Modelling the concentration of anti-SARS-CoV-2 immunoglobulin G in intravenous immunoglobulin product batches.

BACKGROUND: Plasma-derived intravenous immunoglobulin (IVIg) products contain a dynamic spectrum of immunoglobulin (Ig) G reactivities reflective of the donor population from which they are derived. We sought to model the concentration of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG which could be expected in future plasma pool and final-product batches of CSL Behring's immunoglobulin product Privigen. STUDY DESIGN AND METHODS: Data was extracted from accessible databases, including the incidence of coronavirus disease 2019 and SARS-CoV-2 vaccination status, antibody titre in convalescent and vaccinated groups and antibody half-life. Together, these parameters were used to create an integrated mathematical model that could be used to predict anti-SARS-CoV-2 antibody levels in future IVIg preparations. RESULTS: We predict that anti-SARS-CoV-2 IgG concentration will peak in batches produced in mid-October 2021, containing levels in the vicinity of 190-fold that of the mean convalescent (unvaccinated) plasma concentration. An elevated concentration (approximately 35-fold convalescent plasma) is anticipated to be retained in batches produced well into 2022. Measurement of several Privigen batches using the Phadia™ EliA™ SARS-CoV-2-Sp1 IgG binding assay confirmed the early phase of this model. CONCLUSION: The work presented in this paper may have important implications for physicians and patients who use Privigen for indicated diseases.

Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Iodine deficiency during pregnancy might be associated with reduced intelligence quotient (IQ) score in offspring. We assessed the effect of iodine supplementation in mildly iodine-deficient pregnant women on neurodevelopment of their offspring in areas where schoolchildren were iodine sufficient. METHODS: In this randomised, placebo-controlled trial, pregnant women in Bangalore, India, and Bangkok, Thailand, were randomly assigned (1:1) to receive 200 µg iodine orally once a day or placebo until delivery. Randomisation was done with a computer-generated sequence and stratified by site. Co-primary outcomes were verbal and performance IQ scores on the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) and the global executive composite score from the Behaviour Rating Inventory of Executive Function-Preschool Version (BRIEF-P) in the children at age 5-6 years. The trial was double-blinded; some unmasking took place at age 2 years for an interim analysis, but participants and nearly all investigators remained masked to group assignment until age 5-6 years. Analysis was by intention to treat using mixed-effects models. This trial is registered with ClinicalTrials.gov, number NCT00791466. FINDINGS: Between Nov 18, 2008, and March 12, 2011, 832 women entered the trial at a mean gestational age of 10·7 weeks (SD 2·7); median urinary iodine concentration was 131 µg/L (IQR 81-213). Mean compliance with supplementation was 87%, assessed by monthly tablet counts. 313 children (iodine group, n=159; placebo group, n=154) were analysed for verbal and performance IQ with WPPSI-III and 315 (iodine group, n=159; placebo group, n=156) for overall executive function with BRIEF-P. Mean WPPSI-III scores for verbal IQ were 89·5 (SD 9·8) in the iodine group and 90·2 (9·8) in the placebo group (difference -0·7, 95% CI -2·9 to 1·5; p=0·77), and for performance IQ were 97·5 (12·5) in the iodine group and 99·1 (13·4) in the placebo group (difference -1·6, -4·5 to 1·3; p=0·44). The mean BRIEF-P global executive composite score was 90·6 (26·2) in the iodine group and 91·5 (27·0) in the placebo group (difference -0·9, -6·8 to 5·0; p=0·74). The frequency of adverse events did not differ between groups during gestation or at delivery: 24 women in the iodine group and 28 in the placebo group reported adverse events (iodine group: abortion, n=20; blighted ovum, and n=2; intrauterine death, n=2; placebo group: abortion, n=22; blighted ovum, n=1; intrauterine death, n=2; early neonatal death, n=1; and neonatal death, n=2). INTERPRETATION: Daily iodine supplementation in mildly iodine-deficient pregnant women had no effect on child neurodevelopment at age 5-6 years. FUNDING: Swiss National Science Foundation, Nestlé Foundation, Wageningen University and Research, and ETH Zurich.

Simultaneous assessment of iodine, iron, vitamin A, malarial antigenemia, and inflammation status biomarkers via a multiplex immunoassay method on a population of pregnant women from Niger.

Deficiencies of vitamin A, iron, and iodine are major public health concerns in many low- and middle-income countries, but information on their status in populations is often lacking due to high costs and logistical challenges associated with assessing micronutrient status. Accurate, user-friendly, and low-cost analytical tools are needed to allow large-scale population surveys on micronutrient status. We present the expansion of a 7-plex protein microarray tool for the simultaneous measurement of up to seven biomarkers with relevance to the assessment of the key micronutrients iron, iodine, and vitamin A, and inflammation and malaria biomarkers: α-1-acid glycoprotein, C-reactive protein, ferritin, retinol binding protein 4, soluble transferrin receptor, thyroglobulin, and histidine-rich protein II. Assay performance was assessed using international reference standards and then verified by comparing the multiplexed and conventional immunoassay results on a training panel of plasma samples collected from US adults. These data were used to assign nominal concentrations to the calibrators of the assay to further improve performance which was then assessed by interrogating plasma samples from a cohort of pregnant women from Niger. The correlation between assays for each biomarker measured from this cohort was typically good, with the exception of thyroglobulin, and the sensitivity ranged from 74% to 93%, and specificity from 81% to 98%. The 7-Plex micronutrient assay has the potential for use as an affordable tool for population surveillance of vitamin A, iron, and iodine deficiencies as well as falciparum malarial parasitemia infectivity and inflammation. The assay is easy-to-use, requires minimal sample volume, and is scalable, rapid, and accurate-needing only a low-cost reader and basic equipment present in most reference laboratory settings and so may be employed by low and middle income countries for micronutrient surveillance to inform on status in key populations. Micronutrient deficiencies including iron, iodine, and vitamin A affect a significant portion of the world's population. Efforts to assess the prevalence of these deficiencies in vulnerable populations are challenging, partly due to measurement tools that are inadequate for assessing multiple micronutrients in large-scale population surveys. We have developed a 7-plex immunoassay for the simultaneous measurement of seven biomarkers relevant to assessing iodine, iron, and vitamin A status, inflammation and Plasmodium falciparum parasitemia by measuring levels of thyroglobulin, ferritin, soluble transferrin receptor, retinol binding protein 4, α-1-acid glycoprotein, C-reactive protein, and histidine-rich protein II. This 7-plex immunoassay technique has potential as a rapid and effective tool for use in large-scale surveys and assessments of nutrition intervention programs in low- and middle-income countries.

Moderate-to-Severe Iodine Deficiency in the "First 1000 Days" Causes More Thyroid Hypofunction in Infants Than in Pregnant or Lactating Women.

Background: Iodine deficiency early in the life cycle-the "first 1000 days"-can cause hypothyroidism and irreversibly impair neuromotor development. However, the relative vulnerability among women and infants during this critical period is unclear, making it difficult for country-based programs with limited resources to prioritize their iodine interventions.Objective: Our aim was to determine the prevalence of thyroid hypofunction in women and infants living in an area of moderate-to-severe iodine deficiency.Methods: In a cross-sectional survey in Morocco, we measured urinary iodine concentrations (UICs) and concentrations of thyroid-stimulating hormone (TSH) and total or free thyroxine (TT4 or fT4, respectively) in women of reproductive age (n = 156), pregnant women (n = 245), and lactating women (n = 239) and their young infants (n = 239). We calculated daily iodine intakes and measured iodine concentrations in breast milk and household salt. We compared the incidence of hypothyroidism between the 3 groups of women and with the infants.Results: Women of reproductive age, pregnant women, and lactating women had median (IQR) UICs of 41 (29-63), 32 (17-58), and 35 (19-62) µg/L; and estimated iodine intakes were ∼60%, 22%, and 26% of Recommended Nutrient Intakes (RNIs). The infants' median UIC was 73 (28-157) µg/L, which was greater than for all 3 groups of women (P < 0.001), and their dietary intakes were 27% of the RNI. The prevalence of hypothyroidism was not significantly different between the 4 groups, whereas the prevalence of hypothyroxinemia was higher in infants (40%) than in the 3 groups of women (11-14%) (P < 0.001). The median breast-milk iodine concentration was 42 (26-81) µg/L. Only 6% of salt samples were adequately iodized to a concentration of ≥15 ppm; 54% were inadequately iodized and 40% contained no measurable iodine.Conclusions: In an area of moderate-to-severe iodine deficiency, the prevalence of thyroid hypofunction is ∼4-fold higher in young infants compared with the 3 groups of women, suggesting that, in the "first 1000 days," infants are more vulnerable than their mothers and that programs should prioritize iodine prophylaxis for this group.

Urinary iodine concentration identifies pregnant women as iodine deficient yet school-aged children as iodine sufficient in rural Niger.

OBJECTIVE: To assess iodine status among pregnant women in rural Zinder, Niger and to compare their status with the iodine status of school-aged children from the same households. DESIGN: Seventy-three villages in the catchment area of sixteen health centres were randomly selected to participate in the cross-sectional survey. SETTING: Salt iodization is mandatory in Niger, requiring 20-60 ppm iodine at the retail level. SUBJECTS: A spot urine sample was collected from randomly selected pregnant women (n 662) and one school-aged child from the same household (n 373). Urinary iodine concentration (UIC) was assessed as an indicator of iodine status in both groups. Dried blood spots (DBS) were collected from venous blood samples of pregnant women and thyroglobulin (Tg), thyroid-stimulating hormone and total thyroxine were measured. Iodine content of household salt samples (n 108) was assessed by titration. RESULTS: Median iodine content of salt samples was 5·5 ppm (range 0-41 ppm), 98 % had an iodine content 40 µg/l. CONCLUSIONS: In this region of Niger, most salt is inadequately iodized. UIC in pregnant women indicated iodine deficiency, whereas UIC of school-aged children indicated marginally adequate iodine status. Thus, estimating population iodine status based solely on monitoring of UIC among school-aged children may underestimate the risk of iodine deficiency in pregnant women.

Dried Blood Spot Thyroglobulin as a Biomarker of Iodine Status in Pregnant Women.

Context: Thyroglobulin (Tg) could be a sensitive biomarker of iodine nutrition in pregnant women (PW). A dried blood spot (DBS) assay would simplify collection and transport in field studies. Objectives: Our aims were to (1) establish and test a reference range for DBS-Tg in PW; (2) determine whether co-measurement of Tg antibodies (Abs) is necessary to define population iodine status. Design, Setting, and Participants: Standardized cross-sectional studies of 3870 PW from 11 countries. For the DBS-Tg reference range, we included TgAb-negative PW (n = 599) from 3 countries with sufficient iodine intake. Main Outcome Measures: We measured the urinary iodine concentration and DBS thyroid-stimulating hormone, total thyroxin, Tg, and TgAb. Results: In the reference population, the median DBS-Tg was 9.2 µg/L (95% confidence interval, 8.7 to 9.8 µg/L) and was not significantly different among trimesters. The reference range was 0.3 to 43.5 µg/L. Over a range of iodine intake, the Tg concentrations were U-shaped. Within countries, the median DBS-Tg and the presence of elevated DBS-Tg did not differ significantly between all PW and PW who were TgAb-negative. Conclusions: A median DBS-Tg of ∼10 µg/L with <3% of values ≥44 µg/L indicated population iodine sufficiency. Concurrent measurement of TgAb did not appear necessary to assess the population iodine status.

Increasing Awareness and Use of Iodised Salt in a Marginalised Community Setting in North-West Pakistan.

Iodine deficiency is still prevalent in parts of Pakistan, despite the introduction of a national Iodine Deficiency Disorder Control Programme in 1994. The purpose of this study was to gain an understanding of the knowledge, attitudes and practice regarding the use of iodised salt in a brick kiln community, and to use this information to design an intervention to increase its consumption. A cross-sectional survey was used to assess the use of iodised salt and focus group discussions explored the attitudes and barriers to its use. Thematically analysed transcripts informed the design of a 4-month intervention. Iodised salt sales and urine iodine concentration (UIC) were monitored to assess the effectiveness of the intervention. At baseline, 2.6% of households reported use of iodised salt and barriers included its higher cost and belief about a negative impact on reproduction. During the intervention, sales of salt labelled as iodised increased by 45%, however this was not reflected in an increase in UIC. This study highlighted the positive impact of education and awareness raising on iodised salt consumption in a hard to reach, marginalised community. However, issues regarding adequate iodisation by local producers and appropriate storage also need to be urgently addressed at a provincial level.

Development and Validation of a New Low-Cost Enzyme-Linked Immunoassay for Serum and Dried Blood Spot Thyroglobulin.

BACKGROUND: Thyroglobulin (Tg), a biomarker of iodine nutrition, can be measured on dried blood spots (DBS), which simplifies collection and transport in surveys. The World Health Organization recommends DBS-Tg for monitoring iodine status in children. It could also be a useful iodine biomarker during pregnancy. However, the Tg antibody (Ab) used in earlier DBS-Tg assays is no longer commercially available. The aims of the present study were: (i) to develop a new low-cost serum and DBS-Tg sandwich enzyme-linked immunosorbent assay for assessment of Tg in population studies; (ii) to check the stability of DBS-Tg during long-term storage; and (iii) to assess within-subject variability in DBS-Tg. METHODS: Serum and DBS samples were measured from healthy pregnant women (n = 424) with the new assays, as well as the Immulite 2000 (Siemens), including TgAb positive (n = 150) and TgAb negative (n = 274) women. DBS-Tg stability was tested over 15 weeks of storage at -20 °C. Within-subject variability was evaluated over four weeks in four healthy adults. RESULTS: Intra-assay and interassay variability was 4.4-7.3% and 10.1-12.9% for the new serum Tg assay, and 7.6-12.3% and 7.6-16.5% for the DBS-Tg assay. Correlation between the two serum methods was high (r = 0.68, p < 0.01). Assay performance in all women and those TgAb negative was comparable. Correlation between the new serum Tg assay and the DBS-Tg assay was high (r = 0.78, p < 0.01), and agreement expressed as a function of the average Tg concentration for the two methods (X) was 0.59X -4.59 µg/L. DBS-Tg was stable for 15 weeks stored at -20 °C. Within-subject variability in DBS-Tg was 21.1%. Reagents and antibodies costs for the new serum and DBS assays are ∼ US$1. CONCLUSIONS: These new low-cost serum and DBS-Tg assays perform well over a wide range of Tg concentrations, and the field-friendly DBS assay may be particularly useful in population studies of iodine nutrition.

Iodine deficiency in a study population of pregnant women in Sweden.

INTRODUCTION: Iodine deficiency in utero may impair neurological development of the fetus. In Sweden, iodine nutrition is considered to be adequate in the general population. The aim of this study was to evaluate iodine nutrition during pregnancy in Sweden. MATERIAL AND METHODS: In this cross-sectional study, the total study population (n = 459) consisted of two cohorts (Värmland County, n = 273, and Uppsala County, n = 186) of pregnant non-smoking women without pre-gestational diabetes mellitus or known thyroid disease before or during pregnancy. Spot urine samples were collected in the third trimester of pregnancy for median urinary iodine concentration (UIC) analysis. RESULTS: The median UIC in the total study population was 98 µg/L (interquartile range 57-148 µg/L). CONCLUSIONS: According to WHO/UNICEF/IGN criteria, population-based median UIC during pregnancy should be 150-249 µg/L. Thus, our results indicate insufficient iodine status in the pregnant population of Sweden. There is an urgent need for further assessments in order to optimize iodine nutrition during pregnancy.

Iodine Supplementation Decreases Hypercholesterolemia in Iodine-Deficient, Overweight Women: A Randomized Controlled Trial.

BACKGROUND: In iodine deficiency, thyrotropin (TSH) may increase to stimulate thyroidal iodine uptake. In iodine-sufficient populations, higher TSH predicts higher total cholesterol. Whether higher TSH caused by iodine deficiency affects serum lipids is uncertain. OBJECTIVE: Our aim was to determine if iodine repletion decreases serum TSH and improves the lipid profile. METHODS: In this randomized controlled intervention, iodine-deficient, overweight or obese Moroccan women (n = 163) received 200 µg oral iodine or a placebo daily for 6 mo. Main outcomes were serum TSH and plasma total and LDL cholesterol. Secondary outcomes included thyroid hormones and measures of lipid and glucose metabolism and urinary iodine concentration (UIC). Data were compared by using mixed-model analysis. RESULTS: In the intervention group, median UIC increased from 38 (95% CI: 34, 45) µg/L to 77 (95% CI: 59, 89) µg/L (P < 0.001). After 6 mo of intervention, TSH was 33% lower in the treatment group than in the placebo group (P = 0.024). The triiodothyronine (T3) to thyroxine (T4) ratio and thyroglobulin decreased with treatment [-15% (P = 0.002) and -32% (P < 0.001), respectively], whereas T4 concentrations were higher in the treatment group (P < 0.001). Total cholesterol in subjects with elevated baseline cholesterol (>5 mmol/L) was reduced by 11% after the intervention (P = 0.034). At 6 mo, only 21.5% of treated women remained hypercholesterolemic (total cholesterol >5 mmol/L) vs. 34.8% of controls (baseline: 44.2% in the intervention and 36.8% in the control group; P = 0.015). The reduction in the prevalence of elevated LDL cholesterol (>3 mmol/L) in the intervention group (50.6% to 35.4% compared with 47.4% to 44.9% in the control group) was not significant (P-interaction = 0.23). CONCLUSIONS: Our findings suggest that moderate to severe iodine deficiency in overweight women elevates serum TSH and produces a more atherogenic lipid profile and that iodine supplementation in this group reduces the prevalence of hypercholesterolemia. Thus, iodine prophylaxis may reduce cardiovascular disease risk in overweight adults. This trial was registered at clinicaltrials.gov as NCT01985204.

Direct iodine supplementation of infants versus supplementation of their breastfeeding mothers: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Iodine deficiency in infants can damage the developing brain and increase mortality. Present recommendations state that oral iodised oil should be given to breastfeeding mothers to correct iodine deficiency in infancy when iodised salt is not available, and that direct supplementation should be given to infants who are not being breastfed or receiving iodine-fortified complimentary foods. However, there is little evidence for these recommendations. We aimed to assess the safety and efficacy of direct versus indirect supplementation of the infant. METHODS: We did this double blind, randomised, placebo-controlled trial in Morocco. Healthy breastfeeding mothers and their term newborn babies (aged ≤8 weeks) were block randomised by clinic day to receive either: one dose of 400 mg iodine to the mother and placebo to the infant (indirect infant supplementation), or one dose of about 100 mg iodine to the infant and placebo to the mother (direct infant supplementation). Randomisation was masked to participants and investigators. Coprimary outcomes were: maternal and infant urinary iodine concentrations, breastmilk iodine concentration, maternal and infant thyroid-stimulating hormone (TSH) concentrations, maternal and infant thyroxine (T4) concentrations, and infant growth. These outcomes were measured at baseline, and when infants were aged about 3 months, 6 months, and 9 months, and the two groups were compared using mixed effects models. This study is registered with ClinicalTrials.gov, number NCT01126125. FINDINGS: We recruited 241 mother-infant pairs between Feb 25, and Aug 10, 2010, and completed data collection by Aug 6, 2011. At baseline, median urinary iodine concentration was 35 µg/L (IQR 29-40) in mothers and 73 µg/L (29-237) in infants, suggesting iodine deficiency. During the study, maternal urinary iodine concentration (p=0.011), breastmilk iodine concentration (p<0.0001), and infant urinary iodine concentration (p=0.042) were higher in the indirect infant supplementation group than in the direct supplementation group. Maternal TSH (p=0.276) and T4 (p=0.074) concentrations did not differ between the groups over the course of the study, nor did infant TSH (p=0.597) and T4 (p=0.184) concentrations, but the number of infants with thyroid hypofunction was lower (p=0.023) in the indirect supplementation group than the direct supplementation group. The infant groups did not differ in anthropomorphic measures, except that length-for-age Z score was slightly greater in the direct infant supplementation group (p=0.032). At 3 months and 6 months of age, median infant urinary iodine concentration in the indirect infant supplementation group was sufficient (>100 µg/L), whereas infant urinary iodine concentration was sufficient only at 6 months in the direct supplementation group. There were no serious adverse events in either group. INTERPRETATION: In regions of moderate-to-severe iodine deficiency without effective salt iodisation, lactating women who receive one dose of 400 mg iodine as oral iodised oil soon after delivery can provide adequate iodine to their infants through breastmilk for at least 6 months, enabling the infants to achieve euthyroidism. Direct supplementation is less effective in improving infant iodine status. FUNDING: ETH Zurich, Switzerland; the Medicor Foundation, Vaduz, Lichtenstein.