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    • Stunting affects approximately million children under five m

    2018-10-23

    Stunting affects approximately 165 million children human leukocyte elastase under five, many of whom live in Africa (36.5%) (Black et al., 2013) where stunting rates in many areas are over 40% (Global Data Lab, 2016). Besides being associated with an increased mortality, stunting has negative long-term effects on cognitive and psychosocial development (Crookston et al., 2011), school performance (Martorell et al., 2010), and economic productivity (Hoddinott et al., 2008). It is therefore an important outcome to establish the total impact of non-specific effects of vaccination on health status. Recently, the World Health Organization (WHO) has made a 40% human leukocyte elastase of stunting in children under five before 2025 a global target, underlining its importance (WHO, 2014b). The beneficial non-specific effects of BCG suggest that this vaccine may be used to reduce stunting in low- and middle-income countries. If BCG vaccination indeed reduces stunting, there would be substantial potential for improvement, as coverage of BCG vaccination has stalled at 77–85% in Africa since 2009 (WHO, 2014c). Apart from vaccination coverage, timing of vaccination may be important, as the child\'s immune function changes with age (Kollmann et al., 2012) and early immunization had stronger consequences related to non-specific effects in one study (Aaby et al., 2011). This is important knowing that timing of vaccinations still differs widely between and within low- and middle-income countries (Clark and Sanderson, 2009).
    Methods
    Results Of the 368,450 children included, 287,552 (78.0%) had received vaccination with BCG and 151,332 children (41.1%) had a length- or height-for-age z-score (LAZ/HAZ) of two standard deviations below the median and were classified as being stunted. Both BCG coverage and stunting levels differed widely across the 33 Sub-Saharan countries (Fig. 1a, b and Supplementary Table 1). Baseline characteristics of children and mothers are present in Supplementary Tables 2 and 3.
    Discussion Our results are in line with prior studies that examined the role of vaccines on child morbidity and mortality. Vaccination with BCG, which is given early in the EPI schedule (WHO, 2015), is associated with reduced child mortality (WHO, 2014a; Nankabirwa et al., 2015; Garly et al., 2003; Aaby et al., 2011). DTP vaccinations are generally not associated with such an effect and may even be deleterious (WHO, 2014a). Our study indicates that this may be related to the timing of vaccination. This finding is supported by studies that show detrimental effects of DTP vaccination when given after or in combination with MV (late vaccination) (Aaby et al., 2003, 2007), while beneficial effects are reported for early DTP vaccination (Vaugelade et al., 2004; Lehmann et al., 2005). Similar to our findings, combining BCG and DTP1 vaccination was reported to be the most beneficial in several studies (Aaby et al., 2015a; Hirve et al., 2012). In case of MV, vaccination at 4–8months was also associated with lower child mortality than vaccination at 9–11months (Aaby et al., 2015b). Regarding child morbidity, BCG vaccination influenced acute lower respiratory tract infections (ALRI) in a time-dependent manner, in a study by Hollm-Delgado et al. (2014). However, while these authors ascribed this effect to concurrent DTP administration, our present data suggest that the timing of BCG vaccination itself is crucial. An underlying mechanism for the time-dependent association of both BCG and DTP1 vaccination could lie in the different functional status of the neonatal and child immune system. The neonatal immune system has an anti-inflammatory profile mirroring that of the mother during pregnancy, while the child immune system shifts to a more pro-inflammatory profile, increasingly reflecting that of adults (reviewed in Kollmann et al., 2012). It may be hypothesized that when vaccines are given early in life, induction of both specific and non-specific effects results in a more balanced immune reactivity, while when vaccines are given later they trigger a stronger pro-inflammatory response upon encountering a pathogen. On the other hand, unvaccinated neonates may be less able to cope with repeated infections after environmental exposure, leading to prolonged inflammation. As inflammation is associated with down regulation of the expression of growth hormone (GH)/IGF-1, prolonged or increased inflammation negatively influences linear growth, as well as erythropoiesis (Prendergast et al., 2014; Boyer et al., 1992). This would explain the benefits seen for stunting and hemoglobin concentration in children vaccinated early, but not late, in life compared to unvaccinated children, although this hypothesis requires experimental and clinical confirmation in future studies.