Daniel E. Roth

Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh

Aim: Acute lower respiratory tract infection (ALRI) is the most important global cause of childhood death. Micronutrient deficiencies may increase the risk of ALRI. A case–control study was conducted to assess the association between vitamin D status and ALRI in rural Bangladesh.

Association between Vitamin D Receptor Gene Polymorphisms and Response to Treatment of Pulmonary Tuberculosis

BACKGROUND Polymorphisms in the gene that encodes the vitamin D receptor (VDR) may influence the host response to Mycobacterium tuberculosis infection. METHODS In a Peruvian community with a high incidence of tuberculosis (TB), VDR TaqI and FokI polymorphisms were compared among 103 patients with pulmonary TB and 206 matched healthy control subjects. Associations of VDR polymorphisms with treatment outcome were analyzed among 78 patients undergoing treatment of pulmonary TB. RESULTS Sputum mycobacterial culture and auramine stain conversions were significantly faster among participants with the FokI FF genotype, compared with participants with the non-FF genotypes. Sputum culture conversion was faster among participants with the TaqI Tt genotype, compared with those with the TT genotype. Increased probability of culture conversion during TB treatment was independently associated with the TaqI Tt genotype (age- and sex-adjusted relative risk, 4.28; 95% confidence interval, 1.88-9.75; P = .001). VDR polymorphisms were not significantly associated with susceptibility to TB in the case-control study. CONCLUSIONS VDR gene polymorphisms are associated with the time to sputum culture and auramine stain conversion during TB treatment. To our knowledge, the present study is the first report of a specific host gene influence on the outcome of TB treatment. These findings demonstrate the potential clinical relevance of immunomodulatory functions of vitamin D metabolites acting via the VDR in the host response against pulmonary TB.

Acute lower respiratory infections in childhood: opportunities for reducing the global burden through nutritional interventions

Inadequate nutrition and acute lower respiratory infection (ALRI) are overlapping and interrelated health problems affecting children in developing countries. Based on a critical review of randomized trials of the effect of nutritional interventions on ALRI morbidity and mortality, we concluded that: (1) zinc supplementation in zinc-deficient populations prevents about one-quarter of episodes of ALRI, which may translate into a modest reduction in ALRI mortality; (2) breastfeeding promotion reduces ALRI morbidity; (3) iron supplementation alone does not reduce ALRI incidence; and (4) vitamin A supplementation beyond the neonatal period does not reduce ALRI incidence or mortality. There was insufficient evidence regarding other potentially beneficial nutritional interventions. For strategies with a strong theoretical rationale and probable operational feasibility, rigorous trials with active clinical case-finding and adequate sample sizes should be undertaken. At present, a reduction in the burden of ALRI can be expected from the continued promotion of breastfeeding and scale-up of zinc supplementation or fortification strategies in target populations.

Helicobacter pylori Reinfection Is Common in Peruvian Adults after Antibiotic Eradication Therapy

To characterize posttreatment recurrence of Helicobacter pylori in Peru, 192 adults with H. pylori-positive gastric biopsy specimens were monitored by (14)C-Urea breath test, after eradication of H. pylori by use of amoxicillin, clarithromycin, and omeprazole. The cumulative risk of recurrence at 18 months was 30.3% (95% confidence interval, 21.4%-39.3%). Randomly amplified polymorphic DNA patterns and DNA sequence data established that, among 28 pairs of H. pylori isolates from pretreatment and recurrent infections, 6 (21%) were genetically similar, suggesting recrudescence of the previous infection, and 22 (79%) were different, suggesting reinfection with a new strain that differed from that involved in the initial infection. Eating mainly outside of the home was a risk factor for infection with a new strain (adjusted relative risk [RR], 5.07), whereas older age was a protective factor (adjusted RR, 0.20). Although an increase in the anti-H. pylori IgG antibody titer corresponded to recurrence, pretreatment and recurrent infections were similar with respect to quantitative culture colony counts and histologic characteristics, suggesting that neither prior eradication nor the memory immune response measurably alters the risk or burden of recurrent infection. Although eradication with antibiotics was successful, the high rate of reinfection suggests that treatment is unlikely to have a lasting public health effect in this setting.

Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials

Maternal–child health benefits of optimizing vitamin D status during pregnancy may include a reduced risk of pre-eclampsia, improved fetal growth and beneficial effects on infant immune function. These hypotheses require evaluation by randomized controlled antenatal vitamin D supplementation trials using doses that are high enough to elevate serum 25-hydroxyvitamin D concentrations into the range believed to be associated with improved health outcomes. Such doses may be considerably higher than the current recommended dietary allowance (600 IU day–1) or standard prenatal supplement dose (400 IU day–1), and may even be higher than the tolerable upper intake level (4000 IU day–1) advised by the Institute of Medicine (2010). A critical review of the published literature yielded limited data regarding the safety of antenatal vitamin D regimens. There have been no published reports of the teratogenic effects of vitamin D on humans. Some animal studies have suggested the potential for dose-dependent fetal toxicities (for example, growth impairment, skeletal malformations and cardiovascular anomalies), but the relevance of these observations to humans is unknown. Antenatal vitamin D supplementation trials should incorporate a range of methods for objectively establishing maternal and fetal safety, and aim to identify the lowest doses of vitamin D required to achieve target outcomes.

Maternal–fetal–infant dynamics of the C3-epimer of 25-hydroxyvitamin D

BACKGROUND Poor vitamin D status (i.e. low serum 25-hydroxyvitamin D (25(OH)D)) has been associated with adverse clinical outcomes during pregnancy and childhood. However, the interpretation of serum 25(OH)D levels may be complicated by the presence of the C3-epimer of 25(OH)D. We aimed to quantify C3-epi-25(OH)D3 in pregnant women and fetuses, to explore the relationship of the C3-epimer between maternal and cord samples, and to establish whether infant C3-epimer abundance is explained by prenatal formation. METHODS In a sub-study of a randomized trial of prenatal vitamin D3, 25(OH)D3 and C3-epi-25(OH)D3 were quantified by LC-MS/MS in 71 sets of mother-fetus-infant serum samples, including maternal delivery specimens, cord blood, and infant specimens acquired at 3-28 weeks of age. RESULTS Without supplementation, median concentrations of C3-epi-25(OH)D₃ were higher in infants (6.80 nmol/L) than mothers (0.45 nmol/L) and cord blood (0 nmol/L). However, there was substantial variation such that C3-epi-25(OH)D₃ accounted for up to 11% (maternal), 14% (cord), and 25% (infant) of the total 25(OH)D₃. Supplemental vitamin D₃ significantly increased maternal-fetal C3-epi-25(OH)D₃, and was a preferential source of C3-epi-25(OH)D₃ compared to basal vitamin D, possibly due to C3-epi-cholecalciferol in the supplement. Multivariate regression did not suggest transplacental transfer of C3-epi-25(OH)D₃, but rather indicated its generation within the fetal-placental unit from maternally-derived 25(OH)D₃. Neither maternal nor fetal C3-epi-25(OH)D₃ is accounted for the relatively high concentrations of infant C3-epi-25(OH)D₃, suggesting rapid postnatal generation. CONCLUSIONS C3-epi-25(OH)D₃ is present in some pregnant women and fetuses, but does not appear to be efficiently transferred transplacentally. High C3-epimer concentrations in infancy are probably due to postnatal formation rather than fetal stores.

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial

BACKGROUND Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.

Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials

Objectives To estimate the effects of vitamin D supplementation during pregnancy on 11 maternal and 27 neonatal/infant outcomes; to determine frequencies at which trial outcome data were missing, unreported, or inconsistently reported; and to project the potential contributions of registered ongoing or planned trials. Design Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials. Data sources Medline, Embase, PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials. Eligibility criteria for study selection Trials of prenatal vitamin D supplementation with randomised allocation and control groups administered placebo, no vitamin D, or vitamin D ≤600 IU/day (or its equivalent), and published in a peer reviewed journal. Results 43 trials (8406 participants) were eligible for meta-analyses. Median sample size was 133 participants. Vitamin D increased maternal/cord serum concentration of 25-hydroxyvitamin D, but the dose-response effect was weak. Maternal clinical outcomes were rarely ascertained or reported, but available data did not provide evidence of benefits. Overall, vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12 530 additional participants to future reviews. Conclusions Most trials on prenatal vitamin D published by September 2017 were small and of low quality. The evidence to date seems insufficient to guide clinical or policy recommendations. Future trials should be designed and powered to examine clinical endpoints, including maternal conditions related to pregnancy (such as pre-eclampsia), infant growth, and respiratory outcomes. Systematic review registration PROSPERO CRD42016051292

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0–59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. Conclusion: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing.

Pharmacokinetics of High-Dose Weekly Oral Vitamin D3 Supplementation during the Third Trimester of Pregnancy in Dhaka, Bangladesh

A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27–30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (∆) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ∆[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ∆[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (−15 nmol/L, 95% CI −34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ≥ 50 nmol/L and 90% attained [25(OH)D] ≥ 80 nmol/L; in PL, 89% attained [25(OH)D] ≥ 50 nmol/L but 56% attained [25(OH)D] ≥ 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versus PL (117 nmol/L vs. 98 nmol/L; p = 0.07). Vitamin D3 was well tolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [25(OH)D] ≥ 80 nmol/L in virtually all mothers and newborns. Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D] elevations lead to maternal-infant health benefits.