Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic?

The COVID-19 pandemic goes along with increased mortality from acute respiratory disease. It has been suggested that vitamin D3 supplementation might help to reduce respiratory disease mortality. We assessed the prevalence of vitamin D insufficiency and deficiency, defined by 25-hydroxyvitamin D (25(OH)D) blood levels of 30-50 and <30 nmol/L, respectively, and their association with mortality from respiratory diseases during 15 years of follow-up in a cohort of 9548 adults aged 50-75 years from Saarland, Germany. Vitamin D insufficiency and deficiency were common (44% and 15%, respectively). Compared to those with sufficient vitamin D status, participants with vitamin D insufficiency and deficiency had strongly increased respiratory mortality, with adjusted hazard ratios (95% confidence intervals) of 2.1 (1.3-3.2) and 3.0 (1.8-5.2) overall, 4.3 (1.3-14.4) and 8.5 (2.4-30.1) among women, and 1.9 (1.1-3.2) and 2.3 (1.1-4.4) among men. Overall, 41% (95% confidence interval: 20-58%) of respiratory disease mortality was statistically attributable to vitamin D insufficiency or deficiency. Vitamin D insufficiency and deficiency are common and account for a large proportion of respiratory disease mortality in older adults, supporting the hypothesis that vitamin D3 supplementation could be helpful to limit the burden of the COVID-19 pandemic, particularly among women.

The effect of vitamin D administration on vitamin D status and respiratory morbidity in late premature infants.

OBJECTIVE: To assess whether increment of vitamin D daily intake results in improved serum25(OH) vitamin D levels and reduced respiratory morbidity in premature infants. METHODS: A randomized double-blind clinical pilot trial, including preterm infants born at 32 + 6 to 36 + 6 weeks of gestation. The control group received 400 international units (IU) of cholecalciferol daily compared to 800 IU daily in the intervention group. Levels of 25(OH) vitamin D were measured at birth and 6 and 12 months of age. Respiratory morbidity was followed until 1 year of age. RESULTS: Fifty subjects were recruited during the study period; the median measured 25(OH) vitamin D levels in the control vs intervention groups were: 26.5 vs 34 nmol/L (P = .271) at birth, 99 vs 75.5 nmol/L (P = .008) at 6 months and 72.5 vs 75 nmol/L (P = .95) at 12 months of age. Infants with insufficient vitamin D (<75 nmol/L) levels had higher respiratory morbidity. Serum vitamin 25(OH) D is a fair predictor for respiratory symptoms (area under the curve [AUC], 0.697; 95% confidence interval [CI], 0.509-0.885; P = .047) and for recorded acute respiratory illnesses (AUC, 0.745; 95% CI, 0.569-0.922; P = .012). CONCLUSION: Doubling the daily intake of vitamin D in premature infants did not increase serum 25(OH) vitamin D level, due to poor compliance in the intervention group. We found an inverse association between serum 25(OH) vitamin D and respiratory symptoms, indicating vitamin D deficiency is a fair predictor for respiratory morbidity.

Serum Beta Carotene and Overall and Cause-Specific Mortality.

RATIONALE: Although the health effects of beta carotene have been studied extensively, a systematic examination of serum concentrations and long-term mortality, including cardiovascular disease mortality, has not been reported. OBJECTIVE: Explore whether serum beta carotene is associated with overall and cause-specific mortality and to elucidate the strength and dose-response of the association. METHODS AND RESULTS: We conducted a prospective serological analysis of 29 103 men in the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). During 31 years of follow-up, 23 796 deaths occurred, including deaths because of cardiovascular disease (9869), cancer (7692), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2700). Serum beta carotene was assayed using high-performance liquid chromatography. Adjusting for major risk factors measured, men with higher serum beta carotene had significantly lower all-cause mortality (hazard ratios=0.81, 0.71, 0.69, and 0.64 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001). Serum beta carotene was significantly associated with risk of death from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, diabetes mellitus, injuries and accidents, and other causes (Q5 versus Q1, hazard ratio=0.21-0.73, all Ptrend<0.0001). The all-cause mortality association was not materially impacted by adjustment for fruit and vegetable consumption (albeit, estimated with some measurement error) and was generally similar across subgroups of smoking intensity, alcohol consumption, trial supplementation, and duration of follow-up, but was significantly modified by age, years of smoking, and body mass index, with stronger inverse associations among men who were younger, smoked fewer years, and had a lower body mass index (all Pinteraction≤0.0025). CONCLUSIONS: This study provides evidence that higher beta carotene biochemical status is associated with lower overall, cardiovascular disease, heart disease, stroke, cancer, and other causes of mortality. The dose-response associations over a 30-year period were not attenuated by adjustment for other important risk factors and support greater fruit and vegetable consumption as a means to increase beta carotene status and promote longevity.

The intake of maqui (Aristotelia chilensis) berry extract normalizes H2O2 and IL-6 concentrations in exhaled breath condensate from healthy smokers - an explorative study.

BACKGROUND: Respiratory diseases are associated with pulmonary oxidative stress and inflammatory processes. Though studies in animal models suggest that dietary polyphenols improve lung injury, no intervention studies were carried out in humans. The aim of this study was to determine whether the intake of an anthocyanin-rich maqui extract improved H2O2 and IL-6 concentrations in exhaled breath condensates (EBCs) from asymptomatic smokers. FINDINGS: 15 asymptomatic smokers with mild cigarette smoking (3 pack-year [2.4 - 7.7]) (mean [CI95%]) were recruited in this exploratory longitudinal study. They ingested 2 g of maqui extract (polyphenol content = 5.18 ± 2.00 g GAE/100 g; FRAP value = 27.1 ± 2.0 mmol Fe(++)/100 g), twice daily for two weeks. EBCs were collected before and after treatment and the changes in H2O2 and IL-6 concentrations were determined by fluorimetry and Elisa, respectively. The EBC contents of H2O2 and IL-6 H2O2 before and after treatment in smokers were also compared with those determined in single EBC samples from 8 healthy non-smokers subjects. At baseline, the H2O2 concentrations were higher and those of IL-6 lower in the smokers than in the non-smokers. Maqui extract significantly decreased H2O2 (p < 0.0002) and increased IL-6 (p < 0.004) in the EBC from smokers. The EBC concentrations of H2O2 and IL-6 after maqui administration did not differ between smokers and non-smokers. CONCLUSIONS: Maqui extract normalizes IL-6 and H2O2 concentrations in EBC from humans with mild smoking habits. If confirmed, these results suggest that dietary polyphenols might be considered as an interesting alternative for the dietary management of respiratory disorders.

Vitamin A deficiency is associated with gastrointestinal and respiratory morbidity in school-age children.

Infection is an important cause of morbidity throughout childhood. Poor micronutrient status is a risk factor for infection-related morbidity in young children, but it is not clear whether these associations persist during school-age years. We examined the relation between blood concentrations of micronutrient status biomarkers and risk of gastrointestinal and respiratory morbidity in a prospective study of 2774 children aged 5-12 y from public schools in Bogotá, Colombia. Retinol, zinc, ferritin, mean corpuscular volume, hemoglobin, erythrocyte folate, and vitamin B-12 concentrations were measured in blood at enrollment into the cohort. Children were followed for 1 academic year for incidence of morbidity, including diarrhea with vomiting, cough with fever, earache or ear discharge with fever, and doctor visits. Compared with adequate vitamin A status (≥30.0 µg/dL), vitamin A deficiency (<10.0 µg/dL) was associated with increased risk of diarrhea with vomiting [unadjusted incidence rate ratio (IRR): 2.17; 95% CI: 0.95, 4.96; P-trend = 0.03] and cough with fever (unadjusted IRR: 2.36; 95% CI: 1.30, 4.31; P-trend = 0.05). After adjustment for several sociodemographic characteristics and hemoglobin concentrations, every 10 µg/dL plasma retinol was associated with 18% fewer days of diarrhea with vomiting (P < 0.001), 10% fewer days of cough with fever (P < 0.001), and 6% fewer doctor visits (P = 0.01). Every 1 g/dL of hemoglobin was related to 17% fewer days with ear infection symptoms (P < 0.001) and 5% fewer doctor visits (P = 0.009) after controlling for sociodemographic factors and retinol concentrations. Zinc, ferritin, mean corpuscular volume, erythrocyte folate, and vitamin B-12 status were not associated with morbidity or doctor visits. Vitamin A and hemoglobin concentrations were inversely related to rates of morbidity in school-age children. Whether vitamin A supplementation reduces the risk or severity of infection in children over 5 y of age needs to be determined.

Effect of selenium and vitamin C on clinical outcomes, trace element status, and antioxidant enzyme activity in horses with acute and chronic lower airway disease. A randomized clinical trial.

Excess production of reactive oxygen species is involved in the pathogenesis of airway disorders in horses. Trace element antioxidants have a beneficial role in oxidant/antioxidant balance. The aim of the present study was to evaluate the effect of a combination of sodium selenite and ascorbic acid on clinical outcome, antioxidant enzymes, and trace elements status in horses with lower airway disease. For this purpose, 40 draft horses with lower airway disease were randomly selected (acute, n = 20; chronic, n = 20). Both acute and chronic cases were randomly allocated into two subgroups (ten each). Groups 1 and 2 were the horses with acute disease, while groups 3 and 4 were chronically ill. For all groups, each horse was administered antibiotic, non-steroidal anti-inflammatory, and mucolytic drug. In addition, groups 2 and 4 were injected with 15 mg/kg sodium selenite and 30 mg/kg ascorbic acid every 24 h for successive 4 weeks. Venous blood samples were obtained from diseased horses on three occasions; at first examination, and at 2 and 4 weeks post-treatment. Clinically, antioxidant supplementation improved the clinical signs with significant decrease (p < 0.05) of the clinical index score in both acute and chronic cases. In supplemented groups compared with non-supplemented, there was a significant increase (p < 0.05) in the levels of copper, zinc, selenium, and iron as well as in the activity of glutathione-S-transferase and catalase. Meanwhile, there was a significant decrease (p < 0.05) in the levels of manganese, malondialdehyde, hydrogen peroxide, and low-density lipoprotein and in the activity of glutathione reductase. The results of the present study indicate that administration of sodium selenite and ascorbic acid may have beneficial effect on clinical outcome and antioxidant balance in horses with acute and chronic lower airway disease.

Application of metabolomics approaches to the study of respiratory diseases.

Metabolomics is the global unbiased analysis of all the small-molecule metabolites within a biological system, under a given set of conditions. These methods offer the potential for a holistic approach to clinical medicine, as well as improving disease diagnosis and understanding of pathological mechanisms. Respiratory diseases including asthma and chronic obstructive pulmonary disorder are increasing globally, with the latter predicted to become the third leading cause of global mortality by 2020. The root causes for disease onset remain poorly understood and no cures are available. This review presents an overview of metabolomics followed by in-depth discussion of its application to the study of respiratory diseases, including the design of metabolomics experiments, choice of clinical material collected and potentially confounding experimental factors. Particular challenges in the field are presented and placed within the context of the future of the applications of metabolomics approaches to the study of respiratory diseases.

Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults.

BACKGROUND: Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections. This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections. METHODOLOGY/FINDINGS: In this prospective cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009-2010 in 198 healthy adults, blinded to the nature of the substance being measured. The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations. The incidence of infection in participants with different concentrations of vitamin D was determined. One hundred ninety-five (98.5%) of the enrolled participants completed the study. Light skin pigmentation, lean body mass, and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant (p<0.0001) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill. CONCLUSIONS/SIGNIFICANCE: Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections, including influenza, in the general population and in subpopulations with lower 25-hydroxyvitamin D concentrations, such as pregnant women, dark skinned individuals, and the obese.

Low ratios of sodium to potassium in the serum of 238 dogs.

Serum sodium:potassium (Na:K) ratios are often reported in biochemical studies of dogs, although their value has not been assessed. The aims of this study were to identify diseases associated with a low Na:K ratio in dogs and to compare their prevalence with the prevalence in dogs from the same referral hospital with normal Na:K ratios. A total of 238 dogs with a Na:K ratio less than 27 were identified from medical records. Sample contamination with edta was suspected in 74 cases (31 per cent) and these and two cases that had been supplemented with potassium were removed from the analysis. The remaining 162 cases and 147 control dogs were divided into five categories depending on the organ system affected. Among the cases there were significantly more in the endocrine category than among the control dogs. Hypoadrenocorticism was the most single common cause of a low Na:K ratio and affected 27 (16.7 per cent) of the cases. Other clinical problems associated with low Na:K ratios included different urogenital, cardiorespiratory and gastrointestinal diseases.

Association of toxic and essential metals with atopy markers and ventilatory lung function in women and men.

The association of age, smoking, alcohol, superoxide dismutase (SOD), glutathione peroxidase (GPx), blood lead (BPb) and cadmium (BCd) levels, and serum levels of copper (SCu), zinc (SZn) and selenium (SSe) with atopic status and ventilatory function was examined in the groups of 166 women and 50 men with no occupational exposure to metals or other xenobiotics. Markers of atopy included serum total IgE, skin prick test (SPT) to common inhalatory allergens, non-specific nasal reactivity (NNR) and non-specific bronchial reactivity (NBR). Parameters of ventilatory function included forced vital capacity (FVC) and forced expiratory volume in the first second (FEV(1)). Significantly higher BPb, SZn, IgE and prevalence of positive SPT, and lower SCu and NNR was found in men than in women. Fifteen women taking female sex hormones (HT) had significantly higher SCu than women without HT. Regression models showed significant inverse associations between IgE and SCu (P=0.021) and NNR and SCu (P=0.044) in women. When excluding women with HT, the association of SCu and total IgE became of borderline significance (P=0.051), association between SCu and NNR disappeared, and significant positive association between total IgE and BPb emerged (P=0.046). In men, significant inverse association was found between positive SPT and SSe, and between NBR and SSe. A decrease in FVC% and FEV(1)% was associated with an increase in smoking intensity (P<0.001) and a decrease in SZn (P=0.043 and P=0.053, respectively). These results were observed at the levels of the metals comparable to those in general populations worldwide. The observed differences between men and women may partly be explained by different levels of relevant toxic and essential metals, and their combination. The role of female HT in associations of atopy markers and SCu should be further investigated.

Persistence of Mycoplasma gallisepticum in chickens after treatment with enrofloxacin without development of resistance.

The ability of the avian pathogen Mycoplasma gallisepticum to persist despite fluoroquinolone treatment was investigated in chickens. Groups of specific pathogen free chickens were experimentally infected with M. gallisepticum and treated with enrofloxacin at increasing concentrations up to the therapeutic dose. When M. gallisepticum could no longer be re-isolated from chickens, birds were stressed by inoculation of infectious bronchitis virus or avian pneumovirus. Although M. gallisepticum could not be cultured from tracheal swabs collected on several consecutive sampling days after the end of the enrofloxacin treatments, the infection was not eradicated. Viral infections reactivated the mycoplasma infection. Mycoplasmas were isolated from tracheal rings cultured for several days, suggesting that M. gallisepticum persisted in the trachea despite the enrofloxacin treatment. The minimal inhibitory concentration (MIC) of enrofloxacin for most of the re-isolated mycoplasmas was the same as that of the strain with which the birds were inoculated. Furthermore, no mutation could be detected in the fluoroquinolone target genes. These results suggest that M. gallisepticum can persist in chickens without development of resistance despite several treatments with enrofloxacin.

Environmental agents as cause of health disorders in children presented at an outpatient unit of environmental medicine.

There are no publications on the frequency of environmental agents causing diseases in children presented at centers of environmental medicine. The aim of this study was to perform a statistical analysis of the data of children who visited the outpatient Unit of Environmental Medicine (UEM) at the University Hospital of Aachen, Germany. Data of all UEM patient files from January 1988 to September 1996 were evaluated. From a total of 682 patients, 75 were children (40 girls, 35 boys, age range 1-12 years). Forty-six children were presented with unspecific health disorders, 12 to examine a possible relationship between environmental agents and a current condition, mostly atopy (n = 10). Complaints were mucosal irritations (n = 38), unspecific (n = 19), dermatological (n = 16), gastrointestinal (n = 4), heart/circulation-related (n = 2), musculoskeletal (n = 1) and neurological (n = 1) symptoms. Wood preservatives were mentioned as suspected environmental causative agents in 22 cases, followed by unspecific indoor factors (n = 15), factories/disposal sites near homes (n = 9), formaldehyde (n = 5) and unspecific exposures (n = 5). Biomonitoring was done in 44 cases, local inspections and ambient monitoring in 10 cases. No evidence for a cause-and-effect relationship was found in 55 children, but was deemed possible in nine cases. In nine other children, a relatively high degree of exposure was determined by chemical analysis, but clinical relevance remained unclear. One child suffered from subclinical mercury poisoning caused by inadequate homeopathic medication. In most children referred to an environmental medicine center, it is difficult or impossible to verify an environmental cause using the diagnostic instruments currently available.

Subchronic rat inhalation study with Skydrol 500B-4 fire resistant hydraulic fluid.

Skydrol 500B-4 fire resistant hydraulic fluid, a proprietary phosphate ester mixture composed principally of dibutyl phenyl phosphate (DBPP) and tributyl phosphate (TBP) and used as a commercial airline hydraulic fluid, was evaluated in an inhalation toxicity study of Sprague-Dawley rats. Target exposure levels used in the study were 0, 5, 100, and 300 mg/m3, and exposures were maintained for 6 hr/day, 5 days/week. Mass median aerodynamic diameters determined for particles in the mid- and high-exposure inhalation chambers were 2.85 microns and 3.31 microns, with geometric standard deviations of 1.99 microns and 1.92 microns, respectively. The percentage of particles less than 10 microns in diameter were 96.4% in the mid-exposure chamber and 95.5% in the high-exposure chamber. After 6 weeks of Skydrol exposure, 10 rats/sex/group were euthanized and then assessed for indications of possible chemical toxicity. Another 15 rats/sex/group were studied for a total of 13 weeks of exposure. The only clinical sign of chemical toxicity was the observation of a reddish nasal discharge with accompanying oral salivation in mid- and high-exposure animals of both sexes, indicative of an irritant response. Statistically significant reduced body weights; increased absolute and relative liver weights; and decreased erythrocyte counts, hemoglobin levels, and hematocrit values were observed in high-exposure female rats euthanized after 13 weeks of Skydrol exposure. High-exposure male rats also had increased absolute and relative liver weights and decreased hematocrit values after 13 weeks. Plasma cholinesterase levels were decreased in high-exposure female rats both 6 and 13 weeks after the study was initiated.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum copper, zinc, calcium and phosphorus concentrations of calves stressed by bovine respiratory disease and infectious bovine rhinotracheitis.

The relationship between serum minerals and stress and(or) disease has not been fully evaluated in beef cattle. Two trials were conducted to determine the changes in serum Cu and Zn during market-transit stress and(or) disease. Two additional trials were conducted to determine the changes in serum Cu and Zn after inoculation with infectious bovine rhinotracheitis virus (IBRV), with one of the trials determining the changes in serum Ca and P. Trials 1 (n = 80) and 2 (n = 100) utilized calves that were handled through a normal market-transit system and transported 1,967 km to the feedlot. Trials 3 (n = 37) and 4 (n = 8) used calves that were sero-negative to IBRV and then challenged with 2.7 x 10(5) plaque-forming units of the virus. Serum samples were collected at specified intervals and serum minerals were measured for each trial. Serum Zn for morbid or IBRV-challenged calves was decreased by 34, 57, 29 and 15% (P less than .05) for the four trials, respectively, at peak morbidity. Serum Cu of morbid or IBRV-challenged calves increased 5, 15, 40 and 33% for the four trials, respectively, at peak morbidity. Feed intakes were lower during morbidity for market-transit trials and after IBRV inoculation. Lower feed intake could partially explain the decrease in serum Zn; however, when feed intake was held constant, serum Zn concentration still decreased. Serum Zn decreased and serum Cu increased during market-transit morbidity or after IBRV.

Hypoxia-induced tachypnea in carotid-deafferented cats.

Ventilation while breathing air and in response to hypoxia was studied in unanesthetized cats after carotid body chemo-defferentation. Hypoxic exposure (FIO2 equal to 0.07-0.12) of chemo-deafferented animals rapidly produced a high frequency, low tidal volume tachypnea. Tachypneic breathing, although usually associated with an increased expired ventilation, was accompanied by an increase in PACO2. In contrast to intact cats, behavioral arousal during hypoxic exposure was not observed after chemo-deafferentation. The response to milder hypoxia (FIO2 equal to 0.14-0.16) occurred with an increased latency, and there resulted a less marked depression of tidal volume and stimulation of respiratory frequency. Elevation of PACO2 to 5 mm Hg above the resting value, by addition of CO2 to the inspired gas, prevented the appearance of tachypnea upon subsequent reduction of FIO2 from 0.21 to 0.07. Depletion of central catecholamine stores, by administration of reserpine, did not prevent the tachypneic response to hypoxia. Following administration of anesthesia (pentobarbital, 30 mg/kg, IP), hypoxic exposure (FIO2 equal to 0.10) led to depression of both respiratory frequency and tidal volume, resulting in apnea within 1.5 minutes. It is concluded that hypoxia (FLO2 equal to 0.07-0.16) acts, in a concentration-related manner, as a powerful stimulant to central respiratory frequency generation and as a depressant of the tidal volume in the unanesthetized cat.