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PEDIATRICS Vol. 103 No. 5 May 1999, p. e69
in Children Recovering From
Trichuris Dysentery Syndrome
From the Tropical Metabolism Research Unit, University of the West Indies.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Objectives. To explore: 1) the
relationship between plasma insulin-like growth factor-1 (IGF-1) and
other markers of growth; and 2) the effect of serum concentrations of
tumor necrosis factor 
(TNF) on growth variables in children (2-10
years) stunted by Trichuris dysentery syndrome (TDS),
recovering cases, and their matched controls.
Method. Fourteen patients with TDS were admitted to the Tropical Metabolism Research Unit, treated with albendazole and iron, and then followed with matched controls (n = 28) for 1 year. Anthropometric and biochemical measurements were done on admission and then every 3 months for the year. Plasma IGF-1, the carboxyterminal propeptide of type 1 procollagen, serum TNF, total serum protein, serum albumin, and complete blood count were determined.
Results. Low admission plasma levels of IGF-1 in TDS cases were accompanied by high serum levels of TNF, and total serum protein, normal serum albumin, low hemoglobin, reduced collagen synthesis (low plasma carboxyterminal propeptide of type 1 procollagen), and growth failure. These variables improved significantly after treatment. Plasma levels of IGF-1 were significantly related to the Z-scores for height-for-age (r = 0.60, 0.73, 0.68) and weight-for-age (r = 0.69, 0.80, 0.69) of cases and controls, height-for-age (r = 0.51, 0.52, 0.54) and weight-for-age (r = 0.51, 0.52, 0.54) at each measurement throughout the year. Serum levels of TNF were not related to any of the growth variables.
Conclusion. These findings may contribute to the
understanding of growth failure in children affected by other forms of
chronic inflammatory bowel disease.
Key words:
Trichuris dysentery
syndrome,
insulin-like growth factor-1,
type 1 procollagen,
tumor
necrosis factor .
Chronic infection with the geohelminth Trichuris
trichiura in children is significantly associated with anemia and
poor physical and cognitive development.1 Recent studies
in Jamaica have shown a prevalence rate of 38% in rural
schools.2 Trichuris dysentery syndrome (TDS) is
the most severe form of Trichuris infection. Severe growth
impairment occurs in the affected children. The children have chronic
diarrhea with blood and mucus, iron deficiency anemia, anorexia,
geophagia, and lower abdominal pain. Clubbing of fingers and toes may
also be present. Sometimes there is a prolapsed rectum with worms
adhering to the mucosa. Growth failure is reversed after the successful
treatment of the helminthiasis although the diet remains
unchanged.3 Cooper et al4 suggested that the
pattern of catch-up growth in TDS points to the existence of some
specific link between inflammation or allergy in the lower intestinal
tract and the suppression of linear growth.
Insulin-like growth factor-1 (IGF-1) is considered a good
biochemical marker for the evaluation of normal growth, growth
disorders, and nutrition in children.5 It is a growth
hormone-dependent peripheral effector of the anabolic actions of growth
hormone especially skeletal growth and hematopoiesis.6
IGF-1 is a 70-amino acid mitogenic polypeptide structurally homologous to proinsulin.7 It is synthesized in the liver and also in
cells of mesenchymal origin such as fibroblasts, smooth muscle cells,
and glomerular mesangial cells. Plasma IGF-1 concentration increases
during childhood, reaching a peak during puberty.8 There
is a wide range of reference values for each gender and age
group.5 The response to IGF-1 in tissues may be modulated by high-affinity IGF-1 binding proteins, six of which have been identified.6
Type 1 collagen accounts for more than 90% of the organic matrix of
bone. Circulating levels of the type 1 procollagen carboxyterminal propeptide (PICP) reflect the synthesis of type 1 collagen.9 A relationship has been shown between serum
levels of PICP and height velocity.10,11
Tumor necrosis factor There is a systemic as well as a mucosal component of the response to
infection with T trichiura. TDS is associated with an acute
phase plasma protein response. Cooper et al14 reported a
high median plasma viscosity during the first 6 months after treatment
in 53 children affected by TDS. In these children, 39% of the variance
in plasma proteins was explained by plasma levels of fibrinogen and
total globulin. A low mean SA was reported by Gilman et
al.15
In the complete blood count (CBC) there is a microcytic iron deficiency
anemia and a nonspecific leukocytosis in TDS.3
The objectives of this study were to explore 1) the relationship
between plasma IGF-1 and other markers of growth; and 2) the effect of
serum concentrations of TNF on growth variables in children (2-10
years) stunted by TDS, recovering cases, and their unaffected matched
controls.
Study Participants
Fourteen patients with TDS (2-10 years; mean age, 4.19 years; 8 boys and 6 girls), were diagnosed by colonoscopy, admitted to, and
treated at the Tropical Metabolism Research Unit, University of the
West Indies. The Trichuris was expelled in the hospital after treatment with albendazole (400 mg/day for 3 days) and each child
was given a course of iron (60 mg FeSo4 twice daily for 21 days). The
children were then followed as outpatients along with matched controls
(n = 28) for 1 year. The controls were matched for age
(±6 months), gender, socioeconomic status, and neighborhood.
Anthropometric measurements, height, weight, head circumference (HC),
mid-upper arm circumference (MUAC), and triceps and subscapular
skinfold thicknesses were conducted on each child on admission and then
every 12 weeks for 1 year. Additional measurements were done on the
cases at 3, 6, and 9 weeks after discharge. A single trained measurer
(E.M.W.D.) used the same methods and equipment (validated on each
measuring day) throughout the study.16 The mean percent
coefficient of variation (%CV) of the measurements were: height = 3.8%, HC = 1.7%, MUAC = 2.3%, triceps skinfold thickness = 6.7%, and subscapular skinfold thickness = 3.9%.
On admission and at each visit blood was drawn by venipuncture for CBC,
plasma determinations of IGF-1, and PICP. (EMLA topical anesthetic cream [Astra Pharmaceuticals, UK] was applied to the venipuncture site before sampling to avoid discomfort to the child.)
Serum determinations of TNF by radioimmunoassay (RIA), total serum
protein (TSP) and albumin (SA) by Abbott VP (Chicago, IL) analyzer, were done on the TDS cases, one sample on admission and two during recovery. One serum sample from each of the control children was used to determine reference values. A TDS child was considered to be recovering when his or her height velocity reached the
>90th centile, +1.8 standard deviation.17
The study was approved by the ethics committee of the Faculty of
Medical Sciences, University of the West Indies, and the Ministry of
Health, Jamaica. Before the start of the study, an informed written
consent was signed by a parent and/or guardian of each child. Children
with a history of asthma, sickle cell disease, heart disease, current
chronic infections, severe illness, or known growth disorders were
excluded from the study.
Laboratory Procedures
The plasma and serum samples were stored at IGF-1
IGF-1 was extracted from 250 µL of plasma using an
octadeca-sily-silica silica column extraction procedure. Levels of
IGF-1 were determined by RIA using an Incstar IGF-1 125I
RIA Kit (Stillwater, MN). The interassay variation for normal values was as follows: low values, %CV = 8.6; high values,
%CV = 10.7.
PICP
PICP was determined from 50 µL of plasma using a PICP
125I RIA equilibrium RIA kit from Incstar
(Stillwater, MN). The interassay variation for normal values was as
follows: low values, %CV = 2.8; high values, %CV = 13.0.
TNF
A BIOTRAK TNF Data were reduced using a Microsoft RIA curve-fitting
program. Assays were repeated on any samples showing an
intraassay CV >10%.
TSP and Serum Albumin (SA)
TSP and SA were determined using an Abbott VP (Chicago, IL)
analyzer. CBCs were done by the Department of Hematology, the University of the West Indies.
Data Analysis
Height-for-age, weight-for-age, and weight-for-height
Z-scores were calculated using the Centers for Disease
Control and Prevention (Atlanta, GA) Anthropometric Software
Package 1987 (CASP). Multivariate analysis of variance trend
analysis was used to determine any significant trends in the serially
measured variables. Paired t tests and Wilcoxon
matched pairs signed nonparametric tests were used to compare the
within-group variables. Independent samples, t tests, and
Mann-Whitney U nonparametric tests were used to compare between-group variables. Spearman's correlation coefficient and simple
linear regression analysis were used to determine any relationships among the variables. The Statistical Package for the Social Sciences (SPSS, Chicago, IL) Version 6.0 was used.
Anthropometric Markers of Growth
On admission, the mean Z-scores (National Child Health
Statistics) of the TDS children were significantly lower than
the controls. Mean height-for-age Z-score = TABLE 1 (TNF)/cachectin, a macrophage-induced
pleiotropic cytokine, has been implicated in the metabolic derangements of undernutrition and growth failure.12 Increased serum concentrations of TNF have been reported in children affected by
TDS.13
METHODS
Top
Abstract
Methods
Results
Discussion
References
20°C after the
addition of a protease inhibitor, aprotinin 5 µL/mL. All samples were
assayed in duplicate.
125I RIA system from Amersham
(UK) (Little Chafont, Buckinghamshire, UK) was used to
measure the serum levels of TNF on 100 µL of serum.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
2.79,
95% confidence interval (CI) 5.79, 0.21, P < .001;
mean weight-for-age Z = 2.75, 95% CI 4.95, 0.55,
P < .001; and mean weight-for-height Z = 1.53, 95% CI 3.33, 0.27, P < .001. The mean
Z-scores of the controls were 0.40, 0.60, and 0.37,
respectively (Table 1).
Comparison of Height-for-Age, Weight-for-Age, and Weight-for-Height
(Z-scores NCHS) of Trichuris Dysentery Syndrome
Cases and Controls, on Admission, 6 months, and 1 year*
The mean MUAC of the cases was 14.41 cm (95% CI 11.81, 17.01), significantly lower than the controls, 16.53 cm (95% CI 14.29, 18.77; P < .001), until 9 months after treatment. There were no significant differences in mean skinfold thicknesses. The mean HC of the cases, 47.42 cm (95% CI 43.42, 51.42), was also significantly lower than the controls, 50.15 cm (95% CI 46.65, 53.65; P < .001).
At the end of 1 year, the observed mean velocities in height, 8.82 cm/year (95% CI 4.42, 13.22; P = .004) and HC, 1.15 cm/year (95% CI 0.43, 2.73; P = .008) of the cases
were significantly higher than the controls. Mean HC, 48.87 cm (95% CI
44.99, 52.75; P = .006), and mean Z-scores
of the cases, height-for-age, 2.16 (95% CI 4.76, 0.44;
P < .001), and weight-for-age, 1.86 (95% CI 3.46,
0.26; P < .001), were still significantly lower than the controls. There was however, no significant difference in mean
weight-for-height Z-scores between the cases (0.70; 95% CI 2.1, 0.7) and the controls (0.28; 95% CI 1.74, 1.18).
IGF-1
On admission, 57% of the cases were below the IGF-1 reference range for their age and gender. The plasma levels of the controls were within the reference range.18 The median admission plasma level of IGF-1 in the cases, 6.0 nmol/L (range, 1.74, 11.64) was significantly lower than that of the controls, 16.34 nmol/L (range, 4.72, 39.58; P < .001).
Four weeks after worm expulsion, the cases had a significant rise in their median plasma level of IGF-1 to 9.66 nmol/L (P = .002). The median plasma levels of IGF-1 remained below those of the controls throughout the year. The differences were significant at the 6- and 9-month measurements (Table 2). The range of values, although wide, were within the ranges for IGF-1 in boys and girls of 2 to 10 years.18 The high upper limits of the distribution were explained by outliers (Fig 1).
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Associations With Plasma Levels of IGF-1
In both cases and controls, height-for-age Z-scores were associated with plasma levels of IGF-1 at the end of each interval. Weight-for-age Z-scores were similarly associated with plasma levels of IGF-1 (Fig 2A and B, Table 3).
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IGF binding proteins were not measured so that any modulating effects could not be assessed.
PICP
On admission, the median plasma level of PICP in the cases, 124.45 ng/mL, was significantly lower than that of the controls, 131.4 ng/mL (P < .001). Three months after treatment, there was no significant difference between the cases and the controls. At 1 year, however, the median plasma level of PICP in the cases was higher than that of the controls and this approached significance (Table 4). There were no relationships found between plasma levels of PICP, the indices of growth, height, and weight velocities, nor any of the changes in them.
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TNF, TSP Low plasma levels of IGF-1 and PICP in the cases on admission were accompanied by high median serum levels of TNF (Table 5) and high serum levels of TSP (Table 6). The median serum level of TNF was lower on recovery, but this was still significantly higher than that of the controls. There was no relationship between serum TNF levels and any of the growth variables. The median TSP level in the cases remained significantly high during recovery.
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SA Mean SA in the TDS cases on admission, 43.88 g/L (95% CI 37.38, 50.38); mean of the recovering cases, 46.22 g/L (95% CI 41.96, 50.48); mean of the controls, 45.72 g/L (95% CI 42.98, 48.46). These values were within the normal range.
CBC On admission, all the cases had microcytic and hypochromic erythrocytes. Their mean admission hemoglobin concentration, 8.1 g/dL (95% CI 2.56, 13.65) was significantly below that of the controls, 10.91 g/dL (95% CI 8.81, 13.01; P = .002). By 6 months, the mean hemoglobin of the cases had improved significantly, 10.46 g/dL (95% CI 7.98, 12.94) and there was no significant difference between cases and controls. On admission and during reinfection, the cases showed a nonspecific leukocytosis with a high percentage of eosinophils in certain children.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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The low median admission plasma level of IGF-1 in the TDS cases was accompanied by high median serum levels of TNF and serum proteins, normal SA levels, low mean hemoglobin concentration, reduced collagen synthesis (low median plasma PICP), and impaired growth. The TDS children were severely stunted and moderately wasted.
There were no significant differences in skinfold thicknesses between cases and controls throughout. Although the error in measuring skinfold thicknesses in children is high,16 it is possible that chronic Trichuris infection has little effect on peripheral fat. Six weeks after treatment, the cases had a normal mean weight-for-height Z-score and significant improvement in plasma levels of IGF-1 and PICP.
In the year after treatment, the cases' increases in height velocity, which is characteristic of catch-up growth, was apparent. The cases however, remained significantly below the controls in height-for-age and weight-for-age Z-scores and HC. The mean MUAC of the cases was significantly lower than that of the controls until 9 months after treatment. Gain in arm muscle size and recovery from anemia were slow. This slow recovery in muscle protein and hemoglobin synthesis may be partly explained by several factors: the comparatively low levels of IGF-119; iron deficiency anemia and reduced muscle mass as features of the cachectic state induced by TNF12; and increased iron requirements during periods of rapid growth.20 Plasma levels of IGF-1 were significantly related to height-for-age and weight-for-age Z-scores in both cases and controls at each measurement suggesting a consistent relationship between plasma IGF-1 levels and the indices of growth. These findings are consistent with the relationship between IGF-1, IGF-binding protein-3, and body mass index in prepubescent children reported by Mandel et al.21
The failure of the cases to catch-up in height-for-age and weight-for-age Z-scores and MUAC are reflected in the comparatively low levels of IGF-1. Recovery from chronic inflammation and resumption of the growth process imposes additional requirements for specific amino acids.22 Substrate availability is the most important factor regulating the response in protein metabolism to IGF-1.23 Plasma levels of IGF-1 may indicate the extent of protein turnover and nitrogen balance.24
Plasma PICP levels increased in the cases after treatment, exceeding the levels of their controls by the end of the first year. This may indicate increased extracelluar matrix production not yet reflected in height velocity.10 The PICP levels were not related to any of the indices of growth nor height nor weight velocities nor to any changes in them, in this group of children.
TDS children differ from severely malnourished children in that they are able to mount an acute phase inflammatory response which has a systemic as well as a mucosal component.14 Children with protein calorie malnutrition have low serum levels of IGF-1 and low levels of TSP and SA.24,25 They are unable to mount a normal inflammatory response.26 Protein malnutrition impairs the ability for cytokine production.22 High serum levels of TNF and serum proteins reflect the severity of the inflammatory process in TDS. Serum protein levels in the recovering cases were significantly higher than those of their controls. This is similar to the findings of Cooper et al.14 The redistribution of circulating proteins with preference for those of the immune response could limit substrate for the synthesis of IGF-1 and other growth factors which require the same key amino acids for their molecular structure. TNF, by mobilizing muscle protein and stimulating the production of the immune response proteins,27 particularly those high in sulfur amino acids, may contribute to both stunting and wasting in TDS.22
TDS has been compared, in some aspects, to Crohn's colitis.3 The findings of this study may therefore, contribute to the understanding of growth failure in children affected by other forms of chronic inflammatory bowel disease.
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ACKNOWLEDGMENTS |
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This research was funded by the Wellcome Trust and Nestle Nutrition Research.
We acknowledge the technical advice and assistance of Dr Franklin Bennett and the field and laboratory assistance of Ms Sharon Howell, BSc, of the Tropical Metabolism Research Unit, University of the West Indies.
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FOOTNOTES |
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The abstract of this article was presented at the 41st Scientific Meeting of the Commonwealth Caribbean Medical Research Council, April 17-20, 1996, in Port of Spain, Trinidad.
Received for publication Jun 16, 1998; accepted Oct 23, 1998.
Address correspondence to E. Marilyn Watson Duff, RN, PhD (Nutr), MSc (Nutr), BScN, Tropical Metabolism Research Unit, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies. E-mail: nander{at}uwimona.edu.jm
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ABBREVIATIONS |
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TDS, Trichuris dysentery
syndrome;
IGF-1, insulin-like growth factor-1;
PICP, the
carboxyterminal propeptide of type 1 procollagen;
TNF, tumor necrosis
factor ;
TSP, total serum protein;
SA, serum albumin;
CBC, complete
blood count;
HC, head circumference;
MUAC, mid-upper arm circumference;
CV, coefficient of variation;
RIA, radioimmunoassay;
CI, confidence
interval.
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REFERENCES |
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Results
Discussion
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This article has been cited by other articles:
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  K. Tolentino and J. F. Friedman An Update on Anemia in Less Developed Countries Am J Trop Med Hyg, July 1, 2007; 77(1): 44 - 51. [Abstract] [Full Text] [PDF]
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