The Immune System in Children with Malnutrition—A Systematic Review

Citation: Rytter MJH, Kolte L, Briend A, Friis H, Christensen VB ( The Immune System in Children with Malnutrition-A Systematic Review Maren Johanne Heilskov Rytter 0 Lilian Kolte 0 Andre Briend 0 Henrik Friis 0 Vibeke Brix Christensen 0 Taishin Akiyama, University of Tokyo, Japan 0 1 Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen , Frederiksberg , Denmark , 2 Department of Infectious Diseases, Copenhagen University Hospital , Hvidovre , Denmark , 3 Department for International Health, University of Tampere, School of Medicine , Tampere , Finland , 4 Department of Paediatrics, Copenhagen University Hospital Rigshospitalet , Copenhagen , Denmark Background: Malnourished children have increased risk of dying, with most deaths caused by infectious diseases. One mechanism behind this may be impaired immune function. However, this immune deficiency of malnutrition has not previously been systematically reviewed. Objectives: To review the scientific literature about immune function in children with malnutrition. Methods: A systematic literature search was done in PubMed, and additional articles identified in reference lists and by correspondence with experts in the field. The inclusion criteria were studies investigating immune parameters in children aged 1-60 months, in relation to malnutrition, defined as wasting, underweight, stunting, or oedematous malnutrition. Results: The literature search yielded 3402 articles, of which 245 met the inclusion criteria. Most were published between 1970 and 1990, and only 33 after 2003. Malnutrition is associated with impaired gut-barrier function, reduced exocrine secretion of protective substances, and low levels of plasma complement. Lymphatic tissue, particularly the thymus, undergoes atrophy, and delayed-type hypersensitivity responses are reduced. Levels of antibodies produced after vaccination are reduced in severely malnourished children, but intact in moderate malnutrition. Cytokine patterns are skewed towards a Th2-response. Other immune parameters seem intact or elevated: leukocyte and lymphocyte counts are unaffected, and levels of immunoglobulins, particularly immunoglobulin A, are high. The acute phase response appears intact, and sometimes present in the absence of clinical infection. Limitations to the studies include their observational and often cross-sectional design and frequent confounding by infections in the children studied. Conclusion: The immunological alterations associated with malnutrition in children may contribute to increased mortality. However, the underlying mechanisms are still inadequately understood, as well as why different types of malnutrition are associated with different immunological alterations. Better designed prospective studies are needed, based on current understanding of immunology and with state-of-the-art methods. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and supporting information files. Funding: The work was supported by a PhD grant from University of Copenhagen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Malnutrition in children is a global public health problem with wide implications. Malnourished children have increased risk of dying from infectious diseases, and it is estimated that malnutrition is the underlying cause of 45% of global deaths in children below 5 years of age [12]. The association between malnutrition and infections may in part be due to confounding by poverty, a determinant of both, but also possibly due to a two-way causal relationship (Figure 1): malnutrition increases susceptibility to infections while infections aggravate malnutrition by decreasing appetite, inducing catabolism, and increasing demand for nutrients [3]. Although it has been debated whether malnutrition increases incidence of infections, or whether it only increases severity of disease [3], solid data indicates that malnourished children are at higher risk of dying once infected [24]. The increased susceptibility to infections may in part be caused by impairment of immune function by malnutrition [5]. The objective of this study was to investigate the associations of different types of malnutrition with immune parameters in children, through a systematic review of the literature. Since most infections and deaths in malnourished children occur in low-income settings, the organisms causing disease are rarely identified. Therefore, little is known about whether these differ from pathogens infecting well-nourished children, and whether malnourished children are susceptible to opportunistic Figure 1. Conceptual framework on the relationship between malnutrition, infections and poverty. doi:10.1371/journal.pone.0105017.g001 infections. Although opportunistic infections like Pneumocystis jirovecii and severe varicella has been reported in malnourished children [67], these studies were carried out before the discovery of HIV, and may represent cases of un-diagnosed paediatric AIDS. More recent studies have found that Pneumocystis jirovecii pneumonia is not frequent in malnourished children not infected with HIV [8]. However, quasi-opportunistic pathogens like cryptosporidium and yeast are frequent causes of diarrhoea in malnourished children [9], and malnourished children have a higher risk of invasive bacterial infections, causing bacterial pneumonia [8], bacterial diarrhoea [1011], and bacteraemia [1214], with a predominance of gram negative bacteria. Due to the high prevalence of invasive bacterial infections, current guidelines recommend antibiotic treatment to all children with severe acute malnutrition, even though the evidence behind is not very strong [14]. Non-immunological factors may also contribute to increased mortality in malnourished children: reduced muscle mass may impair respiratory work with lung infections [15]; reduced electrolyte absorption from the gut [16] and impaired renal concentration capacity may increase susceptibility to dehydration from diarrhoea [5]; and diminished cardiac function may increase risk of cardiac failure [17]. Thus, immune function may only be one of several links between malnutrition, infections and increased mortality, but most likely an important one. Definitions of malnutrition This review considers childhood malnutrition in the sense of under-nutrition, causing growth failure or weight loss, or severe acute malnutrition, either oedematous, or non-oedematous. Growth failure caused by malnutrition has commonly been defined by low weight-for-age (underweight), length-for-age (stunting), or weight-for-length (wasting) [5]. Generally, older studies diagnosed malnutrition using weight-for-age, while newer studies tend to use (...truncated)