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U.S. Department of Agriculture Western Human Nutrition Research Center, UC Davis Department of Nutrition, University of California, Davis, CA 95616–8669
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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KEY WORDS: • infection • diarrhea • pneumonia • inflammation • acute phase response • linear growth • stunting
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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This paper will briefly consider the following three questions related to the effect of infection on the linear growth of children who grow up in such settings. 1) Do infections affect linear growth and, if so, which infections have the largest impact? 2) How do infections affect linear growth? The answer to this question will focus primarily on the detrimental effect of infection on nutritional status but will also consider the possibility that certain infections may affect the physiologic processes of linear growth more directly. 3)Which public health interventions can diminish the impact of infection on linear growth?
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IMPACT OF INFECTION ON LINEAR GROWTH |
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TOPABSTRACTINTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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). All diarrheal
pathogens do not have the same impact on growth, however. A
longitudinal, 1-y community surveillance of infants enrolled at birth
in The Gambia showed that while an infant was suffering from diarrhea,
~1 mm of length per week was lost compared with his or her own growth
rate during diarrhea-free periods (Rowland et al. 1977
). A similar
study in rural Bangladesh revealed that a child without diarrhea would
gain, on average, 0.42 cm more per year than would a child with the
average prevalence of diarrhea (13% of days) (Black et al. 1984
). More
specifically, Shigella infection (which causes dysentery, an
invasive diarrheal disease) was significantly associated with impaired
linear growth, whereas infection with enterotoxigenic Escherichia
coli or rotavirus (both of which cause watery diarrhea) was not
associated with such deficits. In Brazil, hospitalization for either
diarrhea or pneumonia during a 2-y period was associated with
diminished linear growth (as judge by changes in height-for-age
Z-scores) over that period of time (Victora et al. 1990
). The relative
effect of diarrhea (-1.11 SD for children hospitalized with
diarrhea compared with -0.64 SD for those not hospitalized
with diarrhea; P < 0.001) was somewhat greater than
was that of pneumonia (-0.87 SD for children hospitalized
with pneumonia compared with -0.66 SD for those not
hospitalized with pneumonia; P < 0.001) in this
analysis. Thus, serious acute infections, particularly those that
involve the gastrointestinal tract, impair linear growth.
Chronic infections can also impair linear growth. Such infections may
be subclinical and thus asymptomatic from the viewpoint of the patient
or clinician. However, the cumulative effect of such infections may be
substantial if the appropriate indicator is examined. For example,
infection with Ascaris lumbricoides and other gut helminths
may not produce obvious symptoms of disease but can nonetheless impair
linear growth (Hlaing 1993
, Stephenson 1987
). Early infection with
human immunodeficiency virus
(HIV)2may also be asymptomatic; however, in a 6-y longitudinal study of the
growth of 109 infants born to HIV-infected mothers, infants who were
infected perinatally with HIV (n = 59) had impaired
linear growth by 15 mo of age (compared with the 50 uninfected
subjects) and eventually had a height deficit of ~8 cm (Saavedra et
al. 1995
). Opportunistic infections may have accounted for diminished
growth in some, but not all, children. Helicobacter pylori
can cause a chronic bacterial infection of the stomach and duodenum
and, in some cases, can cause gastric or duodenal ulcer disease. In a
cross-sectional study of 4742 randomly selected subjects 12–64 y of
age in Northern Ireland, past H. pylori infection (diagnosed
with serum antibody) was found to be associated with shorter attained
height in adult women (-0.8 cm, P < 0.05) and men
(-0.6 cm, P < 0.05) after adjustment for other
variables (Murray et al. 1997
). Similar observations have also been
made in Italian children (Perri et al. 1997
). Although it has not yet
been demonstrated that this association is causal, these results imply
that linear growth retardation by infectious diseases is not limited to
poor children living in developing countries.
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IMPACT OF INFECTION ON NUTRITIONAL STATUS |
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TOPABSTRACTINTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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, Rahman et al. 1996
, Sommer et al. 1987
). Micronutrient deficiencies may be produced
by infectious diseases in one of the following five ways: 1)
decreasing food intake (anorexia); 2) impairing nutrient
absorption; 3) causing direct micronutrient losses;
4) increasing metabolic requirements or catabolic losses;
and 5) impairing transport to target tissues (although this
has not been demonstrated conclusively).
Acute infections lead to decreased food intake, although breast-milk
intake may be largely unaffected. The magnitude of the decreases is
typically related to the severity of infection. Community studies in
Guatemala have shown that children with acute respiratory infections or
diarrhea consume ~8 and 18% fewer total calories per day,
respectively, than do children without these infections (Martorell et al. 1980
). More severe infections can lead to much larger deficits in
food intake. African children examined during the acute phase of
measles consumed 75% fewer total calories than they did after recovery
(Duggan et al. 1986
). Interestingly, a community study from Peru has
shown that breast-milk intake is not diminished by infection (Brown et al. 1990
). Although total energy intake from non-breast–milk sources
in a cohort of 131 Peruvian infants decreased by 20–30% when they had
diarrhea or fever, no measurable decrease was seen in breast-milk
intake. Thus the total deficit in calories was only 5–6% and was
accounted for entirely by decreased intake of non-breast–milk foods.
Enteric infections such as diarrhea and gut helminth infections can
lead directly to malabsorption of nutrients, but other infections may
also impair absorption. Both acute diarrhea, caused by bacteria,
viruses and protozoa, and chronic intestinal helminth infections (e.g.,
caused by A. lumbricoides) can damage intestinal mucosal
epithelial cells and thus impair absorption of both macro- and
micronutrients (Mata 1992
, Stephenson 1987
). The severity of the
infection (as measured by the extent of tissue damage, volume of
diarrhea or number of helminth ova per gram of stool) often predicts
the magnitude of malabsorption. Even nonenteric infections may affect
absorption, although the mechanism is unclear. For example, although
uninfected children absorb 99% of a tracer dose of vitamin A, and
children with diarrhea and Ascaris infection absorb 70 and
80%, respectively, children without apparent enteric infection who
have pneumonia absorb only 74% of the dose (Sivakumar and Reddy 1972 and 1975
).
Even after nutrients are absorbed, they may still be lost as a result
of infection with a number of pathogens that can cause direct nutrient
loss, most commonly into the gut or urine. It appears that all febrile
infections cause leakage of low-molecular-weight proteins into the
urine. Although this phenomenon may cause some protein loss, one of the
proteins lost may be retinol-binding protein (RBP), the serum transport
protein for vitamin A. Thus vitamin A may be directly excreted into the
urine with the losses increasing as the severity of infection increases
(Stephensen et al. 1994
). Direct tissue damage can also cause loss of
nutrients in the urine. Egg production by adult pairs of
Schistosoma haematobium living in the vesicular vein will
lead to deposition of these eggs in the wall of the urinary bladder (as
they make their way to the external environment; Stephenson 1987
).
Trapped eggs will cause granuloma formation in the wall of the bladder
and will result in blood loss in the urine. A high intensity of
infection will increase bladder damage and will lead to more blood
loss. Perhaps the best known example of direct nutrient loss is the
blood loss caused by hookworm infection (Stephenson 1987
). These
parasites directly damage the intestinal mucosa in order to derive
nutrients for their own growth. The resulting blood loss can amount to
several milliliters per day and can lead directly to the development of
iron-deficiency anemia, with the severity of the anemia being directly
proportional to the intensity of infection. Other enteric infections
due to diarrheal pathogens can cause effusion of serous fluid into the
gut, resulting in loss of serum proteins. This condition is exacerbated
by measles virus infection and is called "protein-losing
enteropathy" (Sarker et al. 1986
).
Nutrient requirements may also be increased during infection. Although
this has not been well documented for micronutrients, resting energy
expenditure (REE) (and thus basal energy requirement) is increased.
This phenomenon was recently documented in patients with HIV infection
(Melchior et al. 1993
). Subjects with asymptomatic HIV infection had a
mean REE 16% greater than that of uninfected subjects, whereas
HIV-infected subjects who also had opportunistic infections had a mean
REE 57% greater than the control subjects. Infection, inflammation or
increased oxidative stress may also increase catabolic loss of certain
nutrients. For example, increased oxidative stress in the respiratory
tract, particularly in smokers, is thought to lead to increased
catabolic losses of folate (Heimburger 1992
).
Finally, infection with most microorganisms leads to activation of
macrophages and neutrophils by microbial products or by proinflammatory
mediators (e.g., prostaglandins) produced by damaged cells. The release
of the proinflammatory cytokines tumor necrosis factor (TNF)-
,
interleukin (IL)-1ß and IL-6 results in induction of the systemic
acute phase response (Baumann and Gauldie 1994
). This response will
lead directly to responses by the central nervous system (e.g.,
induction of fever and production of cortisol to down-regulate
inflammation) and the liver, which includes the increased production of
positively regulated acute phase proteins (e.g., C-reactive protein, or
CRP) and the decreased synthesis of others, including RBP, which
results in decreased serum retinol concentration. Serum iron and zinc
concentrations are also decreased during the acute phase response. It
is unclear whether these reductions in the serum micronutrient
concentrations lead to decreased transport to target tissues. It has
been suggested that chronic inflammatory diseases such as rheumatoid
arthritis cause a mild, micro- to normocytic, hypochromic anemia termed
the "anemia of chronic disease" (Walter et al. 1997
). This seems
plausible, but the cytokines produced during chronic inflammation may
directly affect hematopoiesis and thus produce the anemia. It is also
plausible that decreased serum retinol concentrations during infection
could lead to decreased tissue concentrations of vitamin A, as recently
discussed (Olson 1995
); however, concrete data are lacking. Thus, the
true effect of altered serum micronutrient concentration on the
nutritional status of the host, or of specific tissues in the host,
remains uncertain.
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POSSIBLE DIRECT IMPACT OF INFECTION ON LINEAR GROWTH |
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TOPABSTRACTINTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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, IL-1ß and IL-6 may
directly affect the process of bone remodeling that is required for
long bone growth. For example, osteoclasts are produced from the same
myeloid precursor cell which, depending on the signals received, can
also differentiate into monocytes. Although the network of cytokines
and growth factors involved in the regulation of myeloid cell
development is complex, increased production of TNF- could lead to
increased production of macrophages and diminished production of
osteoclasts (Skerry 1994
). The proinflammatory cytokines, particularly
IL-6, may also directly affect osteoclast development and activity and
may play a role in the pathologic bone loss seen in osteoporosis or in
Paget's disease, which is characterized in part by increased osteoclast
activity (Barton 1997
). IL-6 is also hypothesized to play a pathologic
role in the impaired growth seen in children with inflammatory bowel
disease. Malabsorption could play a role in this impaired growth but is
apparently not the complete explanation because nutritional support
does not fully restore normal growth. Experimental colitis in rats was
induced as a model of inflammatory bowel disease and the effects on
tibial growth plates were examined (Koniaris et al. 1997
). A decrease
in the proliferative zone was found compared with pair-fed control
animals without colitis, and the extent of the decrease correlated with
increased serum IL-6 concentrations. Thus, acute or chronic
inflammation may modulate long bone growth via induction of IL-6
production.
Viral infection of osteoclasts or osteoblasts might also affect long
bone growth. Osteoclasts can be infected with paramyxoviruses, such as
the measles virus, and such infection may thus also play a role in bone
loss, again including Paget's disease (Shepard et al. 1996
). It is also
plausible that HIV, many strains of which infect macrophages, could
infect osteoclasts and thus directly affect linear growth. Such a
phenomenon could account for the observation in the cohort of infants
infected perinatally with HIV (Saavedra et al. 1995
) that linear growth
was impaired at 15 mo of age, long before weight gain
(weight-for-height) was affected (at 36 mo of age). Although this
mechanism is speculative, it is clear that there are multiple pathways
by which acute or chronic infections could directly modulate long bone
growth.
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INTERVENTIONS TO DIMINISH THE IMPACT OF INFECTION ON LINEAR GROWTH |
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TOPABSTRACTINTRODUCTIONIMPACT OF INFECTION ON...IMPACT OF INFECTION ON...POSSIBLE DIRECT IMPACT OF...INTERVENTIONS TO DIMINISH THE...REFERENCES |
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). Promotion of breast-feeding will also
decrease the morbidity from diarrhea and other infections, and will
help maintain nutrient intake during infection (Brown et al. 1990
).
Targeted therapeutic interventions to decrease the incidence of gut
helminth infections, such as Ascaris infection, have been
shown to improve linear growth among children where such infections are
prevalent (Hlaing 1993
). Such selective chemotherapy, combined with
improvements in sanitation to interrupt transmission, could well have
significant benefits with regard to childhood growth.
In closing, it should be noted that all of these interventions can be
justified on the grounds that they will decrease the total burden of
disease during childhood. However, because such interventions will also
decrease the incidence of stunting and wasting, they will also decrease
the long-term (indeed, intergenerational) detrimental effect of
malnutrition on populations. This point should be made to policy makers
in the health field because it is important to understand that the
benefit of improving nutritional status can be measured long after the
immediate effect on the health of individual children has been assessed
(Martorell 1995
).
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FOOTNOTES |
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2 Abbreviations used: HIV, human immunodeficiency
virus; IL, interleukin; RBP, retinol-binding protein; REE, resting
energy expenditure; TNF, tumor necrosis factor.
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