Depression of neutrophil function followed by severe infection in a child with Marasmic Kwashiorkor.

Malnutrition in childhood continues to be one of the most important risk factor for secondary immunodeficiency in the world; therefore one should think of existence of malnutrition in a child suffering of frequent infections, not only in developing country, rarely but still possible in developed country also. Undernourishment in the early childhood is a trigger for starting a vicious cycle of impaired immunity, recurrent infections, and worsening malnutrition. Taking out from that cycle is an urgent and complex process, in which in parallel the infection should be controlled and the nutritional status solved out, and then, slowly follows the restoration of the immune system. We present a patient at the age of 13 months, with marasmic kwashiorkor accompanied by severe infection manifested with sepsis. The laboratory investigations revealed severe anaemia, hypoproteinemia and impaired immunological response, first of all neutrophil dysfunction with decreased oxidative metabolic response during the phagocytosis, paralyzed first line of defense of the organism and open possibility for bacterial or fungal invasion, multiorgan failure and high risk for fatal outcome. Because malnutrition and infections had many causes, only multiple and synergistic interventions embedded in true multisectoral programs, fortunately, were effective and got positive outcome.

A non-inflammatory form of immune competence prevails in acute pre-pubescent malnutrition: new evidence based on critical mRNA transcripts in the mouse.

The declining inflammatory immune competence of acute (i.e. wasting) pre-pubescent protein-energy malnutrition has been regarded as reflecting an unregulated immunological disintegration. Recent evidence, however, suggests that malnutrition stimulates a regulated immunological reconfiguration to achieve a non-inflammatory form of competence, perhaps offering protection against autoimmune reactions - the 'Tolerance Model'. Our objective was to determine the influence of acute pre-pubescent malnutrition on the expression of genes critical to tolerogenic regulation. Male and female C57BL/6J mice, initially 19 d old, consumed a complete purified diet either ad libitum (age-matched controls) or in restricted daily quantities (mimicking marasmus), or consumed an isoenergetic low-protein diet ad libitum (mimicking incipient kwashiorkor) for 14 d (six animals per dietary group). Gene expression in the spleen, typically an inflammatory organ, and in the small intestine, a site designed for non-inflammatory defence, was assessed by real-time quantitative RT-PCR, and normalised to ß-actin. In the spleen of the malnourished groups, both IL-10 and transforming growth factor-ß1 mRNA expression increased compared with controls (P < 0.05), whereas mRNA expression of IL-12p40 decreased (P < 0.05). Conversely, malnutrition exerted no influence on the expression of mRNA for these cytokines in the small intestine (P>0.05). Moreover, forkhead box P3 mRNA expression, indicative of cell-based tolerogenic potential, was sustained in both the spleen and intestine of the malnourished groups (P>0.05). Thus, despite limited supplies of energy and substrates, the spleen shifted towards a non-inflammatory character and the intestine was sustained in this mode in advanced pre-pubescent weight loss. These findings provide the first support for the Tolerance Model at the level of mRNA transcript expression.

Constitutive, but not challenge-induced, interleukin-10 production is robust in acute pre-pubescent protein and energy deficits: new support for the tolerance hypothesis of malnutrition-associated immune depression based on cytokine production in vivo.

The tolerance model of acute (i.e., wasting) pre-pubescent protein and energy deficits proposes that the immune depression characteristic of these pathologies reflects an intact anti-inflammatory form of immune competence that reduces the risk of autoimmune reactions to catabolically released self antigens. A cornerstone of this proposition is the finding that constitutive (first-tier) interleukin(IL)-10 production is sustained even into the advanced stages of acute malnutrition. The IL-10 response to inflammatory challenge constitutes a second tier of anti-inflammatory regulation and was the focus of this investigation. Weanling mice consumed a complete diet ad libitum, a low-protein diet ad libitum (mimicking incipient kwashiorkor), or the complete diet in restricted daily quantities (mimicking marasmus), and their second-tier IL-10 production was determined both in vitro and in vivo using lipopolysaccharide (LPS) and anti-CD3 as stimulants of innate and adaptive defences, respectively. Both early (3 days) and advanced (14 days) stages of wasting pathology were examined and three main outcomes emerged. First, classic in vitro systems are unreliable for discerning cytokine production in vivo. Secondly, in diverse forms of acute malnutrition declining challenge-induced IL-10 production may provide an early sign that anti-inflammatory control over immune competence is failing. Thirdly, and most fundamentally, the investigation provides new support for the tolerance model of malnutrition-associated inflammatory immune depression.

Prostaglandin E2 is raised in kwashiorkor.

OBJECTIVE: Infection is a common occurrence in children with kwashiorkor. It has been suggested that infection in kwashiorkor results from immune depression, and that the immune depression of kwashiorkor is caused by a diet-associated elevation of prostaglandin E2 (PGE2). The purpose of this study was to determine whether levels of PGE2 are abnormal in children with kwashiorkor. SETTING AND SUBJECTS: Plasma PGE2 and plasma proteins were measured in children admitted with oedematous kwashiorkor, and compared with PGE2 in children with cerebral palsy. RESULTS: Plasma PGE2 was higher in children with kwashiorkor than in control children (7.25 +/- 3.5 v. 3.51 +/- 1.59, P < 0.01). Within the kwashiorkor study group there was a significant negative correlation between log-transformed serum PGE2 and total plasma protein (r = -0.59, P < 0.001), plasma albumin (r = -0.63, P < 0.001), weight-for-age (r = -0.37, P < 0.05), and height-for-age (r = -0.37, P < 0.05). The difference in mean values of PGE2 in children with kwashiorkor who recovered from the illness and those who died was not significant (7.1 +/- 2.6 v. 9.1 +/- 4.8, P = 0.36). CONCLUSION: Significantly higher PGE2 levels in children with kwashiorkor provide adequate reason for the depression of immune function known to occur in these children. Elevated PGE2 levels may also be implicated in other components of the illness.

Dietary linoleic acid, immune inhibition and disease.

Review of the evidence available in published literature supports a radical change in viewpoint with respect to disease in countries where maize is the predominant dietary component. In these countries, the pattern of disease is largely determined by a change in immune profile caused by metabolites of dietary linoleic acid. High intake of linoleic acid in a diet deficient in other polyunsaturated fatty acids and in riboflavin results in high tissue production of prostaglandin E2, which in turn causes inhibition of the proliferation and cytokine production of Th1 cells, mediators of cellular immunity. Tuberculosis, measles, hepatoma, secondary infection in HIV and kwashiorkor are all favoured by this reduction in cellular immunity. Diet-associated inhibition of the Th1 subset is a major contributor to the high prevalence of these diseases found in areas of sub-Saharan Africa where maize is the staple.

Leucocyte migration inhibition factor (L-MIF) in malnourished Nigerian children.

Leucocyte Migration Inhibition Factor (L-MIF) was measured in 41 children with marasmus, 19 with kwashiorkor, 5 with marasmic-kwashiorkor and 35 well-fed healthy children serving as controls. For L-MIF assay, two different antigens (live attenuated measles virus vaccine and diptheria pertussis tetanus (DPT) vaccine were used. Percentage migration indices obtained with the two antigens were significantly higher in the malnourished than in the well-fed healthy sex and age-matched controls (P < 0.01). The total serum protein and albumin concentrations were significantly reduced in the malnourished children compared with the controls (P < 0.01). Mean total leucocyte numbers were not significantly different in marasmic and marasmic-kwashiorkor children compared with the controls (P > 0.21).

Comparison of milk and maize based diets in kwashiorkor.

UNLABELLED: The dual sugar test of intestinal permeability is a reliable non-invasive way of assessing the response of the small intestinal mucosa to nutritional rehabilitation. AIM: To compare a local mix of maize-soya-egg to the standard milk diet in the treatment of kwashiorkor. DESIGN: The diets were alternated three monthly in the sequence milk-maize-milk. There were a total of 533 kwashiorkor admissions of at least five days during the study who received either milk or maize. Intestinal permeability was assessed at weekly intervals by the lactulose-rhamnose test in 100 kwashiorkor cases, including 55 on milk and 45 on the maize diet. RESULTS: Permeability ratios (95% confidence interval) on the milk diet improved by a mean of 6.4 (1.7 to 11.1) compared with -6.8 (-16.8 to 5.0) in the maize group. The improved permeability on milk occurred despite more diarrhoea, which constituted 34.8% of hospital days (29.8 to 39.8) compared with 24.3% (17.8 to 30.8) in the maize group. Case fatality rates for all 533 kwashiorkor admissions were 13.6% v 20.9%, respectively, giving a relative risk of death in the maize group of 1.54 (1.04 to 2.28). The maize group also had more clinical sepsis (60% v 31%) and less weight gain (2.9 v 4.4 g/kg/day) than the milk group. IMPLICATIONS: Milk is superior to a local maize based diet in the treatment of kwashiorkor in terms of mortality, weight gain, clinical sepsis, and improvement in intestinal permeability.

In vitro lymphocyte-differentiating effects of thymulin (Zn-FTS) on lymphocyte subpopulations of severely malnourished children.

This work investigates how thymic dysfunction contributes to the depression of cell-mediated immunity in protein-energy malnutrition (PEM). In Bolivian children hospitalized for severe PEM, the size of the thymus was measured by echography, and the lymphocyte subpopulations were detected by using monoclonal antibodies. These data were compared with those obtained from healthy control subjects. Regardless of the clinical form of PEM, our results show a high degree of T lymphocyte immaturity in severely malnourished children, which correlates with a severe involution of the thymus. Before in vitro incubation with thymulin, this significant increase in the percentage of circulating immature T lymphocytes was concomitant with a decrease in mature T lymphocytes and a slight increase in cytotoxic T subpopulations. After in vitro incubation with thymulin, immature T lymphocytes decreased and mature T lymphocytes increased.

Comparación del complemento sérico (C3-C4) en niños desnutridos grado III y en niños sanos

Se realizó un estudio prospectivo, analítico y comparativo con 25 niños desnutridos grado III y 25 niños sanos escogidos al azar con edades de 0-5 años que acudieron en el período octubre-deciembre 1986 al Hospital Materno Infantil San Lorenzo de Los Mina, para determinar los valores de los complementos séricos (C3-C4). Los desnutridos tipo Kwashiorkor mostraram mayor porcentaje de disminución de C3(73%) que los desnutridos Marasmáticos (50%). El cuarto complemento sérico (C4) se encontró dismunuido en el 27% de los desnutridos tipo Kwashiorkor, y en el 21% de los desnutridos Marasmáticos. Estos resultados confirman que el sistema de complemento es más sensible a la magnitud de la deficiencia de ingesta calórica que a la magnitud de la deficiencia proteica

Interleukin-1 in malnutrition.

The effect of malnutrition on the in vitro production of interleukin-1 by lipopolysaccharide stimulated circulating monocytes has been investigated in children suffering from kwashiorkor and marasmus. The interleukin-1 activity was significantly lower in children with severe malnutrition. Furthermore, macrophages from children with kwashiorkor produced factors that suppressed mouse thymocyte proliferation. These observations show a significant impairment of macrophage function and provide a mechanism for the suppression of cellular immunity in malnutrition.

Monocyte factors modulate in vitro T-lymphocyte mitogenesis in protein malnutrition.

This study investigated changes in T-lymphocyte mitogenesis and immunoregulatory cytokines during protein malnutrition. In vitro T cell response to concanavalin A was compared among protein deprived (PD), energy restricted pair fed control (PF), and ad libitum control (C) rabbits. Cell cultures were supplemented with crude monocyte supernatants (CMS) from PD, PF or C animals at either 1% or 8% final concentration in culture. Prostaglandin E2 (PGE2) concentration of unstimulated or stimulated lymphocyte culture supernatants and CMS was determined. Lymphocyte cultures from PD, PF and C animals had enhanced 3H-thymidine incorporation when supplemented with C and/or PF derived CMS. Addition of 8% CMS from PD rabbits inhibited proliferation below levels observed in mitogen-only stimulated groups in all cultures. At the 1% concentration, inhibition was seen in PD and C derived cells cultures and modest enhancement was seen in PF cultures. PGE2 concentration in supernatants from stimulated and unstimulated lymphocyte cultures from PD rabbits were higher than in C and PF cell cultures. These results suggest (a) that under appropriate culture conditions lymphocytes from PD donors are capable of enhanced proliferation and (b) that depressed T cell mitogenesis observed in protein malnutrition may reflect alterations in immunoregulatory signals. The role of interleukin 1 (IL-1) and PGE2 in the modulation of this response is discussed.

Soluble immune complexes, acute phase proteins and E-rosette inhibitory substance in sera of malnourished children.

The percentage of circulating E-rosetting lymphocytes and the presence of serum E-rosette inhibitory substance were determined in 58 marasmic, 13 kwashiorkor and 22 well-fed children. The blood levels of soluble immune complexes and some acute phase proteins were also measured. The percentage of E-rosetting lymphocytes was significantly higher in the well-fed than in the malnourished children. The presence of the inhibitory substance in serum correlated with depressed levels of circulating mean percentage E-rosetting lymphocytes. Elevation in the level of soluble immune complexes was observed to correlate closely with the presence of serum E-rosette inhibitory substance and with a diminished percentage of E-rosetting lymphocytes. There was no significant correlation between the percentage of circulating E-rosetting lymphocytes and the serum alpha 1 antitrypsin, alpha 2 macroglobulin or C-reactive protein levels. It is suggested that at high serum concentrations soluble immune complexes may bind selectively to human T lymphocytes in vivo, thereby inhibiting the latter's ability to form E-rosettes in vitro.

Depressed natural killer cell activity in children with protein--calorie malnutrition. II. Correction of the impaired activity after nutritional recovery.

Natural killer (NK) cell activity and responsiveness to interferon (IFN) were measured in the peripheral blood of infants having kwashiorkor or marasmus and of nutritionally recovered malnourished children. Depression of NK activity in the peripheral blood lymphocytes (PBLs) of the malnourished children was noted, while normal levels of activity were observed in the nutritionally recovered infants. Addition of exogeneous interferon in vitro potentiated the NK levels of PBLs from well-nourished and nutritionally recovered infants, but had either a nonsignificant impact on cells from the marasmic infants or a suppressive effect on the cells from infants with kwashiorkor. The success of exogenous interferon to potentiate the NK levels of PBLs from nutritionally recovered infants suggests that nutritional repletion corrects the impaired cellular responsiveness in these patients.

Secretory IgA synthesis in Kwashiorkor.

The synthesis of intestinal secretory IgA was studied in in vitro cultures of duodenal mucosal biopsies from children with Kwashiorkor. Production of secretory IgA was measured by the incorporation of radioactive label and visualized following PAGE and autoradiography. Results obtained before and after nutritional rehabilitation demonstrate an enhanced synthesis of sIgA in children with acute Kwashiorkor. Histological examination of plasma cells in the biopsy tissue confirms a twofold increase in IgA staining plasma cells in acute Kwashiorkor. Peripheral blood B lymphocytes in acute Kwashiorkor however, showed a reduction in IgA synthesis in the acute stage. These results suggest an effective mucosal sIgA response to the increased intestinal antigen load in Kwashiorkor.