Effect of probiotics on thymus size and markers of infection in late infancy: a randomized controlled trial.

BACKGROUND: Probiotics are known to stimulate the immune system but the effect on thymus size in late infancy is unknown. We examined the effect of probiotics on thymus size and C-reactive protein (CRP) in healthy Danish infants starting daycare. We further examined associations between thymus size, CRP and recent infections. METHODS: The study included 186 children randomized to a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® or placebo for 6 months. Thymus size, assessed as thymus index (TI) and thymus weight index (TWI), was measured by ultrasound at baseline and at endpoint. Blood samples were drawn to measure CRP. Infections were parent-reported. RESULTS: There was no significant difference in thymus size between the probiotic group and placebo (p ≥ 0.248) but TWI tended to be higher in the probiotic group corresponding to 5% higher than placebo (p = 0.068) in an adjusted model. There was no effect of probiotics on CRP (p = 0.331). At the endpoint, thymus size was inversely associated with CRP (p ≤ 0.040), diarrhea (p ≤ 0.050), and TI was also associated with the absence from daycare due to respiratory or gastrointestinal infections (p = 0.010). CONCLUSION: The probiotic intervention had no effect on thymus size or CRP in Danish children at the age of starting daycare. IMPACT: Overall there was no effect on thymus size of a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® administered to Danish children starting daycare. This study examines the effect of probiotics on thymus size in healthy children when they start daycare thus exposed for infections while their immune system is still developing. This has to our knowledge not been described before. We found no significant difference in thymus size between the probiotic and placebo groups, but for thymus weight index, there was a trend. This should be investigated further in studies designed for this as primary outcome.

Thymus size in children with moderate malnutrition: a cohort study from Burkina Faso.

BACKGROUND: Moderate acute malnutrition (MAM) affects millions of children, increasing their risk of dying from infections. Thymus atrophy may be a marker of malnutrition-associated immunodeficiency, but factors associated with thymus size in children with MAM are unknown, as is the effect of nutritional interventions on thymus size. METHODS: Thymus size was measured by ultrasound in 279 children in Burkina Faso with MAM, diagnosed by low mid-upper arm circumference (MUAC) and/or low weight-for-length z-score (WLZ), who received 12 weeks treatment with different food supplements as part of a randomized trial. Correlates of thymus size and of changes in thymus size after treatment, and after another 12 weeks of follow-up were identified. RESULTS: Thymus size correlated positively with age, anthropometry and blood haemoglobin, and was smaller in children with malaria. Children with malnutrition diagnosed using MUAC had a smaller thymus than children diagnosed based on WLZ. Thymus size increased during and after treatment, similarly across the different food supplement groups. CONCLUSIONS: In children with MAM, the thymus is smaller in children with anaemia or malaria, and grows with recovery. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low WLZ in children with MAM. IMPACT: Thymus atrophy is known to be a marker of the immunodeficiency associated with malnutrition in children. In children with moderate malnutrition, we found the thymus to be smaller in children with anaemia or malaria. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low weight for length. Thymus atrophy appears reversible with recovery from malnutrition, with similar growth seen in children randomized to treatment with different nutritional supplements.

Thymus size is associated with breastfeeding and having pets in a sex-specific manner.

AIM: The aim was to examine associations between thymus size and anthropometric measurements, sex, age, breastfeeding status, presence of siblings, household pets, and infections and allergies since birth in 8- to 13-month-old healthy Danish infants. METHODS: Data collected from 256 healthy infants enrolled in the ProbiComp study were used. Thymus size was assessed using sonographic measures, and thymic index (TI) and thymus weight index (TWI) was used as an absolute and a relative volume estimate, respectively. RESULTS: In terms of TI and TWI, boys had approximately 15% and 5% larger thymus than girls (P < .001 and P < .02, respectively). TWI was larger in girls who were still breastfed than girls who were no longer breastfed (ß: 0.16 cm3 /kg; 95% CI: 0.004, 0.29; P = .01), but no difference was observed for boys. Having household pets was associated with a larger TI (P = .02), which seemed to be driven by associations for boys (ß: 1.38 cm3 ; 95% CI: 0.02, 2.74). No other factors associated with thymus size were identified. CONCLUSION: Thymus size was associated with current breastfeeding in girls and with having household pets in boys. Sex-specific associations should be further explored in future studies on factors associated with thymus size.

Effectiveness of food supplements in increasing fat-free tissue accretion in children with moderate acute malnutrition: A randomised 2 × 2 × 3 factorial trial in Burkina Faso.

BACKGROUND: Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplement (LNS) or corn-soy blend (CSB). We assessed the effectiveness of (a) matrix, i.e., LNS or CSB, (b) soy quality, i.e., soy isolate (SI) or dehulled soy (DS), and (c) percentage of total protein from dry skimmed milk, i.e., 0%, 20%, or 50%, in increasing fat-free tissue accretion. METHODS AND FINDINGS: Between September 9, 2013, and August 29, 2014, a randomised 2 × 2 × 3 factorial trial recruited 6- to 23-month-old children with MAM in Burkina Faso. The intervention comprised 12 weeks of food supplementation providing 500 kcal/day as LNS or CSB, each containing SI or DS, and 0%, 20%, or 50% of protein from milk. Fat-free mass (FFM) was assessed by deuterium dilution technique. By dividing FFM by length squared, the primary outcome was expressed independent of length as FFM index (FFMI) accretion over 12 weeks. Other outcomes comprised recovery rate and additional anthropometric measures. Of 1,609 children, 4 died, 61 were lost to follow-up, and 119 were transferred out due to supplementation being switched to non-experimental products. No children developed allergic reaction. At inclusion, 95% were breastfed, mean (SD) weight was 6.91 kg (0.93), with 83.5% (5.5) FFM. In the whole cohort, weight increased 0.90 kg (95% CI 0.88, 0.93; p < 0.01) comprising 93.5% (95% CI 89.5, 97.3) FFM. As compared to children who received CSB, FFMI accretion was increased by 0.083 kg/m2 (95% CI 0.003, 0.163; p = 0.042) in those who received LNS. In contrast, SI did not increase FFMI compared to DS (mean difference 0.038 kg/m2; 95% CI -0.041, 0.118; p = 0.35), irrespective of matrix. Having 20% milk protein was associated with 0.097 kg/m2 (95% CI -0.002, 0.196) greater FFMI accretion than having 0% milk protein, although this difference was not significant (p = 0.055), and there was no effect of 50% milk protein (0.049 kg/m2; 95% CI -0.047, 0.146; p = 0.32). There was no effect modification by season, admission criteria, or baseline FFMI, stunting, inflammation, or breastfeeding (p > 0.05). LNS compared to CSB resulted in 128 g (95% CI 67, 190; p < 0.01) greater weight gain if both contained SI, but there was no difference between LNS and CSB if both contained DS (mean difference 22 g; 95% CI -40, 84; p = 0.49) (interaction p = 0.017). Accordingly, SI compared to DS increased weight by 89 g (95% CI 27, 150; p = 0.005) when combined with LNS, but not when combined with CSB. A limitation of this and other food supplementation trials is that it is not possible to collect reliable data on individual adherence. CONCLUSIONS: Based on this study, children with MAM mainly gain fat-free tissue when rehabilitated. Nevertheless, LNS yields more fat-free tissue and higher recovery rates than CSB. Moreover, current LNSs with DS may be improved by shifting to SI. The role of milk relative to soy merits further research. TRIAL REGISTRATION: ISRCTN registry ISRCTN42569496.

Changes in whole-blood PUFA and their predictors during recovery from severe acute malnutrition.

Children with severe acute malnutrition (SAM) with complications require in-patient management including therapeutic feeding. Little attention has been given to the effects of these feeds on the essential fatty acid status of children with SAM. The objective of this study was to describe changes in the PUFA composition in whole blood in children with SAM during treatment and to determine predictors of change. This prospective study took place in a paediatric nutrition rehabilitation unit in Kampala, Uganda, and assessed whole-blood fatty acid composition of children with SAM at admission, transition, discharge and follow-up (8 and 16 weeks). ANCOVA was used to identify predictors of change in whole-blood PUFA. The study included 120 children with SAM and twenty-nine healthy control children of similar age and sex. Among the SAM children, 38 % were female and 64 % had oedema. Whole-blood n-6 PUFA proportions increased from admission to follow-up, except for arachidonic acid, which decreased by 0·79 (95 % CI 0·46, 1·12) fatty acid percentage (FA%) from admission to transition and 0·10 (95 % CI 0·23, 0·44) FA% at discharge. n-3 Long-chain (LC) PUFA decreased by 0·21 (95 % CI 0·03, 0·40) FA% at discharge and 0·22 (95 % CI 0·01, 0·42) FA% at 8 weeks of follow-up. This decrease was greater in children from families with recent fish intake and those with nasogastric tube feeding. Current therapeutic feeds do not correct whole-blood levels of LCPUFA, particularly n-3 LCPUFA, in children with SAM. Increased attention is needed to the contents of n-3 LCPUFA in therapeutic feeds.

Serum phosphate and magnesium in children recovering from severe acute undernutrition in Ethiopia: an observational study.

BACKGROUND: Children with severe acute malnutrition (SAM) have increased requirements for phosphorus and magnesium during recovery. If requirements are not met, the children may develop refeeding hypophosphatemia and hypomagnesemia. However, little is known about the effect of current therapeutic diets (F-75 and F-100) on serum phosphate (S-phosphate) and magnesium (S-magnesium) in children with SAM. METHODS: Prospective observational study, with measurements of S-phosphate and S-magnesium at admission, prior to rehabilitation phase and at discharge in children aged 6-59 months admitted with SAM to Jimma Hospital, Ethiopia. Due to shortage of F-75, 25 (35 %) children were stabilized with diluted F-100 (75 kcal/100 ml). RESULTS: Of 72 children enrolled, the mean age was 32 ± 14 months, and edema was present in 50 (69 %). At admission, mean S-phosphate was 0.92 ± 0.34 mmol/L, which was low compared to normal values, but increased to 1.38 ± 0.28 mmol/L at discharge, after on average 16 days. Mean S-magnesium, at admission, was 0.95 ± 0.23 mmol/L, and increased to 1.13 ± 0.17 mmol/L at discharge. At discharge, 18 (51 %) children had S-phosphate below the normal range, and 3 (9 %) had S-phosphate above. Most children (83 %) had S-magnesium above normal range for children. Both S-phosphate and S-magnesium at admission were positively associated with serum albumin (S-albumin), but not with anthropometric characteristics or co-diagnoses. Using diluted F-100 for stabilization was not associated with lower S-phosphate or S-magnesium. CONCLUSION: Hypophosphatemia was common among children with SAM at admission, and still subnormal in about half of the children at discharge. This could be problematic for further recovery as phosphorus is needed for catch-up growth and local diets are likely to be low in bioavailable phosphorus. The high S-magnesium levels at discharge does not support that magnesium should be a limiting nutrient for growth in the F-100 diet. Although diluted F-100 (75 kcal/100 mL) is not designed for stabilizing children with SAM, it did not seem to cause lower S-phosphate than in children fed F-75.

Mycoplasma pneumoniae incidence, phenotype, and severity in children and adolescents in Denmark before, during, and after the COVID-19 pandemic: a nationwide multicentre population-based cohort study.

Background: Mycoplasma pneumoniae infections resurged globally in 2023-2024 after a three-year decline during the COVID-19 pandemic. We explored the incidence and severity of M pneumoniae infections in children and adolescents before, during, and after the pandemic. Methods: This nationwide, population-based cohort study included all Danish children and adolescents aged 0-17 years with a positive M pneumoniae PCR test from May 1, 2016, to April 30, 2024. We obtained clinical details for patients hospitalised for 24 h or more. Risk ratios for infections, hospitalisations, and disease manifestations in 2023-2024 versus pre-COVID-19 seasons were calculated using Fisher's exact and Pearson's χ2 tests. A season was defined from May 1 to April 30. Findings: Among the Danish population of 1,152,000 children and adolescents, 14,241 with a positive PCR test for M pneumoniae were included. In 2023-2024, children and adolescents with a positive PCR rose 2.9-fold (95% CI 2.8-3.1; p < 0.0001) compared to the pre-COVID-19 seasons, and hospitalisations rose 2.6-fold (95% CI 2.0-3.3; p < 0.0001). M pneumoniae-induced rash and mucositis increased 5.3-fold (95% CI 1.8-15.3; p = 0.0007). In 2023-2024 compared to the pre-COVID-19 seasons, there was no difference in the proportion of hospitalisation (360 [4%] of 8165 versus 230 [4%] of 6009; p = 0.09), the median duration of hospital stay (3 days [IQR 2-5] versus 3 days [IQR 2-5]; p = 0.84), or paediatric intensive care unit admission (14 [4%] of 360 versus 9 [4%] of 230 p = 1.00). Interpretation: In Denmark, M pneumoniae infections and hospitalisations increased three-fold in 2023-2024 compared with the pre-COVID-19 seasons, indicating an immunity debt caused by the decline in M pneumoniae during the COVID-19 pandemic. While the severity of M pneumoniae infections did not change in 2023-2024, the five-fold increase in M pneumoniae-induced rash and mucositis in children and adolescents highlights M pneumoniae as an important pathogen causing mucocutaneous eruptions. Funding: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark.

BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Prevalence of SARS-CoV-2-Antibodies in Danish Children and Adults.

In Denmark, severe acute respiratory syndrome coronavirus 2 antibodies were assessed in a cross-sectional study among 1033 children visiting pediatric departments and 750 blood donors in June 2020, using a point-of-care test. Antibodies were detected in 17 children (1.6%) and 15 blood donors (2.0%) (P = 0.58). In conclusion, children and adults were infected to a similar low degree.