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Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial.
Ciampi, E, Uribe-San-Martin, R, Cárcamo, C, Cruz, JP, Reyes, A, Reyes, D, Pinto, C, Vásquez, M, Burgos, RA, Hancke, J
BMC neurology. 2020;(1):173
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Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS. METHODS A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change. RESULTS Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was - 0.679% for the AP group and - 1.069% for the placebo group (mean difference: -0.39; 95% CI [- 0.836-0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200-1.777], p = 0.06). The mean EDSS change was - 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia. CONCLUSIONS AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial. TRIAL REGISTRATION ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.
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A randomized controlled trial of different young child formulas on upper respiratory and gastrointestinal tract infections in Chinese toddlers.
Leung, TF, Ulfman, LH, Chong, MKC, Hon, KL, Khouw, IMSL, Chan, PKS, Delsing, DJ, Kortman, GAM, Bovee-Oudenhoven, IMJ
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2020;(7):745-754
Abstract
BACKGROUND Bioactive proteins and human milk oligosaccharides (HMOs), important ingredients in breast milk, that protect against infections are lacking in young child formula (YCF). This study investigated the effects of new YCFs on respiratory and gastrointestinal infections in toddlers. METHODS Four hundred and sixty one healthy Chinese children aged 1-2.5 years were recruited in this randomized, controlled, double-blind, parallel-group clinical trial of different YCFs. They were randomly assigned to either standard milk formula (YCF-Ref) or one of three new YCFs containing bioactive proteins and/or the HMO 2'-fucosyllactose (2'-FL) and/or milk fat for six months. Primary outcomes were incidence of upper respiratory tract infection (URTI) and duration of gastrointestinal tract infections (GITI). RESULTS There were no significant between-group differences in primary outcomes. For secondary outcomes, subjects receiving 2'-FL-supplemented YCF had longer URTI. Subjects receiving YCF supplemented with milk fat and intact bioactive proteins, and 2'-FL at levels found in breast milk, had more GITI episodes and shorter time to first GITI but similar effects on URTI duration than YCF-Ref recipients. No effects on URTI and GITI were observed in toddlers receiving YCF with bioactive proteins at lower levels than breast milk. Occurrence of adverse events and anthropometry were similar in all groups. CONCLUSIONS All three YCFs supplemented with different combinations of intact bioactive proteins, 2'-FL, and milk fat are safe in toddlers. No difference is detected among YCFs on URTI incidence and GITI duration. Further studies are needed to verify these findings especially in infants who may benefit most from the immune-boosting effects of bioactive proteins and HMOs.
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Feasibility of manual white blood cell counts as a predictor of neonatal sepsis in a low-resource setting.
Golding, CN, Schaltz-Buchholzer, F, Sanca, L, Clipet-Jensen, C, Benn, CS, Au, N, Chipperfield, K, Kollmann, TR, Amenyogbe, NA
Transactions of the Royal Society of Tropical Medicine and Hygiene. 2020;(8):566-574
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Abstract
BACKGROUND Manual white blood cell (WBC) differential counts as a predictor for neonatal sepsis development in a low-resource setting have not been thoroughly evaluated. We hypothesized that manual differentiation (specifically immature:total [I:T] neutrophil ratios) would be feasible and useful as an adjunct to predict early-onset neonatal sepsis (EONS). Secondarily, we hypothesized that vaccination with bacillus Calmette-Guérin (BCG) and oral polio vaccine (OPV) could alter WBC differential counts and thus might reduce its predictive performance. METHODS We performed a prospective cohort study within a randomized trial, randomizing healthy, high-risk newborns admitted to the nursery at the national hospital in Guinea-Bissau 1:1 to BCG+OPV at admission or at discharge (usual practice). Thin capillary blood films were prepared at 2 d of age in a subset of 268 neonates. WBC counts were assessed by microscopy and neonates were followed up for sepsis development within 2 weeks. RESULTS Ninety-eight percent (264/268) of smears provided interpretable reads. Of the 264 children, 136 had been randomized to receive BCG+OPV prior to sampling; the remaining 128 were vaccinated at discharge. The I:T ratio (average 0.017) was lower among children who did not develop clinical sepsis but did not predict sepsis (p=0.70). Only three children had an I:T ratio >0.2 (associated with a higher probability of clinical sepsis in previous studies) but did not develop sepsis. Immunization did not alter WBC composition. CONCLUSIONS Manual WBC differentials are feasible in low-resource settings. WBC differentials are not affected by standard newborn immunization. However, the I:T ratio had no value in predicting subsequent development of sepsis.
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A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Lactobacillus casei Shirota in Stable Cirrhotic Patients.
Macnaughtan, J, Figorilli, F, García-López, E, Lu, H, Jones, H, Sawhney, R, Suzuki, K, Fairclough, S, Marsden, J, Moratella, A, et al
Nutrients. 2020;(6)
Abstract
Background: In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Lactobacillus casei Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods: 92 cirrhotic patients (Child-Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results: Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1β (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1β (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion: LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.
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Efficacy of 4 wk of home enteral feeding supplementation after esophagectomy on immune function: A randomized controlled trial.
Li, XK, Cong, ZZ, Wu, WJ, Ji, SG, Zhou, H, Liu, KC, Xu, Y, Shen, Y
Nutrition (Burbank, Los Angeles County, Calif.). 2020;:110787
Abstract
OBJECTIVES In recent years, home enteral nutrition (HEN) has been adopted as a feasible and safe form of nutrition for patients undergoing esophagectomy. The aim of this study was to compare the effects of 4 wk of HEN with standard enteral nutrition (SEN) on immune function, nutritional status, and survival in patients undergoing esophagectomy. METHODS A parallel-group, randomized, single-blind, clinical trial was conducted between April 1 and August 1, 2017. Eighty patients were enrolled in the study and 62 were eligible for analysis. An enteral feeding pump was used to infuse enteral nutrition via jejunostomy tube postoperatively. Patients in HEN group were instructed to independently administer jejunostomy feeds at home. Immune parameters and nutritional indicators were measured at preoperative day 7 and at postoperative day 30. RESULTS There were no significant differences in baseline characteristics between the two groups. The levels of immunoglobulin (Ig)A and IgG, which can reflect a patient's immune function, significantly increased in the HEN group compared with those in the SEN group (P = 0.042 and P = 0.003, respectively). Comparing the two groups, 2-y progression-free survival and overall survival had no significant differences in survival curves (P = 0.36 and P = 0.29, respectively). CONCLUSION Four weeks of HEN is a safe and feasible nutritional strategy to improve immune function and nutritional status after esophagectomy. Although there was no significant difference in survival between the two groups, HEN could still be more effective and beneficial than SEN to patients with defective nutritional and immune status.
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Effect of postoperative early enteral nutrition on clinical outcomes and immune function of cholangiocarcinoma patients with malignant obstructive jaundice.
Ma, BQ, Chen, SY, Jiang, ZB, Wu, B, He, Y, Wang, XX, Li, Y, Gao, P, Yang, XJ
World journal of gastroenterology. 2020;(46):7405-7415
Abstract
BACKGROUND Most cholangiocarcinoma patients with malignant obstructive jaundice (MOJ) have varying degrees of malnutrition and immunodeficiency preoperatively. Therefore, perioperative nutritional support has important clinical significance in the treatment of cholangiocarcinoma. AIM: To investigate the effects of postoperative early enteral nutrition (EEN) on immunity function and clinical outcomes of cholangiocarcinoma patients with MOJ. METHODS This prospective clinical study included 60 cholangiocarcinoma patients with MOJ who underwent surgery. The patients were randomly divided into an experimental group and a control group according to the nutrition support modes. The control group received postoperative total parenteral nutrition (TPN), whereas the experimental group received postoperative EEN and parenteral nutrition (PN; EEN + PN). The clinical outcomes, postoperative immune function, incidences of surgical site infection and bile leakage, intestinal function recovery time, average hospitalization days, and hospitalization expenses of the two groups were assessed on postoperative days (PODs) 1, 3, and 7. RESULTS The CD3+T, CD4+T, CD8+T, and CD4+T/CD8+T cell count and the immunoglobulin (Ig) G, IgM, and IgA levels in the EEN + PN group were significantly higher than those in the TPN group on PODs 3 and 7 (P < 0.05), whereas no significant differences in the CD3+T, CD4+T, CD8+T, and CD4+T/CD8+T cell counts and IgG, IgM, and IgA levels before operation and on POD 1 were found between the two groups (P > 0.05). The intestinal function recovery time and postoperative hospital stay were shorter (P < 0.001 for both) in the EEN + PN group than in the TPN group. The hospitalization expenses of the EEN + PN group were lower than those of the TPN group (P < 0.001). However, the incidence of abdominal distension was higher than in the EEN + PN group than in the TPN group (P < 0.05). The incidence rates of biliary leakage and surgical site infection were not significantly different between the two groups (P > 0.05). CONCLUSION A postoperative EEN program could reduce the incidence of postoperative complications and improve the clinical outcomes and immune functions of cholangiocarcinoma patients with MOJ and is thus beneficial to patient recovery.
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Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.
Stoffel, NU, Uyoga, MA, Mutuku, FM, Frost, JN, Mwasi, E, Paganini, D, van der Klis, FRM, Malhotra, IJ, LaBeaud, AD, Ricci, C, et al
Frontiers in immunology. 2020;:1313
Abstract
Background: Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. Methods: We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. Findings: In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk (p = 0.0071, p = 0.0339) and 18 mo (p = 0.0182, p = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk (p = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo (p = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria (p = 0.0484, p = 0.0439) and pneumococcus 19 at 18 mo (p = 0.0199, p = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG (p = 0.0415), seroconversion (p = 0.0531) and IgG avidity (p = 0.0425) at 11.5 mo. Interpretation: In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
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Refractory neutrophil activation in type 2 diabetics with chronic periodontitis.
Herrmann, JM, Sonnenschein, SK, Groeger, SE, Ewald, N, Arneth, B, Meyle, J
Journal of periodontal research. 2020;(2):315-323
Abstract
BACKGROUND Inflammation increases diabetes mellitus type 2 (T2DM) progression and severity. T2DM patients are at high risk of the rapid development of chronic periodontitis (CP). Topical presence, high numbers, and bactericidal effects of immune cells are challenged by augmented antigen-induced inflammation, which promotes both diseases. OBJECTIVES To investigate gingival cellular inflammatory responses in individuals with previously undiagnosed T2DM with CP or CP alone and in systemically and periodontally healthy controls (H) in vivo and to establish an ex vivo technique permitting quantitative and qualitative assessments of gingival crevicular immune cells. MATERIALS AND METHODS T2DM + CP, CP, and H individuals (n = 10, each) received a 2-week oral hygiene regimen (OHR). Afterwards, a noninvasive sampling technique was performed to evaluate gingival inflammation induced under standardized conditions in vivo, that is, in the absence of severe periodontal destruction and inflammation at clinically healthy sites. Stimuli (casein/test or phosphate-buffered saline w/o. Ca2+ or Mg2+ , PBS(-/-) /control) were randomly applied contralaterally in the gingival sulci of participants' upper dentes canini. One day after completion of the OHR, gingival crevicular fluid (GCF) was kinetically assayed between the time of the baseline (BL) measurement and 55 minutes. Polymorphonuclear leukocyte (PMN) content (PMNGCF ) was quantitated at an optimum time of 35 minutes. PMNGCF counts reflect local inflammation. Ex vivo samples were fluorimetrically labeled, gated according to the donor's peripheral blood polymorphonuclear neutrophils (PMNPB ), and then counted, employing flow cytometry. RESULTS PMNGCF counts in unstimulated gingival crevices (at BL) in the T2DM + CP group were higher than those in the CP and H groups. PMNGCF counts were elevated in casein vs PBS(-/-) -stimulated gingival crevices in all groups. Patients with T2DM + CP showed increased PMNGCF counts compared to those with CP (P = .035) according to scatter plots. CD45+ counts in the stimulated sites in T2DM + CP patients were higher than those in CP and H patients (P = .041). Under stimulation conditions, the CD45+ counts differed from those under placebo conditions (P = .019), indicating augmented, inducible inflammatory leukocyte infiltrate in T2DM + CP patients. CONCLUSIONS This noninvasive technique permits quantitative assessment of (experimental) gingival inflammation in vivo, revealing an influence of T2DM + CP on the number of primary immune cells in the gingival crevice. Patients who are challenged with (local) leukocytosis are likely at risk of collateral damage to the gingival crevice neighboring tissues, favoring the severity and progression of CP and consequently T2DM (www.clinicaltrials.gov NCT01848379).
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Impact of extended-release niacin on immune activation in HIV-infected immunological non-responders on effective antiretroviral therapy.
Lebouché, B, Yero, A, Shi, T, Farnos, O, Singer, J, Kema, I, Costiniuk, CT, Thomas, R, Brouillette, MJ, Engler, K, et al
HIV research & clinical practice. 2020;(6):182-190
Abstract
BACKGROUND Background: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) is involved in immune dysregulation during HIV infection. Niacin (vitamin B3) could control the excess of tryptophan depletion and represents a potential strategy to improve immune functions and CD4 count recovery in immunological non-responder HIV-infected individuals on antiretroviral therapy (ART). METHODS Methods: In the CTN PT006 phase 2 pilot randomized trial, 20 adults on ART with CD4 ≤ 350 cells/µl, despite an undetectable viral load (VL) for at least 3 months, received 2000 mg of extended-release (ER)-niacin orally once daily for 24 weeks. Side effects, VL, CD4/CD8 counts, lipid profile, T-cell activation and senescence, Tregs and Th17 cell frequencies, Kyn/Trp ratio, and levels of IL-6, IP-10, sST2, I-FABP, and LBP were assessed following ER-niacin treatment. RESULTS Results: Thirteen participants completed the study. Treatment was interrupted in 4 patients due to loss of follow-up or personal reasons and 3 patients were discontinued due to comorbidity risks. All participants maintained a VL < 40 copies/ml, while ER-niacin did not affect CD4 and CD8 cell counts. Plasma levels of triglycerides, total, and LDL cholesterol significantly decreased, following ER-niacin treatment. ER-niacin also diminished Kyn plasma levels and slightly decreased CD4 T-cell activation. However, no improvement in CD8 subsets, Kyn/Trp ratio, Th17/Treg balance, and plasma inflammatory markers was observed. CONCLUSIONS Conclusions: Although ER-niacin combined with ART was well-tolerated among immune non-responders and decreased plasma lipids, it did not improve systemic inflammation, Kyn/Trp ratio, and CD4 cell recovery. Overall, ER-niacin was not effective to overcome chronic inflammation in PLWH.
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[Clinical effect of recombinant human interferon α1b adjuvant therapy in infectious mononucleosis: a prospective randomized controlled trial].
Dai, SS, Zhou, K
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2020;(9):953-957
Abstract
OBJECTIVE To study the clinical effect of recombinant human interferon α1b assisting acyclovir on immune function, inflammatory factors, and myocardial zymogram in children with infectious mononucleosis (IM). METHODS A total of 182 children with IM who were admitted to the hospital from January to December, 2018, were divided into an observation group with 91 children and a control group with 91 children using a random number table. The children in the control group were treated with intravenous drip of acyclovir, and those in the observation group were treated with inhalation of recombinant human interferon α1b in addition to the treatment in the control group. The two groups were compared in terms of clinical symptoms, immune function, inflammatory response, myocardial zymogram, and adverse reactions. RESULTS Compared with the control group, the observation group had significantly shorter time to body temperature recovery and disappearance of isthmopyra, cervical lymph node enlargement, hepatomegaly, and splenomegaly (P<0.05). After treatment, both groups had significant increases in CD4+, CD4+/CD8+, and CD19+, and the observation group had significantly higher levels of these markers than the control group (P<0.05). After treatment, both groups had significant reductions in the levels of CD8+, tumor necrosis factor-α, interlukin-6, creatine kinase, and creatine kinase-MB, and the treatment group had significantly lower levels of these markers than the control group (P<0.05). There was no significant difference in the incidence rate of adverse reactions between the two groups after treatment (P>0.05). CONCLUSIONS For children with IM, recombinant human interferon α1b assisting acyclovir can effectively improve immune function, inhibit inflammatory reaction, reduce myocardial injury, and thus alleviate clinical symptoms.
