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Copyright 2007, The Johns Hopkins University and Keith West. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.
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Interactions between Nutrition and Infection in the Developing World
Keith P. West, Jr., DrPH, MPHJohns Hopkins University
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Keith P. West, Jr., DrPH, MPH
George G. Graham Professor of Infant and Child Nutrition in the Department of International Health at the Johns Hopkins Bloomberg School of Public HealthHas worked in international health for three decades, concentrating on the epidemiology and prevention of malnutrition in the developing worldPresently directing a large research project on maternal and child micronutrient deficiency prevention in northern Bangladesh
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Overview
Section A−
Defining and Quantifying Undernutrition
Section B−
The Effects of Undernutrition on Infection
Section C−
Micronutrient Deficiencies
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Section A
Defining and Quantifying Undernutrition
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Food and Agriculture Organization (FAO) of the United Nations, 2001
Definitions Related to Undernutrition
Undernutrition−
Result of undernourishment, poor absorption and/or poor biological use of nutrients consumed
Vulnerability−
Presence of factors that place people at risk of becoming food insecure or malnourished, including factors that affect their health and ability to cope
Vulnerable group−
Group of people with common characteristics, a high proportion of whom are food-insecure or at risk of becoming food insecure
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Undernutrition Leads to Deficiencies in . . .
1.
Protein−
Deficit in amino acids needed for cell structure, metabolic function
2.
Energy−
Calories (joules) derived mostly from macronutrients
a.
Proteinb.
Carbohydrate
c.
Fat3.
Micronutrients−
For example, vitamins A, D, E and K; B-complex (thiamin [B1], riboflavin [B2], niacin, folate, pyridoxine [B6], cyanocobalamin
[B12]), vitamin C; iron, zinc,
iodine, calcium, others
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Undernutrition can be milder, “hidden,”
affecting:•
Survival
•
Development•
Behavior
•
quality of life•
economic potential.
Undernutrition Can Be Hidden
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Undernutrition
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Population Distribution of Nutritional Status
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Population Distribution of Nutritional Status
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Population Distributions of Micronutrient Status
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Malnutrition Anthropometric Definitions
Underweight−
Weight for age < -2 SD of the median value of the NCHS/WHO reference; BMI < 18.5 (wt in kg/Ht2
in m) in adults
Stunting−
Height for age < -2 SD of the median value of the NCHS/WHO reference
Wasting−
Weight for height < -2 SD of the median value of the NCHS/WHO reference
Overweight−
Weight > 2 SD above median value of NCHS/WHO reference; BMI > 25 in adults
Obesity−
BMI > 30 kg/Ht2
in adults
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Normal (> -
2 SD HAZ)Stunted
(< -2 SD HAZ)
Normal(> -2 SD WHZ) Normal Stunted
Wasted(< -2 SD WHZ) Wasted Stunted and wasted
Classification of Child Undernutrition by Anthropometry
General classification of child undernutrition by anthropometry (Waterlow classification)
Height for age
Weight for height
Waterlow, J. C. (1977). BWHO, 55, 489.
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Weight for Age by Region
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Proximal Causes of Childhood Undernutrition
Maternal undernutrition leading to intrauterine growth retardation (IUGR; small size at birth)Chronic low energy and protein intake−
Unclean/non-nutritious, complementary foods of low energy and micronutrient density
−
Too early displacement of breast−
Dilution of formula
−
Exclusive breast feeding for too longInfection (e.g., measles, diarrhea, others)Xenobiotics (aflatoxins)
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Complementary Feeding in Developing Countries
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Breast Feeding . . .
Breast milk supplies ideal mix, density, and physiologic form of nutrients to promote adequate infant growth and developmentReduces exposure of infant to enteropathogens Antibacterial and antiviral Reduces infant infectionsProvides biologic and emotional bond between mother and infant Healthy for mother—reduces risk of ovarian and breast cancer, post-partum hemorrhage and anemia;increases birth spacingLow cost
Photo source: K. West, Jr.
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Nutritional Concerns about Complementary Feeding
Density and total intake of energyQuality vs. quantityHygienic deliveryAppropriate age at introductionImpact of complementary feeding (CF) intake on breast milk intake
Source: Piwoz
et al. (2003). FNB.
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Section B
The Effects of Undernutrition
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Malnutrition–Infection Interactions
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General Effects of Undernutrition on Immune System
Diminished T-cell help in immune responses dependent on mature CD4 cellsDelayed Ab responses to certain AgDepressed mucosal SIgA and associated Ab in response to mucosal infectionsImpaired complement activationImpaired opsonic activityThymic atrophy
Source: Keusch, G. T. (1999). Trop Infectious Diseases.
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Effects of Infection on Nutritional Status
Protein catabolism and negative nitrogen balanceAltered priorities for protein anabolismDepletion of CHO storesIncreased resting energy metabolismIncreased gluconeogenesisPeripheral insulin resistanceAltered lipid metabolismTrace element (Fe, Cu, Zn) redistributionIncreased vitamin utilization and excretion
Source: Keusch, G. T. (1999). Trop Infectious Diseases.
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The “Vicious Cycle” of Undernutrition and Infection
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Wasting Lengthens Infection
Diarrhea in South Asian children (e.g., children under 24 months in Bangladesh)
Black et al. (1984). Am J Clin Nutr.
Weight for length Duration
(mean days)
Incidence(episodes per
1,000 child days)
Percent median≥90%80–89%<80%
6.88.5
10.6*
16.916.216.4
*p < 0.05
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Nutritionalstatus
(% median) nAttack rate per
child in 3
months% time with
diarrhea
Weight/age>75%<75%
220123
1.21.5
8.511.3*
Height/age>90%<90%
24598
1.41.4
7.910.8*
Weight/height>80%<80%
30241
1.31.9*
7.613.6*
Undernutrition and Incidence and Duration of Diarrhea
Undernutrition and incidence and duration of diarrhea in African children
Source: Tomkins, A. (1981). Lancet.
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Infection/Morbidity Impairs Weight Gain
Country Age Diarrhea Fever Apathy
Uganda 6–36 -5.4 -4.0 –
Bangladesh 6–48 -5.0 – –
Bangladesh 6–32 -4.4 -10.3 –
Jamaica 9–48 -8.4 -16.8 -15.0
Guatemala 12–36 -3.5 – -2.3
GambiaRuralUrban
6–360–24
-25.8-3.7
-20.0–
––
Sudan 3–12 -32.1 -29.5 –
Weight gain per day of illness (g)
Source: Walker, S. P., et al. (1992, September). Am J Clin Nutr, 56(3), 504–510.
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Effects of Severe Undernutrition Persist after Recovery
One year after discharge, Bangladesh−
Diarrhea
67%
−
Pneumonia
58%−
Mortality
2.3%
−
Mean WHZ
adequate−
Mean HAZ
very low
Returning to same high-risk home setting
Source: Khanum
et al. (1998). Am J Clin Nutr, 67, 940–945.
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Relative Risk of Death by Cause Attributed to Underweight
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Each year due to child and maternal undernutrition…
– 3.75 million deaths– 137 million DALYs– Ezzati et al. (2002). Lancet, 360, 1347
Total population attributable rise(PAR) = 0.87 + 1.42X – 0.0075X2
Malnutrition Prevalence and Malnutrition Deaths
As the percent of children who are malnourished increases in a population, so too does the proportion of child deaths attributable to undernutrition
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PAR: Potentiating Effects of Mild to Moderate Malnutrition
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Major Causes of Death among Children
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Major Causes of Death among Children
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Section C
Micronutrient Deficiencies
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Micronutrient Deficiencies: Hidden Hunger
About 2 billion people affectedMajor deficiencies−
Iodine, vitamin A, iron, and zinc
Effects−
Poor growth, increased morbidity, impaired intellect, increased mortality
Preventable−
Supplements, fortification, diet change
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Micronutrient Deficiencies and Infection
Vitamin A deficiency−
Increases risk of severe diarrhea, fp
malaria, measles
severity; child mortalityZinc deficiency−
Increases risk of diarrhea, ALRI, fp
malaria; (likely
child mortality)Iron deficiency−
Unclear effects on infectious disease risk
Other micronutrient deficiencies−
Adverse effects on host defenses are likely but remain to be elucidated
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Metaplasia, impaired immunity,
morbidity, anemia, poor growth
Corneal blindness
Xerophthalmia
Tissue and plasma
depletion
Chronic dietary
deficit
Mor
tality
risk Systemic
effects
Vitamin A Deficiency Disorders
Gradient of health consequences
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Dietary Diversification
38Photo source: K. West, Jr.
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Xerophthalmia
Source: CDC
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Child Mortality and Mild Eye Signs
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Fever-Related Mortality—Sarlahi, Nepal
0.66
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Vitamin A Deficiency and Preschool Child Mortality
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Vitamin A Reduces Measles Case Fatality Rate (CFR)
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RR (VA/control) 95% CI
Clinic attendances 0.88 (0.81-0.95)
Hospital admissions 0.62 (0.42-0.93)
Mortality 0.81 (0.68-0.98)
Arthur et al. (1992). Lancet.Ghana Vast Team. (1993). Lancet.
Vitamin A and Severity of Morbidity: Ghana VAST Trials
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Report of a Joint WHO/USAID/NEI Consultation of Principal Investigators
International Vitamin A Consultative Group
Vitamin A Policy Statements
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Zinc Deficiency
Vast problem!Highly prevalent in cultures with−
Low meat and fish (low zinc) intakes
−
High grain (high phytate) intakes
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Effects of Zinc Deficiency on Immune FunctionReduces nonspecific immunity, including PMN and NK function and complement activityReduces T and B lymphocytesMultiple effects on function, including suppressed delayed hypersensitivity, cytotoxic activity and antibody production
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Daily Zinc Supplement Use and Diarrhea and Pneumonia
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49USAID-JHU Workshop, June 2004
Zinc for Treating and Preventing Acute Diarrhea
Treatment (based on 12 RCTs): Zinc ~2x RDA…−
Reduced duration by ~15%
−
Reduced severity by ~20% (for episodes of >7 d)−
Reduced stool output and frequency
−
Reduced antibiotic usePrevention (based on 3 RCTs, 2–3 mo surveillance): Zinc for 14 d after end of episode of acute diarrhea at 2–4x RDA…−
Reduced incidence of diarrhea by 11%
−
Reduced prevalence of diarrhea by 34%
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WHO/UNICEF Joint Statement
More than 1.5 million children die of acute diarrhea each yearCase fatality can be reduced with ORS, fluids in the home, breast feeding, continued feeding, selective use of antibiotics and zinc supplementation for 10–14 daysProvide 20 mg per day of zinc (half-dose < 6 mo)Available in 20 mg dispersible tablets as zinc sulfate
June 2004
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1Mahalanabis et al. (2002). Am J Clin Nutr.2Zinc Against Plasmodium Study Group. (2002). Am J Clin Nutr.
Efficacy of Zinc in Therapy of Measles and Malaria
Indian study found no effect of 20 mg zinc per day in therapy of measles1
Multicenter study (Ecuador, Ghana, Tanzania, Uganda, Zambia) found no effect of 20/40 mg zinc per day in therapy of malaria2
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Zinc and Malaria Attacks in Papua New Guinea
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Efficacy Trials of Zinc Supplementation on Child Mortality
Children 1–35 months old (30,000–70,000)Randomized, controlled trialsAll children receiving vitamin AZanzibar−
Zinc and/or iron and folate factorial
Nepal−
Zinc and/or iron and folate factorial
India−
Zinc (all receive iron and folate)
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Conclusions: Zinc Supplementation
Reduces diarrhea, pneumonia, and possibly malaria incidenceReduces diarrhea duration and severityPreliminary—may reduce child deathSupplements and fortification along with iron (and other MN) need more study
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Iron: Double-Edged Sword?
Iron supplementation increases hemoglobin production and reduces risk of anemiaBut potential hazardous effect of iron on infection—based on reviews,* generally where malaria is endemic, iron…−
Increased episodes of clinical malaria (5/9 trials)
−
Increased episodes of other infections in 4/8 trialsMechanisms related to malaria−
Iron supplementation may inhibit zinc absorption
−
Iron is essential for pathogen (plasmodium, bacteria) growth
*Oppenheimer, S. (2001). J Nutr, 131, 616S–635S.
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56Sazawal
et al. (2006). Lancet, 367, 133–143.
Iron + Folic Acid Trial in Pemba, Zanzibar
Randomized, double-masked, 2 x 2 factorial trial of daily iron (12.5 mg) + folic acid (50 ug), zinc, or both vs. placeboN = 24,076 children 1–35 months of ageHalf-doses to infants 1–11 months of age
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Outcome RR (95% CI) p-value
Mortality (n = 295) 1.15 (0.93–1.41) 0.19
Hospitalization (n = 1840) 1.11 (1.01–1.23) 0.03
Adverse event (n = 2135) 1.12 (1.02–1.23) 0.02
Effect of Iron + Folic Acid (± Zinc)
Effect of iron + folic acid (± zinc) on mortality and hospital admissions
Sazawal
et al. (2006). Lancet, 367, 133–143.
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Micronutrient Deficiency Prevention
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Dietary Diversification
Photo source: K. West, Jr.
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Micronutrient Supplementation
Photo source: K. West, Jr.
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Fortification with Micronutrients
E.g., The UN World Food Programme is establishing regional mill capabilities in Bangladesh to fortify wheat flour with iron, zinc, vitamin A, and multiple water-soluble vitamins