore, unraveling the association between the exocrine pancreas

and malnutrition is of great importance. We systematically assessed the evidence

con-cerning the relation between EPI and malnutrition in children.

We developed the following PICOS: participants: children with malnutrition or EPI;

inter-ventions: treatment for malnutrition and or EPI; comparisons: none or healthy controls;

outcomes: pancreatic function and nutritional status; study design: systematic review.

METHODS

Search strategy

The databases Embase, PubMed, and Cochrane Database of Systematic Reviews were

searched from inception to February 2017 (full search strategy and keywords shown in

Appendix 1). To identify additional studies, reference lists of relevant studies identified

in the literature search were searched by hand. During this process, the exact reporting

guidelines as described in the PRISMA statement (www.prisma-statement.org) were

followed.

Study selection

Two investigators (RB and DB) independently reviewed titles and abstracts of all

cita-tions in the literature results. Possible relevant studies were retrieved for full-text review.

Cohort, randomized controlled trials, or case-controlled studies in children (aged 0-18

years) were included if studies were reporting on prevalence or incidence of EPI or

mal-nutrition. A clear definition and assessment of EPI and malnutrition had to be provided

by the authors. Study aim was to determine any relation between EPI and malnutrition.

No language restriction was used. Case reports and animal studies were excluded.

Dis-agreements between reviewers were adjudicated by discussion and consensus with two

other authors (MT and WV).

Data extraction and analysis

For each included trial in the final analysis, data were extracted by using structured

data extraction forms, which contained items such as author, participants, definitions of

EPI and malnutrition, method of EPI assessment, method of malnutrition assessment,

outcomes, and author’s conclusions.

Methodological quality of the included articles was assessed using the National Heart,

Lung, and Blood Institute (NHLBI) quality assessment tool (i.e. risk of bias).(28) Three

NHLBI tools were used: one for observational cohort and cross-sectional studies, a

sec-ond tool for case control studies, and thirdly a separate tool for controlled intervention

studies. Using these tools, two authors (RB, DB) independently evaluated the selected

articles using “yes”, “no”, “cannot determine”, “not reported”, or “not applicable”. These

2

were discussed and used to frame an overall rating for the quality of each study as “good”,

“fair”, or “poor”. Ratings were based on number of quality assessment questions that

were confirmed with a ‘yes’: poor ≤6, fair >6 and <10, and good ≥10 questions answered

with ‘yes’. For the case-control studies that had 12 questions instead of 14 we adjusted

the rating: poor ≤5, fair >5 and <9, and good ≥9. A third and fourth author were consulted

on any discrepancies between the two independent evaluations (MT, WV)

ReSUlTS

Study search and quality assessment

After deducting duplicates, the search strategy and manual search generated 1273

stud-ies that were screened for eligibility (Appendix 1). 1219 were excluded as they were

not relevant to our search question (Figure 1. Flowchart). After evaluating the full text,

another 35 studies were excluded for not meeting our inclusion criteria (no clear

defini-tion of malnutridefini-tion (n=12), no clear definidefini-tion of EPI (n=7), or both (n=3), different study

design(n=4), full text non-retrievable (n=1), adult population (n=6), or not reporting on

relation EPI and malnutrition (n=2)).

The remaining 19 studies were divided into 2 groups: (1) studies reporting patients

diagnosed with EPI who are later found to be malnourished (n=10);(29–38) (2) studies

reporting patients diagnosed with malnutrition who are later found to have EPI (n=9).

(16,18,21,23,24,27,39–41) Due to heterogeneity in design, definitions and outcome

measures, pooling of results was impossible. Therefore, studies are discussed separately.

Quality assessments are shown in supplemental tables 1 – 3. Four studies had an overall

quality considered to be good (23,29,30,36), 12 were rated to be fair (16,18,24,27,31–

33,35,38–41), and the remaining 3 studies were rated to be poor (21,34,37). Only four

studies did account for key potential confounding variables(24,31,35,41) and just 1 study

had a sample size justification.(27) Blinding of treatment of participants and researchers

was only performed in one study.(36) Cohen’s κ was calculated to determine the

inter-observer variation between the reviewers that assessed the articles using the quality

assessment tool (RB and DB). There was moderate agreement between the two

review-ers, κ=.602 (95% CI, .522 to .682),

p < .0005.(42) After discussion agreement was reached

in 100% of cases.

Study and patient characteristics

In total, 2271 children were included in 19 studies (Table 1) with sample sizes ranging

from 13 to 659 children (32,41) Of the included 19 studies, 12 only included children

less than 5 years old.(16,18,23,24,27,30,32,36–40) These studies were conducted in 13

different countries including resource-high/developed countries: USA, Italy, Australia,

France, Poland, UK, and Canada; as well as resource-poor/developing countries: Egypt,

Ivory Coast, Malawi, Senegal, Uganda, and South Africa. Ten studies included patients

that were diagnosed with a condition known to be associated with EPI such as CF, SDS,

Celiac disease, human immunodeficiency virus (HIV), and CP.(29–38) Of all studies,

Kolodziejczyk et al. was the only study which included CP patients, while Carrroccio et

al. solely included HIV infected children.(31,35) Three studies included participants

diag-nosed with SDS.(32–34) Celiac disease was studied by two separate studies conducted by

Carroccio et al.(36,37) Lastly 3 studies focused on CF patients.(29,30,38) The remaining

nine studies investigated malnourished children who had either moderate or severe

malnutrition.(16,18,21,23,24,27,39–41)

Records identified through Pubmed and Embase searching

(n =1629) Sc re en in g In cl ud ed El igi bi lit y Id en tifi cati

on _{Additional records identified}

through other sources (hand searched) (n =18)

Records after duplicates removed (n =1273)

Records screened

(n =1273) Records excluded (n =1219)

Full-text articles assessed for eligibility

(n = 54)

Full-text articles excluded, reasons: • no clear definition of

malnutrition (n=12),

• no clear definition of EPI (n=7),

• no clear definition of malnutrition and no clear definition of EPI (n=3), • no cohort, controlled trial, or

case-control study design (n=4),

• full text non-retrievable (n=1) • adult population (n=6),

• not reporting on relation EPI and malnutrition (n=2) Studies included in

qualitative synthesis (n =19)

Figure 1. Flowchart of study screening and selection process.

2

Pancreatic function assessment:

The criterion standard test of pancreatic function is the pancreatic stimulation test,“Dreiling

tube test”, (9,43) This

direct pancreatic test was used in 7 studies.(16,21,32,34,36,37,39)

Cutoff values were provided by the author in 1 of those studies,(32) 3 studies used

control values of non-malnourished children,(16,21,39) 2 studies used control values of

non-celiac children,(36,37) and one study did not provide any cutoff values at all.(34) The

current most widely used pancreatic function test is an

indirect test measuring faecal

levels of zymogen FE-1.(9,44) This was measured in 4 studies which reported clear cutoff

values.(27,29,31,33)

Fat malabsorption was reported in 8 studies.(16,21,32,34,36,37,39) Of these,

Kolodziejczyk et al. was the only study using a control group, while Bines et al. did not

report on cutoff values at all.(35,38) Immuno-reactive trypsinogen was tested in 5

stud-ies,(24,27,32,40,41) of which two were using cutoff values,(27,32) and 3 were using a

control group.(24,40,41) Serum amylase was measured in 5 studies(23,27,31,32,35) with

3 of them also measuring lipase.(23,32,35) All reported clear cutoff values except for

one, El-Hodhod et al, who used values of a control group.(23) Fecal CMT was assessed

in two studies with clear cutoff values.(31,32) Additional, less commonly used, tests for

pancreatic function included ultrasound evaluations,(23,33,35) autopsy,(18) and

endo-scopic retrograde cholangio-pancreatography (ERCP).(35)

Malnutrition assessment

Assessment of malnutrition was more consistent across the selected articles, with

stud-ies using anthropometry, clinical indicators, and albumin as markers of malnutrition.

Weight-for-age Z-scores (WAZ), height-for-age Z-scores (HAZ), and/or weight-for-height

Z-scores (WHZ), currently recommended by WHO for defining malnutition,(45) were

used in 14 studies.(16,23,24,27,29–33,36–38,40,41) Growth percentiles were used by

Hill et al. and El-Hodhod et al. and a BMI ratio (Cole’s ratio: BMI actual/BMI for the 50

centile x100%) was used to classify malnutrition by Kolodziejczyk et al.(23,34,35) Four

studies used clinical indicators such as pitting edema and skin lesions for malnutrition.

(16,18,21,39) Lastly albumin was used as a marker of malnutrition by 4 studies, of which

three used controls but El-Hodhod did not have cutoff values.(16,23,30,37)

Group 1: Articles reporting patients diagnosed with ePI who are later found to

be malnourished (supplemental Table 4)(29–38)

Eight out of 10 studies describe the association between EPI and malnutrition.(29,30,32–

36,38) Quality assessment was rated ‘poor’ for two studies,(34,37) ‘fair’ for five

stud-ies,(31–33,35,38) and ‘good’ for three studies.(29,30,36) Cohen et al. reported that CF

children with no pancreatic activity (n=75/84) (FE-1<15 ug/g) had a significantly lower

WAZ and more fat malabsorption compared to CF children with residual activity (n=9/84)

(FE-1≥15 ug/g).(29) Significantly greater fat malabsorption in pancreatic insufficient CF

children (n=16/29) versus pancreatic sufficient CF patients (n=13/29) was also reported

by Bronstein et al. which was significantly correlated with a decrease in WAZ.(30) Bines

et al. reported that pancreatic insufficiency (found in n=35/46 CF children) was strongly

associated with poor weight and length gains.(38)

All three studies of children with Shwachman-Diamond syndrome, reported high

num-bers of EPI, (Pichler et al. 95.2%, Cipolli et al. 100%, Hill et al. 100%).(32–34) Of these,

Cipolli et al. had the highest proportion of malnourished children (n=11/13, 84%). This

study followed up 6 children at a mean age of 10 years, and found a significant increase in

both weight and height z-scores although unclear if on pancreatic enzyme replacement

therapy (PERT) or not (from -3.8 to -1.4 and from -3.6 to -1.8 respectively, both

p<0.001).

(32) Hill et al. reported that 64% (n=7/11) had a weight below the 3

_{percentile but}

did not report on anthropometry during follow up.(34) Pichler et al. reported only 33%

(n=7/21) to be malnourished and on follow up of unclear duration only 38% (n=5/13)

experienced catch up growth.(33) Pichler et al. described that poor nutritional status

in SDS is multifactorial and can be caused by several other factors than EPI, like feeding

difficulties (in 43% (n=9/21) of their population) and enteropathy (50% n=7/14). None of

the three SDS studies demonstrated a direct correlation between EPI and malnutrition.

Carroccio et al. found EPI in 30% of HIV infected children and a significant correlation

between EPI and fat malabsorption.(31) However, only 14% (n=2/14) of patients with

EPI had SAM and no direct correlation between was mentioned. In children with CP, 25%

(n=52/208) was malnourished and this was only significantly correlated with a higher age

of onset of CP, but not with fat absorption.(35)

In two different studies also carried out by Carroccio et al. pancreatic function in

children with celiac disease was studied. (36,37) In one study, they found EPI in 29%

(n=15/52) of the celiac children and 37% of the patients (n=19/52) had SAM but no

correlation between the two was reported.(37) In the other study they investigated the

effect of pancreatic enzyme therapy in children with celiac disease, and showed that

38% (n=15/40) suffered from EPI and 15% (n=6/40) from severe EPI.(36) Celiac patients

who were given pancreatic enzymes had a significant increase in weight after 30 days of

therapy, compared to those that did not receive therapy, but this difference disappeared

after supplementation of 60 days.

Group 2: Articles reporting patients diagnosed with malnutrition who are later

found to have ePI (Supplemental Table 5)(16,18,21,23,24,27,39–41)

All nine studies described some association, but not always causality, between

malnu-trition and EPI.(16,18,21,23,24,27,39–41) Quality assessment was rated ‘poor’ for one

study,(21) ‘fair’ for seven studies,(16,18,24,27,39–41) and ‘good’ for one study.(23)

Seven studies reported that EPI in children with malnutrition is correctable after

nutri-2

tional rehabilitation.(16,18,21,23,24,27,39) El-Hodhod et al. showed that malnourished

children (n=33) had significantly lower serum amylase, serum lipase, and pancreatic

head size compared to a group of normally nourished controls (n=12), and a significant

improvement was seen in all measures of pancreatic function and weight after

nutri-tional rehabilitation.(23) Barbezat et al. examined pancreatic enzyme markers in gastric

juice and found these to be significantly lower in children with kwashiorkor (n=14) and

marasmus (n=7) than in healthy controls (n=7), and these enzymes to significantly

im-prove after nutritional rehabilitation.(16) Durie et al. reported a significant correlation

between severity of malnutrition (n=50) and IRT, with IRT reverting to normal in patients

with improvement in nutritional status.(24) Although no statistical values were provided,

Thompson et al. also showed that children with kwashiorkor had lower levels of amylase

and lipase compared to controls and that these improved after nutritional rehabilitation.

(18) In a study conducted in Ivory Coast and France, Sauniere et al. concluded that in

chil-dren with kwashiorkor (n=25) pancreas function (based on a total of 5 different enzymes)

was significantly decreased compared to healthy African (n=11), and European children

(n=62) and that this disappeared after refeeding.(21) A second study by Sauniere et al.

discussed pancreatic function in malnourished children in Dakar (n=13) and Abidjan

(n=15) in West Africa, which was decreased compared to healthy children in France.

(39) After nutritional rehabilitation pancreatic secretion levels significantly increased but

remained subnormal in the children from Abidjan and no improvement was found in

children from Dakar. This was similar to our own previous study in which we found EPI

in 92% (n=71/77) and severe EPI in 77% (n=59/77) of children with SAM and also found

an significant improvement but no normalization of pancreatic function after nutritional

rehabilitation.(27) Additionally, we found the degree of EPI to be significantly worse in

children with kwashiorkor compared to children with marasmus (median FE-1 of 22u/g

versus 80ug/g) and elevated IRT levels in 28% (n=11/39) of the patients.

Two studies reported on EPI in malnourished Australian Aboriginal children.(40,41)

Similar to Durie et al., Cleghorn et al. also reported on pancreatic damage in children

with malnutrition, demonstrated by a significant correlation between IRT and degree of

malnutrition (n=78/198 moderately and n=63/198 severely malnourished).(40) Briars et

al. also found increased IRT levels related to decreased weight z-scores but no relation to

other nutritional indices like arm circumference and skinfold thickness. A potential

con-founder could have been gastroenteritis in these patients potentially causing elevated

IRT.(41)

Table 1. Study Demographics (n=19)

Author Country Study Population Inclusion Criteria exclusion Criteria Methods (measurement) Main Findings Remarks

Bartels et al. 2016

Malawi -89 children with severe acute malnutrition (SAM) admitted to nutritional rehabilitation unit (NRU) (median age 21 months).

-Children 6-60 months old -Diagnosis of SAM, by World Health Organization (WHO) definitions: weight for height Z-score (WHZ) < -3 SD, mid upper arm circumference (MUAC) <115 mm, and/or presence of bilateral edema -Previously admitted to NRU within a year -Severe hemodynamic instability, hematocrit level of ≤15%, or severe neurological symptoms

-Observational study part of nutrient prospective intervention trial

1. Clinical parameters and anthropometry daily

2. Stool samples for FE-1 analysis <200 μg/g = exocrine pancreatic insufficiency (EPI) 3. S. trypsinogen and pancreatic amylase determined in subsets, n=39 and n=80 respectively stratified for HIV status

-71/77 (92%) EPI

-More edematous patients had EPI, 47/48 (98%), vs. non-edematous, 24/29 (83%), (p=0.03)

- Lower FE-1-levels in edematous group (p=0.009)

-Severe EPI (FE-1 <100 μg/g) higher in edematous group (p=0.006)

-Mortality higher non-edematous group (p=0.03)

-Trypsinogen elevated, especially in edematous group (p=0.03) suggesting pancreatic inflammation,

- No correlation trypsinogen and FE-1 levels (p=0.4)

-Differences in mortality between HIV reactive and non-reactive patients ns. Pichler et al. 2015 UK -21 children with Shwachman diamond syndrome (SDS) (median age 7.8 years). -Genetically confirmed SDS -Attended the tertiary/ quaternary SDS referral center

-Not mentioned -Retrospective observational study. -Visits every 3 months

1. Weight for age z-score (WAZ) and height for age Z-score (HAZ)

2. FE-1, pancreatic insufficiency (PI) defined as FE-1<200 μg/g

3. Ultrasound (US) for fatty replacement pancreas Baseline results: -20/21 (95%) PI -7/21 (33%) WAZ <-2, 9/21 (43%) HAZ <-2 -Abnormal US in 7/21 (33%)

-Exact results FE-1 not shown -Longitudinal data only available for 13/21 children

Kolodziejczyk et al. 2014

Poland -208 children with chronic pancreatitis (CP) (mean age 10.8 years).

-Age <18 years

-CP features verified by one imaging technique (ERCP, MRCP, CT, or US scan) and/ or by EPI tests (72 h fecal fat quantification, elastase-1 stool test, breath test)

-Observation period of ≥ 1 year first episode of pancreatitis

-Age > 18 years -Lack of imaging studies, or the absence of CP features -CF -Inability of long-term observation

-Patients divided into 5 groups: 1) hereditary pancreatitis (n=26), 2) CFTR and/ or SPINK1 mutations without a known cause (n=46), 3) anatomic duct anomalies (n=20), 4) patients with two or more coexisting etiologic factors of CP (n=24), 5) patients with idiopathic CP (n=92);

-Mean follow up 5 years

1. BMI ratio to evaluate anthropometric index, classify nutritional status

2. 72-hour fecal fat quantification used to diagnose EPI with fat maldigestion. 3. Cambridge classification grades CP by ECRP findings from normal (grade 1) to marked

(grade 4)

-52/208 (25.0%) malnutrition (14/52 (26.9%) mild; 36/52, (69.2%) moderate; 2/52 (3.8%) severe

-Fecal fat and Cambridge grades NS between the 5 groups

-Mean age at disease onset higher in group 1 vs. group 2 (p<0.05) -72 hour fecal fat quantification only measured in 152/208 (73.0%) -Vague description of histological classification

2

Table 1. Study Demographics (n=19)

Author Country Study Population Inclusion Criteria exclusion Criteria Methods (measurement) Main Findings Remarks

Bartels et al. 2016

Malawi -89 children with severe acute malnutrition (SAM) admitted to nutritional rehabilitation unit (NRU) (median age 21 months).

-Children 6-60 months old -Diagnosis of SAM, by World Health Organization (WHO) definitions: weight for height Z-score (WHZ) < -3 SD, mid upper arm circumference (MUAC) <115 mm, and/or presence of bilateral edema -Previously admitted to NRU within a year -Severe hemodynamic instability, hematocrit level of ≤15%, or severe neurological symptoms

-Observational study part of nutrient prospective intervention trial

1. Clinical parameters and anthropometry daily

2. Stool samples for FE-1 analysis <200 μg/g = exocrine pancreatic insufficiency (EPI) 3. S. trypsinogen and pancreatic amylase determined in subsets, n=39 and n=80 respectively stratified for HIV status

-71/77 (92%) EPI

-More edematous patients had EPI, 47/48 (98%), vs. non-edematous, 24/29 (83%), (p=0.03)

- Lower FE-1-levels in edematous group (p=0.009)

-Severe EPI (FE-1 <100 μg/g) higher in edematous group (p=0.006)

-Mortality higher non-edematous group (p=0.03)

-Trypsinogen elevated, especially in edematous group (p=0.03) suggesting pancreatic inflammation,

- No correlation trypsinogen and FE-1 levels (p=0.4)

-Differences in mortality between HIV reactive and non-reactive patients ns. Pichler et al. 2015 UK -21 children with Shwachman diamond syndrome (SDS) (median age 7.8 years). -Genetically confirmed SDS -Attended the tertiary/ quaternary SDS referral center

-Not mentioned -Retrospective observational study. -Visits every 3 months

1. Weight for age z-score (WAZ) and height for age Z-score (HAZ)

2. FE-1, pancreatic insufficiency (PI) defined as FE-1<200 μg/g

3. Ultrasound (US) for fatty replacement pancreas Baseline results: -20/21 (95%) PI -7/21 (33%) WAZ <-2, 9/21 (43%) HAZ <-2 -Abnormal US in 7/21 (33%)

-Exact results FE-1 not shown -Longitudinal data only available for 13/21 children

Kolodziejczyk et al. 2014

Poland -208 children with chronic pancreatitis (CP) (mean age 10.8 years).

-Age <18 years

-CP features verified by one imaging technique (ERCP, MRCP, CT, or US scan) and/ or by EPI tests (72 h fecal fat quantification, elastase-1 stool test, breath test)

-Observation period of ≥ 1 year first episode of pancreatitis

-Age > 18 years -Lack of imaging studies, or the absence of CP features -CF -Inability of long-term observation

-Patients divided into 5 groups: 1) hereditary pancreatitis (n=26), 2) CFTR and/ or SPINK1 mutations without a known cause (n=46), 3) anatomic duct anomalies (n=20), 4) patients with two or more coexisting etiologic factors of CP (n=24), 5) patients with idiopathic CP (n=92);

-Mean follow up 5 years

1. BMI ratio to evaluate anthropometric index, classify nutritional status

2. 72-hour fecal fat quantification used to diagnose EPI with fat maldigestion. 3. Cambridge classification grades CP by ECRP findings from normal (grade 1) to marked

(grade 4)

-52/208 (25.0%) malnutrition (14/52 (26.9%) mild; 36/52, (69.2%) moderate; 2/52 (3.8%) severe

-Fecal fat and Cambridge grades NS between the 5 groups

-Mean age at disease onset higher in group 1 vs. group 2 (p<0.05) -72 hour fecal fat quantification only measured in 152/208 (73.0%) -Vague description of histological classification

Table 1. Study Demographics (n=19) (continued)

Author Country Study Population Inclusion Criteria exclusion Criteria Methods (measurement) Main Findings Remarks

El Hodhod et al. 2005

Egypt -33 children protein energy malnutrition (PEM) (mean age 11.87±7.8 months) -12 controls (mean age 14.83±7.7 months)

- Children with PEM (according to

Wellcome criteria)48 -Not mentioned -Phase 1: pre-interventional assessment _{-Phase 2: nutritional intervention program}

with breast-feeding.

-Phase 3: post-intervention assessment (3-6 months after starting date)

Assessments in phase 1 and 3:

1.Dietetic history, history of GI symptoms, anthropometry, clinical signs of malnutrition 2. S. lipase, S. Amylase

3. US of pancreas

Phase 1:

-Pancreatic head size significantly lower marasmus, kwashiorkor (KWO), marasmic kwashiorkor (MKWO), vs. controls (p<0.001, p<0.01, p<0.05) -S. amylase significantly lower all groups of PEM (p<0.001)

-S. lipase significantly lower marasmus, KWO, MKWO (p<0.01, p<0.001, p<0.001)

Phase 3 post-intervention: -S. amylase significantly increased all malnourished groups (p<0.001) -S. lipase significantly increased in marasmus, KWO, MKWO (p<0.001, p<0.01, p<0.001)

-Pancreatic head size significantly improved in marasmus, KWO, MKWO (p<0.001, p<0.05, p<0.05)

-Weight and length significantly improved all groups (p<0.001) Cohen et al.

2005

USA -91 CF children (6-8.9 years)

-Both mild to moderate CF lung disease and PI;

-CF diagnosed: sweat sodium and chloride concentrations >60 mEq/L

-PI diagnosed: 72 hour fecal fat analysis <93% absorption or stool trypsin concentration <80 μg/g -Forced expiratory volume in 1 second (FEV1) <40% -Liver disease -Diabetes type 1 -Burkholderia cepacia in sputum

-12 and 24 month hospital visit -6 and 18 month home visit -Pulmonary function, anthropometric assessment, blood, urine and fecal samples 1. Dietary assessment; 7-day weighed food records

2. 72 hour stool samples collected annually 3. Height and weight using standard techniques

4. Random stool samples; fecal elastase (FE-1) analysis

-Group with residual pancreatic activity (R-FE) higher percent coefficient of fat absorption (%CoA) than no pancreatic activity (NO-FE) group (p<0.01) [94%±3% vs. 81%±14%] at baseline. -R-FE group also had a better growth at baseline (p=0.03)

-FE-1 levels only obtained for 85 children -1 child did not complete 24 month study; excluded from analysis Bines et al. 2002

Australia -46 CF infants (mean age 7.7 weeks)

-24 controls (mean age 9 weeks)

-Positive newborn CF screening: homozygosity for ΔF508 deletion

or sweat chloride concentration ≥60 mmol/L

-Infants with meconium ileus studied after clinical condition stabilized

-Not mentioned 1. Prospective 3-day dietary record 2. Stool microscopy and/or 3-day fecal fat balance to determine PI

3. Weight and length measured; measurements converted to percentile values and Z-scores (ANTHRO Pediatric Anthropometry Software program)

-Mean weight and length significantly lower than controls or reference values (p<0.05)

-PI significantly associated with lower weight and length than controls (p<0.05)

-No cutoff values provided for 3 day fecal fat balance and stool microscopy

2

Table 1. Study Demographics (n=19) (continued)

Author Country Study Population Inclusion Criteria exclusion Criteria Methods (measurement) Main Findings Remarks

El Hodhod et al. 2005

Egypt -33 children protein energy malnutrition (PEM) (mean age 11.87±7.8 months) -12 controls (mean age 14.83±7.7 months)

- Children with PEM (according to

Wellcome criteria)48 -Not mentioned -Phase 1: pre-interventional assessment _{-Phase 2: nutritional intervention program}

with breast-feeding.

-Phase 3: post-intervention assessment (3-6 months after starting date)

Assessments in phase 1 and 3:

1.Dietetic history, history of GI symptoms, anthropometry, clinical signs of malnutrition 2. S. lipase, S. Amylase

3. US of pancreas

Phase 1:

-Pancreatic head size significantly lower marasmus, kwashiorkor (KWO), marasmic kwashiorkor (MKWO), vs. controls (p<0.001, p<0.01, p<0.05) -S. amylase significantly lower all groups of PEM (p<0.001)

-S. lipase significantly lower marasmus, KWO, MKWO (p<0.01, p<0.001, p<0.001)

Phase 3 post-intervention: -S. amylase significantly increased all malnourished groups (p<0.001) -S. lipase significantly increased in marasmus, KWO, MKWO (p<0.001, p<0.01, p<0.001)

-Pancreatic head size significantly improved in marasmus, KWO, MKWO (p<0.001, p<0.05, p<0.05)

-Weight and length significantly improved all groups (p<0.001) Cohen et al.

2005

USA -91 CF children (6-8.9 years)

-Both mild to moderate CF lung disease and PI;

-CF diagnosed: sweat sodium and chloride concentrations >60 mEq/L

-PI diagnosed: 72 hour fecal fat analysis <93% absorption or stool trypsin concentration <80 μg/g -Forced expiratory volume in 1 second (FEV1) <40% -Liver disease -Diabetes type 1 -Burkholderia cepacia in sputum

-12 and 24 month hospital visit -6 and 18 month home visit -Pulmonary function, anthropometric assessment, blood, urine and fecal samples 1. Dietary assessment; 7-day weighed food records

2. 72 hour stool samples collected annually 3. Height and weight using standard techniques

4. Random stool samples; fecal elastase (FE-1) analysis

-Group with residual pancreatic activity (R-FE) higher percent coefficient of fat absorption (%CoA) than no pancreatic activity (NO-FE) group (p<0.01) [94%±3% vs. 81%±14%] at baseline. -R-FE group also had a better growth at baseline (p=0.03)

-FE-1 levels only obtained for 85 children -1 child did not complete 24 month study; excluded from analysis Bines et al. 2002

Australia -46 CF infants (mean age 7.7 weeks)

-24 controls (mean age 9 weeks)

-Positive newborn CF screening: homozygosity for ΔF508 deletion

or sweat chloride concentration ≥60 mmol/L

-Infants with meconium ileus studied after clinical condition stabilized

-Not mentioned 1. Prospective 3-day dietary record 2. Stool microscopy and/or 3-day fecal fat balance to determine PI

3. Weight and length measured; measurements converted to percentile values and Z-scores (ANTHRO Pediatric Anthropometry Software program)

-Mean weight and length significantly lower than controls or reference values (p<0.05)

-PI significantly associated with lower weight and length than controls (p<0.05)

-No cutoff values provided for 3 day fecal fat balance and stool microscopy