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Author Manuscript
Food Nutr Bull. Author manuscript; available in PMC 2014 December 06.
Published in final edited form as:
Food Nutr Bull. 2014 June ; 35(2 0): S64S70.

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Childhood malnutrition: Toward an understanding of infections,

inflammation, and antimicrobials
Kelsey D. Jones,
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; Imperial College, London
Johnstone Thitiri,
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
Moses Ngari, and
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
James A. Berkley
KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya; University of Oxford, Oxford, UK

Abstract
BackgroundUndernutrition in childhood is estimated to cause 3.1 million child deaths
annually through a potentiating effect on common infectious diseases, such as pneumonia and
diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter
nutrient intake, absorption, secretion, diversion, catabolism, and expenditure.

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ObjectiveA narrative overview of the current understanding of infections, inflammation, and

antimicrobials in relation to childhood malnutrition.
MethodsSearches for pivotal papers were conducted using PUBMED 1966-January 2013;
hand searches of the references of retrieved literature; discussions with experts; and personal
experience from the field.
ResultsAlthough the epidemiological evidence for increased susceptibility to life-threatening
infections associated with malnutrition is strong, we are only just beginning to understand some of
the mechanisms involved. Nutritional status and growth are strongly influenced by environmental
enteric dysfunction (EED), which is common among children in developing countries, and by
alterations in the gut microbiome. As yet, there are no proven interventions against EED.
Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown
striking efficacy on mortality and on growth in children with uncomplicated severe acute
malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may
act indirectly by reducing subclinical infections and inflammation. We describe an ongoing

2014 (supplement), The Nevin Scrimshaw International Nutrition Foundation.

Please direct queries to the corresponding author: James A. Berkley, KEMRI/Wellcome Trust Research Programme, PO Box 230,
Kilifi, 80108, Kenya; jberkley@kemri-wellcome.org.
Authors contributions
All authors contributed to discussion and development of the ideas contained in this manuscript. James A. Berkley wrote the first
draft, which was reviewed and edited by all of the other authors.
Conflicts of interest
The authors declare no conflicts of interest.

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multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent

death in children recovering from complicated SAM. Secondary outcomes include growth,
frequency and etiology of infections, immune activation and function, the gut microbiome, and
antimicrobial resistance. The trial is expected to be reported in mid-2014.

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ConclusionsAs well as improving nutritional intake, new case management strategies need to
address infection, inflammation, and microbiota and assess health outcomes rather than only
anthropometry.
Keywords
Antibiotics; infection; immunity; microbiome; nutrition

Introduction
Undernutrition in childhood, including fetal growth restriction, stunting, wasting,
deficiencies of vitamin A and zinc, and suboptimal breastfeeding, has recently been
estimated to cause 3.1 million child deaths annually, representing 45% of all childhood
mortality [1]. Most of these deaths are from infections, such as pneumonia and diarrhea.
Overt infections that are not fatal and subclinical infections alter nutrient intake, absorption,
secretion, diversion, catabolism, and expenditure and thereby affect growth. Environmental
enteric dysfunction (EED) is also emerging as a widespread and important cause of chronic
inflammation in the developing world that contributes to this cycle. We aimed to give an
overview of the current understanding of infections, inflammation, and antimicrobials in
relation to childhood malnutrition.

Methods
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Searches for pivotal papers were conducted using PUBMED 1966January 2013; hand
searches of the references of retrieved literature; discussions with experts; and personal
experience from the field.

Results
Epidemiology of infection in relation to malnutrition
The increased childhood mortality associated with undernutrition is almost entirely due to
the elevated risk of death from common infectious diseases such as pneumonia, diarrhea,
and bacterial sepsis. Pooled global data show that the increased susceptibility occurs across
the nutritional status spectrum. Among young children in community settings, a mild degree
of acute malnutrition is associated with slightly increased risks, while moderate acute
malnutrition (MAM) and severe acute malnutrition (SAM) are associated with
correspondingly greater risks [2, 3]. Although SAM is associated with the greatest risk of
death, worldwide it is relatively uncommon. Moderate wasting and stunting are far more
common and are responsible for the greatest proportion of childhood mortality attributable
to undernutrition. This was elegantly shown in an analysis of data from Senegal by Garenne
and colleagues in 2006 [4].

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A vicious cycle between malnutrition and infection has been long recognized (fig. 1A).
Episodes of infection potentiate undernutrition via anorexia, reduced nutrient absorption,
nutrient losses (such as vitamin A and proteins in diarrhea), diversion of nutrients to
inflammatory responses, and tissue repair. Diarrhea is associated with malabsorption and
marked losses of protein, vitamin A, zinc, and other micronutrients. All infections are
associated with net protein loss with diversion of amino acids to acute phase and immune
response proteins. Activation of inflammatory cascades also causes reduced appetite and
loss of lean tissue and fat. Thus, episodes of infection, especially diarrhea, result in both
linear and ponderal growth-faltering.
Catch-up growth may be seen between infectious episodes, provided adequate nutritional
intake is maintained and the interval between infections is long enough [5, 6]. Specific
pathogens may cause more persistent growth-faltering because they result in chronic
infections, chronic inflammation, or gut mucosal damage; these include HIV, tuberculosis,
cryptosporidiosis, and giardiasis.
Mechanisms of susceptibility to infection

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Although the epidemiological evidence for increased susceptibility to infection associated

with malnutrition and for growth-faltering during and following infections is strong, our
understanding of the cellular and molecular immunologic mechanisms, and of potentially
differential impacts of acute versus chronic undernutrition, is limited at present. For
example, one of the most frequently described immunologic abnormalities in acute
malnutrition is impaired cell-mediated immunity, as evidenced by reduced response to skin
test with tuberculin or candida antigens. Although this has conventionally been ascribed to
T-cell anergy (partly because of limited in vitro evidence of impaired T-cell mitogen
response), an important recent study showed that such defects may result from reduction in
the provision of appropriate help by cells of the innate immune system rather than by a Tcell-integral deficit [7]. Although numerous small and highly heterogeneous studies have
demonstrated various (and variable) abnormalities in innate immune function associated
with acute malnutrition, the overall picture of innate responsiveness in vivo remains unclear.
The developing understanding of the critical role of innate players in integrating divergent
environmental stimuli in the initiation and modulation of immune responses suggests that
this may be an important area for future work.
On the other hand, it is important to recognize that the presence of multifarious acute and
chronic infections in the context of reduced skin and mucosal integrity in children living in
deprived conditions will likely result in measurable immune abnormalities, regardless of the
presence of malnutrition. These factors, and their presence at varying levels in both cases
and properly selected controls, represent extremely important potential confounders in all
human studies of immune responses to malnutrition. It is noteworthy that antibody responses
to routine childhood vaccinations, the generation of which is considered a proxy for a whole
pathway of immune activation, appear to be preserved in malnourished children [8].
Longitudinal studies during nutritional rehabilitation of cohorts of malnourished children
who are carefully characterized clinically, immunologically, and in terms of diarrhea
infection, could help to resolve this issue.

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There have been a number of important recent immunologic breakthroughs that have direct
relevance for understanding the relationship between infection and nutrition. These include
the recognition that retinoic acid (a vitamin A metabolite) signaling pathways are
functionally essential to the generation of Th1 and Th17 responses in a murine model [9],
the emergence of the critical dynamic role of hepcidin in regulating iron trafficking during
infection and its interaction with innate effector mechanisms [10], and the discovery of the
Th22 T-cell subclass, which appears to be important in the regulation of intestinal
inflammation and is potentially subject to regulation by some dietary factors [11].
Other factors influencing nutrition and infection
The interaction between undernutrition and infection is influenced by a syndrome of chronic
enteropathy with reduced mucosal barrier function, called environmental enteric dysfunction
(EED), which may affect the majority of children living in developing countries [12].
Importantly, markers of enteropathy have been associated with stunting in studies in Gambia
and Malawi [13, 14], and stunting itself is associated with mortality and impaired
development. The etiology and epidemiology of EED have not yet been fully described, and
although household living conditions appear important [15], any relationships between EED
and infections with specific enteric pathogens, weaning practices, or specific nutritional
factors have not been established. Clinical trials of a gut-specific antimicrobial, rifamixin,
and of a probiotic organism, Lactobacillus GG, in Malawi had no effect on enteropathy [16].
Interactions between inflammation and growth may not be entirely gut-specific, since other
chronic inflammatory conditions in childhood, such as juvenile arthritis, are also associated
with growth impairment.

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It is becoming clear that the gut microbiome plays an important role in growth and
nutritional status through processing nutrients and immunological and metabolic signaling.
The composition of gut microbiota varies with age, and between developed and developing
country settings [17]. In a landmark study, Smith and colleagues have recently shown that
germ-free mice colonized by gut microbiota from Malawian children with kwashiorkor
exhibited an immature gut metabolic profile and became wasted when fed a typical
Malawian diet (unlike mice colonized with the microbiome of a non-malnourished co-twin,
which did not lose weight). Nutritional rehabilitation resulted in a temporary restoration of
metabolic maturity [18].
Intergenerational, preconceptional, and antenatal factors and the development of the infant
immune system are also likely to be important and have recently been reviewed by Prentice
and colleagues [19].
Antimicrobials in SAM
Since 1999, the World Health Organization (WHO) has recommended that all severely
malnourished children receive a broad-spectrum antibiotic, regardless of whether or not
clinical features of infection are present. The rationale behind this is that acute infections can
be difficult to diagnose accurately, since malnourished children may not show the usual
clinical signs of infection [20]. In fact, the use of antimicrobials in malnourished children
without overt signs of infection was published as early as 1957. In Nairobi, Dr. Lorna

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MacDougall conducted a trial of aureomycin versus placebo among 72 severely

malnourished children without signs of infection and demonstrated a threefold increase in
daily weight gain [21].

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Antibiotics have long been used as animal growth promoters in the agricultural sector. In
early experimental work with chicks, it was observed that addition of procaine penicillin to
the diet improved growth when chicks were kept in dirty conditions, but not if they were
housed in clean conditions, and a transmissible infectious agent was suspected to be
affecting growth [22]. In a subsequent trial published in 1963 by Eyssen and de Somer,
chicks temporarily lost weight when fecal contamination was introduced into their quarters,
but this effect was eliminated by administration of virginiamycin (fig. 2) [23]. This suggests
a direct effect of antibiotics on nutritional status in response to insults from an unhealthy
environment.

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The need for a routine course of oral antibiotics in children with uncomplicated SAM with
good appetite and no signs of infection has been questioned, and some therapeutic programs
and clinics have not prioritized oral antibiotics. In Malawi, Manary and colleagues initiated
a formal, double-blinded, randomized, controlled trial in three arms: placebo, amoxicillin
(recommended by WHO), or an oral third-generation cephalosporin, cefnidir [24]. The
decision to include a cephalosporin was informed by the antimicrobial sensitivity patterns
observed in bacteria isolated from children admitted to a nearby hospital, where resistance to
amoxicillin was common. The results showed a highly statistically significant reduction in
mortality during 12 weeks of follow-up from 7.4% in the placebo arm to 4.8% in the
amoxicillin arm and 4.1% in the cefnidir arm. There were no statistically significant
differences in outcome between the two antibiotic arms. Growth was improved with
antibiotics, leading to greater gain in mid-upper-arm circumference (MUAC) in children
receiving antibiotics than in those receiving placebo and a non-statistically significant
increase in height gain. In an effort to replicate the conditions of normal practice at the study
sites, HIV testing of participants was not routinely conducted, despite a relatively high
prevalence of HIV infection compared to many other areas in sub-Saharan Africa. This has
led to discussion about the generalizability of the results to settings with lower HIV
prevalence and/or assured HIV testing programs. Furthermore, there are concerns over the
widespread use of a cephalosporin as first-line therapy in the community because of its
ability to induce resistance. At a therapeutic program in Niger where ceftriaxone was used
for complicated SAM in place of the recommended penicillin and gentamicin combination,
there was a huge rise in the prevalence of carriage of gram-negative bacteria carrying genes
for extended-spectrum beta-lactamase production giving resistance to multiple antibiotic
classes [25].
In the groundbreaking CHAP trial in Zambia of cotrimoxazole prophylaxis among HIVinfected children, not only did cotrimoxazole almost halve mortality [26], but it was also
associated with improved growth [27]. The protective efficacy of cotrimoxazole against
death in HIV-infected children is striking, given that it does not target the underlying
immunodeficiency of HIV infection. Other immunomodulatory effects are likely, especially
in view of the fact that cotrimoxazole has been shown to retain activity against pathogens

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(both bacterial and malaria) that demonstrate resistance to its direct antimicrobial effect in
vitro.

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The mechanisms by which these trials not only reduced mortality, but improved growth, are
not clear. They may include treatment of active (but covert) infection; prevention of
colonizing microorganisms causing disease; reduction of inflammatory responses, resulting
in less nutrient diversion and less cytokine-mediated impairment of growth through
hormonal control; nonantibiotic effects, including direct anti-inflammatory effects; reduction
in enteropathy; and alterations in gut microbiome.

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With these mechanisms in mind, and drawing on the wealth of experience in management of
pediatric HIV, we hypothesized that long-term antimicrobial prophylaxis might improve
both survival and growth in children admitted to hospital with complicated SAM (fig. 3). A
study evaluating long-term outcomes in Kilifi, Kenya, among children discharged from
hospital had identified underweight children as having very high mortality in the year after
discharge [28], similar to that found in Malawi during long-term follow-up of HIVuninfected children who were enrolled in the PRONUT trial of pre-/probiotic-enhanced,
ready-to-use therapeutic food (RUTF) (approximately 18% mortality within 1 year of
stabilization) [29]. The factors associated with postdischarge mortality are likely to
include incomplete correction of nutritional deficiencies; delayed immune reconstitution;
chronic immune stimulation and gut inflammation; a diet inadequate for immunologic
recovery; inadequately treated infections, including tuberculosis, viral infections, and occult
bacterial infections; a high burden of exposure to pathogens; and ongoing poverty and food
insecurity. Because of its diverse mechanisms of action, it is possible that cotrimoxazole
chemoprophylaxis could impact many of these potential problems. It has the added benefits
of proven prophylactic efficacy in the Zambian HIV trial; known efficacy in prophylaxis in
immunodeficiency conditions, including dysfunctional neutrophil function; an established
side effect profile in African populations; low cost; and widespread availability because of
its use in HIV programs.
We are currently conducting a double-blind, randomized, placebo-controlled trial of daily
cotrimoxazole prophylaxis among HIV-uninfected children who are admitted to two rural
and two urban hospitals in Kenya with complicated SAM (NCT00934492). The trial
includes children from 2 months to 5 years of age who are admitted to hospital usually
because of severe pneumonia or severe diarrhea and severe malnutrition, identified by
MUAC or the presence of edema. Infants as young as 2 months are included, because it is
increasingly recognized that infants under 6 months of age represent a significant proportion
of the case load of severe malnutrition [30]. In Kenya, as in many other developing
countries, complementary foods are commonly introduced as early as 2 months of age, often
with low nutritional value and the inherent risks of microbial contamination. In our trial,
children are randomly allocated to daily cotrimoxazole or placebo for 6 months and
followed up for 12 months. They are given standard medical and nutritional care following
WHO and national guidelines. The trial has greater than 90% power to detect a 33%
reduction in mortality during 12 months of follow-up. Secondary endpoints include toxicity,
growth, frequency and microbial causes of readmission to hospital, markers of inflammatory
response and growth regulators, phagocyte function, changes in gut microbiota, and nasal

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and rectal carriage of resistant bacteria. Recruitment was completed in March 2013, and the
last participant will be followed up to March 2014.

Conclusions
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It is clear that an enormous burden of child mortality results from malnutrition, as a

consequence of its potentiating effect on common infectious diseases. Most deaths, on a
population basis, are related to mild or moderate malnutrition. Despite improvements in
nutritional status in many countries in recent years, many populations include a large
proportion of young children whose nutritional status places them at elevated risk. We do
not yet have a full understanding of the mechanisms that cause increased susceptibility to
infection and how to tackle them. However, a combination of inadequate nutritional intake,
exposure to infections, and the home environment results in a complex interplay involving
chronic gut inflammation and alterations in the gut microbiota and its associated metabolic
functions.
Our current understanding of the relationships between undernutrition and infection is
summarized in fig. 1B. Traditional intervention strategies are largely focused on increasing
nutritional intake. The current view, however, is that in addition to nutritional interventions,
new approaches are needed that will also address infection, inflammation, and a disturbed
intestinal microbiome. Finally, when assessing interventions, clinical outcomes such as
episodes of infection should be measured, rather than anthropometric features alone.

Acknowledgments
We wish to thank our coinvestigators, team members of the CTX trial, and collaborators for enlightening
discussions. We especially thank the staff at the trial sites and the participants and their families. This article is
published with permission from the Director of the Kenya Medical Research Institute.

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Kelsey Jones and James Berkley are funded by personal fellowships by the Wellcome Trust (UK) and a Grand
Challenges Explorations grant from the Bill & Melinda Gates Foundation.

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FIG. 1.

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A. Historical view of the vicious cycle of malnutrition and infection. B. Our current
understanding also involves subclinical infection, intestinal inflammation, and altered gut
microbiota

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FIG. 2.

Effect of an antibiotic on the weight of chicks housed in a clean environment (new quarters)
before and during introduction of contamination from chicks housed in a dirty environment
(old quarters) H. Eyssen and P. de Somer, 1963. Originally published in The Journal of
Experimental Medicine 117:127-38

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FIG. 3.

Hypothesis underlying a randomized, double-blind, controlled trial of daily cotrimoxazole

prophylaxis following stabilization in HIV-uninfected children with complicated severe
acute malnutrition (SAM)

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