Abstract
Background
Severe acute malnutrition (SAM) is associated with immune dysregulation and increased infection risk. Nutritional rehabilitation is essential for recovery; adjunctive topical therapy with sunflower seed oil (SSO) has shown benefits in improving skin barrier function and reducing infection risk. This study investigates the impact of emollient therapy on systemic immune responses in young children with SAM.
Methods
A nested study within a randomized controlled trial was conducted among 212 Bangladeshi children aged 2–24 months with SAM. Participants received standard acute nutritional rehabilitation alone or along with adjunctive SSO therapy. Serum cytokine levels were measured at baseline and after 10 days of treatment. Statistical analysis using general linear regression assessed treatment effects on cytokine changes.
Results
Cytokine levels were generally low, with no clinically relevant differences in IL-8, IL-10, or TNF-α levels between treatment groups. A decreasing trend in IL-8 coincided with weight gain, suggesting a potential inverse relationship between inflammation and nutritional recovery.
Conclusions
While emollient therapy improved skin barrier function and reduced infection risk, its effects appear to be mediated through local cutaneous rather than systemic immune modulation. Further research is needed to explore impacts of emollient therapy on local and systemic immunological effects in malnourished children.
Impact
This is the first study to investigate whether topical therapy with sunflower seed oil (SSO) influences systemic immune responses in children with severe acute malnutrition (SAM) undergoing standard acute nutritional rehabilitation.
We found no significant changes in systemic cytokine levels attributable to 10 days of SSO treatment.
Previous studies have shown that emollient therapy improves skin barrier integrity and function and reduces infection risk; this study underscores the need for further research (e.g., larger samples size, longer duration of treatment) into the immune response in malnourished children and how interventions like nutritional rehabilitation and emollient therapy interact with systemic inflammation.
Introduction
Childhood malnutrition remains a pressing global public health problem, with insufficient progress to meet global nutrition targets.1,2 In 2022, an estimated 45 million children had acute malnutrition [weight <-2 standard deviations (SDs) below expected weight for height according to the World Health Organization (WHO) Child Growth Standards median].3 As malnutrition becomes severe (weight <-3 SDs below expected weight for height as per the WHO Child Growth Standards median), it has more adverse systemic health consequences. Severe acute malnutrition (SAM) or severe wasting affects an estimated 13.7 million children globally, and 2% of children in Bangladesh are severely wasted.4
Children suffering from wasting have weakened immunity, are susceptible to long-term developmental delays, and face an increased risk of death, particularly when wasting is severe.5 Moreover, SAM is associated with diarrhea, heightened intestinal and systemic inflammation, and reduced blood concentrations of fecal short-chain fatty acids. Notably, these relationships are not mediated by the presence of specific intestinal pathogens,6 rather impaired immune response increases susceptibility to infections.7,8 Adequate treatment for infection is thus a cardinal feature of malnutrition management.
Malnutrition is associated with multiple immune alterations, including impaired skin and gut barrier function,9,10 reduced exocrine secretion of protective substances, and low levels of plasma complement.11,12 Lymphatic tissue, particularly the thymus, undergoes atrophy, delayed-type hypersensitivity responses are reduced, and cytokine patterns are skewed towards a Th2-response.13 Levels of immunoglobulins, particularly immunoglobulin A, are high, while leukocyte and lymphocyte counts are unaffected.14 The acute phase response appears intact and sometimes is present in the absence of clinical infection.7
To assess child immunological responses and infection status, measurement of acute-phase proteins is widely used. The varied reactions of the host to infection, inflammation, or trauma are collectively known as the acute-phase response and encompass a wide range of pathophysiological responses to minimize tissue damage while enhancing the repair process. The acute-phase response is induced by protein hormones called cytokines acting as messengers between the local site of injury and the hepatocytes synthesizing the acute-phase proteins.15 Cytokines are small, secreted proteins released by cells (e.g., immune cells, endothelial cells, epithelial cells) that specifically affect the interactions and communications between cells.16 They are critical effector and messenger molecules in the immune system and are integral to immune responses during infection and inflammation.17 Some cytokines play pivotal roles in host defense against microbes and in the development of chronic inflammatory diseases.18
Malnourished children retain some ability to mount an inflammatory response during systemic infection; however, this response is weaker compared to that of well-nourished children with a systemic infection.19 During the acute stage of malnutrition, the immune system shifts to a non-inflammatory state rather than simply becoming weakened, a concept referred to as the ‘tolerance model.’ This adaptation helps protect against excessive immune activation while the body catabolizes its own tissues for energy.20 Instead of triggering immune responses such as the production of proinflammatory cytokines, the immune system mediates increased bacterial binding, potentially making malnourished children more susceptible to bacterial infections.21
Levels of cytokines vary in malnourished children compared to those of well-nourished children.19 Malnourished children appear to have relatively high levels of anti-inflammatory cytokines and less clearly affected levels of pro-inflammatory cytokines in the blood, in contrast to the predominantly pro-inflammatory cytokine expression in the gut of malnourished children.7 Thus, it would be worthy to assess the changes in cytokine levels in malnourished children during the management of malnutrition to advance understanding of how their immune responses and infection status change in response to treatment.
Nutritional rehabilitation of severely malnourished children has been shown to recover impaired immune function. For example, studies have demonstrated that children who received WHO-recommended therapeutic food experienced measurable improvements in both innate and adaptive immune parameters, including enhanced phagocytic activity and normalization of T-cell subpopulations after just a few weeks of treatment. While complete immune recovery may require longer intervention periods, the evidence clearly indicates that nutritional rehabilitation is a powerful tool to help regain normal immune function in severely malnourished children.8
During the nutritional rehabilitation phase of malnutrition treatment of young children with SAM, topical emollient therapy with sunflower seed oil (SSO) as an adjunct to dietary management showed several benefits, including improved skin barrier function, a trend toward accelerated weight gain, reduced risk for infection, reduced blood C-reactive protein levels, increased fatty acid levels in the blood, and greater diversity of the skin microbiome.22–24 However, the relationship between emollient therapy and immune response is an unexplored aspect of SAM treatment and prevention. In a pilot clinical study on the role of emollient therapy in modulating cytokine levels in chronically aged humans, topical applications of a physiologic lipid-containing emollient known to improve epidermal barrier function in humans normalized circulating levels of key pro-inflammatory cytokines—interleukin (IL)-1b and IL6—that activate the immune response and reduce the capability of replication of pathogens.25 Thus, improving epidermal function in malnourished children may also reduce cutaneous as well as circulating levels of cytokines.
The present study seeks to investigate the impact of emollient therapy on systemic immunity in young children with SAM. Previously we reported on clinical22 and serum fatty acid changes23 in 2–24 month-old hospitalized children with SAM undergoing enteral nutritional rehabilitation plus emollient therapy with SSO compared to children treated with enteral therapy alone over a 10-day period. We sought to capture the immunologic alterations in malnourishment and responses to emollient treatment over and above changes due to enteral nutritional rehabilitation.
Methods
Study design and participants
This study was nested in an individually 1:1-randomized, two-arm, controlled, proof-of-concept clinical trial in Bangladesh. The main study included 212 children, aged 2 to 24 months, who had SAM (weight for length <-3 standard deviations (SDs) per World Health Organization growth standards) and visited ‘Dhaka Hospital’ of the International Center for Diarrheal Disease Research, Bangladesh (icddr,b), during January 2016 to December 2017. The study aimed to assess the benefits of topical applications of emollient [high linoleic acid (>60%)-containing SSO] as an adjunct therapy for SAM management in the hospital. One group received routine standard-of-care for SAM plus topical applications of SSO by whole-body massage three times daily with 3 grams of oil per kg of body weight per application for 10 days, and another group received routine standard-of-care for SAM alone. Methodological details of the main trial are described elsewhere.22 In this nested study, we included children from our main study who were assessed for cytokines in their blood before (on day 0) and after (day 10) the study intervention. Patients and the public were not involved in the design, conduct, and reporting of the trial.
Outcome measures
We measured 17 cytokines before and after the intervention. We prioritized cytokines IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, and IFN-γ as our cytokines of interest due to their importance in systemic immune responses.26 In this paper, we report the values of three cytokines (IL-8, IL-10, and TNF-α,) which had <50% missing values below the lower level of quantification (LLQ).
Sample collection and laboratory procedures
At baseline (hospital admission) and after 10 days of treatment, we collected 2 ml of venous blood from each participant using sterile technique. After separating serum by centrifuging the blood sample, we sent 0.5 ml of aliquoted serum to the Nutritional Biochemistry Laboratory of the icddr,b for cytokine analysis. In the laboratory, serum samples were tested undiluted to measure cytokines according to the manufacturer’s guidelines using bead-based multiplex assays by the Luminex Bio-Plex Pro™ Human Cytokine 17-plex Assay Kit (Bio-Rad Laboratories, Inc., Hercules, California, Catalog No-M5000031YV). Plates were read using a Luminex instrument (Bio-Plex 200 system from Bio-Rad Laboratories, Inc., Hercules, California). Data analysis was performed using Bio-plex Manager 6.1 software. A standard curve for each cytokine was generated by mixing known concentrations of recombinant human cytokines. For all cytokines, there was a specific value as their corresponding LLQ as well as extrapolated values beyond the LLQ. In some cases, an out-of-range reading was generated and considered as a missing value. The LLQ values of all cytokines have been documented in Supplementary Table S1.
Data visualization and statistical analysis
We visualized the data for the descriptive statistics of three cytokine levels across the two treatment groups using R Studio (version 1.1.456, RStudio, Boston, Massachusetts). Other statistical analyses were performed using STATA (StataCorp, version 16.0, College Station, Texas). Statistical analysis was performed on data from all randomized patients in the study on an intention-to-treat basis. We compared different sociodemographic and clinical characteristics of the participants between the two groups and expressed their differences by percentage (for categorical variables) or by mean and standard deviation (SD) (for continuous variables). To assess the treatment effect on the changes in cytokine levels over the treatment period, a general linear model (GLM) with a gamma family and log-link function was fitted with day 10 values as the response, adjusting for baseline and other covariates in the model. Stepwise selection method was used to eliminate potential confounding variables one-by-one from the model (age, sex, baseline weight-for-length, duration of diarrhea, duration of fever, duration of cough on enrollment). Interaction terms (duration and treatment) were also assessed. The final model selected was adjusted only for baseline value and treatment (routine standard-of-care for SAM plus topical applications vs routine standard-of-care for SAM). We performed regression analysis to determine the treatment effect only on IL-8 as the other two cytokines (IL-10 and TNF-α) had >50% of values below the LLQ. For undetectable values of cytokines below the LLQ, we followed a predefined technique to impute the values (Supplementary Text S1).
Trial registration and ethical considerations
This study was approved by the institutional review board (IRB) of icddr,b, including scientific review by the Research Review Committee and ethical review by the Ethics Review Committee (protocol # PR-15101). This study was also approved by the IRB of the Stanford University School of Medicine (protocol # 34646) and was registered with the clinicaltrials.gov registry (NCT02616289). Trial oversight was provided by an independent Data Safety and Monitoring Board formed by the IRB at icddr,b.
Results
From our main trial, we included 212 children in this nested study who were assessed for cytokine levels on enrollment in the main trial.22 Among them, 67 were in the younger age group (2- < 6 months) and 145 were in the older age group (6–24 months). We analyzed both baseline (day 0) and endline (day 10) samples for 65 children (33 intervention, 32 control) in the younger age group and 137 children (67 intervention, 70 control) in the older age group. Figure 1 illustrates the study flow chart of patient enrollment, randomization, and measurement of outcomes. All enrolled children in the intervention group received emollient therapy as intended.
Fig. 1.
Study flow chart.
Table 1 describes the baseline characteristics among the treatment (emollient) and control groups irrespective of their age sub-groups. The treatment and control groups had comparable sociodemographic and clinical characteristics (p > 0.05 for all variables).
Table 1.
Baseline characteristics of study participants
| Variables | Participants N = 212 |
|
|---|---|---|
| Emollient (n = 106) | Control (n = 106) | |
| Age, months (standard deviation, SD) | 9.43 (± 5.06) | 10.07 (± 5.47) |
| Male sex (%) | 78 (73%) | 61 (57%) |
| Weight, kg (SD) | 5.53 (± 1.07) | 5.66 (± 1.28) |
| Length, cm (SD) | 65.99 (± 5.91) | 66.83 (± 7.00) |
| Weight-for-length z-score (SD) | −3.49 (± 0.49) | −3.44 (± 0.56) |
| Mid-upper arm circumference, mm (SD) | 117.52 (± 9.10) | 118.66 (± 9.58) |
| Presence of edema, n (%) | 5 (5%) | 2 (2%) |
| Immunization status up-to-date, n (%) | 67 (63%) | 70 (66%) |
| Duration of exclusive breastfeeding, months (SD) | 1.89 (± 2.23) | 2.04 (± 2.18) |
| Duration of diarrhea*, days (SD) | 4.30 (± 2.47) | 4.50 (± 2.16) |
| Duration of fever*, days (SD) | 1.33 (± 2.18) | 0.95 (± 1.14) |
| Duration of cough*, days (SD) | 0.85 (± 1.78) | 0.87 (± 1.89) |
| Growth of bacteria in the urine*, n (%) | 8/104 (8%) | 10/104 (10%) |
| Growth of bacteria in the stool*, n (%) | 25 (23%) | 18 (17%) |
| Growth of bacteria in the blood*, n (%) | 19 (18%) | 12 (11%) |
| Chest x-ray suggested pneumonia or abnormal findings*, n (%) | 14 (13%) | 5 (5%) |
No measured values of IL-8 were below the LLQ (Table 2). However, 47% of IL-10 and 44% of TNF-α values were below their respective LLQs (Table 2), where the machine extrapolated the values or we manually imputed the values (Supplementary Text S1, Supplementary Table S1). Levels of IL-1β, IL-2, IL-4, IL-6, and IFN-γ were above the LLQ in only 3 to 37% of participants. The lowest levels (pg/mL) were observed for IL-4 while the highest levels were detected for IL-8 (Supplementary Table S2).
Table 2.
Assessment outcomes of samples for cytokines
| Cytokines | Lower limit of quantification (LLQ) values | Baseline (day 0) | Endline (day 10) | |||||
|---|---|---|---|---|---|---|---|---|
| Amount of data above the LLQ | Amount of data below the LLQ, but machine detected | Amount of data below the LLQ and imputed manually | Amount of data above the LLQ | Amount of data below the LLQ, but machine detected | Amount of data below the LLQ and imputed manually | Missing data (test not done due to lost to follow-up) | ||
| IL-8 | 1.41 | 212/212 (100%) | 0 (0%) | 0 (0%) | 202/202 (100%) | 0 (0%) | 0 (0%) | 10/212 (5%) |
| IL-10 | 3.39 | 112/212 (53%) | 55/212 (26%) | 45/212 (21%) | 107/202 (53%) | 60/202 (30%) | 35/202 (17%) | 10/212 (5%) |
| TNF-α | 3.18 | 118/212 (56%) | 23/212 (11%) | 71/212 (33%) | 108/202 (53%) | 23/202 (11%) | 71/202 (35%) | 10/212 (5%) |
Box plots (Fig. 2) show the distribution of cytokine levels across the treatment groups on a log scale. IL-8 levels were higher visually in the emollient treatment group compared to the control group at baseline and after 10 days of treatment, and levels appeared to decrease from baseline to day 10 in both groups (Fig. 2a). IL-10 (Fig. 2b) and TNF-α (Fig. 2c) showed no changes visually over the treatment period. GLM analysis showed that the changes in IL-8 over the treatment period were not statistically significantly different in the emollient group compared to the control group, overall and in both age subgroups (Table 3).
Fig. 2. Distribution of cytokine levels at baseline and endline among the two study groups.
(Panel a is for IL-8, b is for IL-10, and c is for TNF-a).
Table 3.
Effects of emollient treatment on changes in IL-8 levelsa
| Cytokines | All participants | 2- < 6 months | 6–24 months | |||
|---|---|---|---|---|---|---|
| Rate ratio (RR) [95% confidence interval (CI)] | pvalue | RR (95% CI) | pvalue | RR(95% CI) | pvalue | |
| IL-8 | 1.06 (0.84. 1.36) | 0.610 | 0.97 (0.68, 1.39) | 0.878 | 1.09 (0.83, 1.45) | 0.525 |
aA generalized linear model with a gamma distribution and log-link function, adjusting for baseline values and treatment group was fitted.
Discussion
To our knowledge, this is the first study reported in the peer-reviewed literature which examines systemic levels of cytokines in the blood of young children with SAM treated topically with adjunctive emollient therapy. We hypothesized that a boost in systemic immune responses may be found in association with our previous findings of benefits from emollient therapy with SSO in young children with SAM, including improved skin barrier function and reduced risk for infection.22–24 However, we found overall low levels of cytokines and for the cytokines for which we obtained reliable measurements, we found no significant changes due to emollient treatment. This non-significant treatment effect was consistent in our overall study population as well as in the two age groups. However, our main study22 showed that changes (reduction in level from baseline to endline) in another inflammatory marker, C-reactive protein (CRP), were significantly higher in the younger age stratum treated with emollient. There is also strong evidence that age influences the expression of cytokine profiles in healthy children;27 thus, we also hypothesized that we would see some differences in the age-stratified analysis for cytokines levels. Perhaps the pathophysiology of the immune response to infection in children with SAM may differ from that in healthy children, requiring further study.
These results, taken in the context of our other findings, suggest that effects of emollient therapy in children with SAM associated with reduced risk for infection—detected according to clinical suspicion—may be due primarily to localized effects on the skin, as manifest in improved skin barrier function and microbiome diversity.22,24 Some evidence for reduction in infections occurring through the skin in association with greater skin barrier function has been observed in preterm infants treated with SSO,28–30 although this requires further research in children with SAM.
Our study also showed no changes in cytokine levels in the blood over the course of 10 days of nutritional rehabilitation of young children with SAM, although there was a suggestion visually of reduced levels of IL-8 over the 10-day course of nutritional rehabilitation that was common to the treatment and the control groups. The few studies that have examined immunological responses in children with SAM during nutritional rehabilitation31 have not reported on effects on cytokine levels in the blood. However, an earlier study in South America showed a significant increase of IL-1β and TNF-α among moderately malnourished infants after nutritional rehabilitation.32 A recent study demonstrated that several pro-inflammatory cytokines, including IL-6, IFN-γ, and TNF-α, were elevated in stunted children (a chronic form of malnutrition) following nutritional intervention.33 This suggests that nutritional intervention may influence the capacity of peripheral blood mononuclear cells to produce inflammatory cytokines in stunted children. Another study in children with SAM found that higher concentrations of systemic inflammatory markers were associated with anthropometric deficits, suggesting that inflammation may negatively impact recovery from wasting.34 In our study, children exhibited a trend in weight gain22 by the end of the nutritional rehabilitation phase, which coincided with a declining trend in IL-8 levels and reduced levels of CRP, suggesting a potentially inverse relationship between pro-inflammatory markers and weight gain during nutritional rehabilitation.
Our findings indicate that while emollient therapy with SSO has demonstrated benefits in improving skin barrier function and reducing infection risk, these effects do not appear to be mediated by significant systemic immune modulation, although this requires further research, given our small sample size, short (10-day) period of treatment, and low levels of cytokines in some samples. Although no significant changes in cytokine levels were observed during nutritional rehabilitation, a decreasing trend in IL-8 was noted, coinciding with weight gain. This potential inverse relationship suggests a possible link between inflammation and nutritional recovery. However, our study had some potential limitations, including a small sample size, short intervention duration (10 days), low level of measured cytokines, and potential confounding factors, such as the presence of infection. Given the limited understanding of immune responses in children with SAM, particularly in relation to cytokine dynamics during treatment, future larger longitudinal studies are warranted to explore the role of inflammation in malnutrition recovery and to further assess both local cutaneous and systemic effects of emollient therapy. Such studies should extend the period of treatment and evaluate a broader range of immunologic markers, considering the low levels of cytokines detectable in the blood of these children.
Supplementary information
Acknowledgements
The authors would like to thank enrolled patients and their families for their participation in the study. The authors would also like to acknowledge Lindsay Kendall and Rachel A. Gibson for their assistance in the set-up, securing of funding and input into the analysis of the main study, which comprised of a 1:1-randomized, two-arm, controlled, proof-of-concept clinical trial in Bangladesh, from which this subset of patients was drawn. This study was funded by GSK, UK, under a research collaboration, as part of the GSK / Save the Children partnership, and by the Thrasher Research Fund through a grant to Leland Stanford Junior University, USA, grant number 61147865-120965. The funders had no role in the design, conduct, analysis, and reporting of the trial.
Author contributions
K.M.S., T.A., and G.L.D. were responsible for the original proposal, and K.M.S. and G.L.D. were primarily responsible for securing funding for the trial. K.M.S. had overall responsibility for the management of the study on-site. K.M.S., M.I.H., and M.M. had overall responsibility for data collection and were supported by G.L.D. K.M.S., M.I.H., and M.M. wrote the statistical analysis plan with input from A.N. and G.L.D. K.M.S. did the main analyses with input from A.N. and G.L.D. K.M.S. and G.L.D. wrote the initial draft of the report with input from A.N. G.L.D. is the guarantor. All authors reviewed the manuscript for intellectual content and approved the final report. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Data availability
Data are not publicly available owing to data privacy, but access to the anonymized dataset along with the trial protocol and analysis plan can be obtained from the corresponding author on reasonable request.
Competing interests
AN is employed by GSK and holds financial equities in GSK. All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no other competing interests.
Consent statement
All participants gave written informed consent prior to taking part in the study.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at https://doi.org/10.1038/s41390-025-04602-z.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are not publicly available owing to data privacy, but access to the anonymized dataset along with the trial protocol and analysis plan can be obtained from the corresponding author on reasonable request.