Serum LL-37 Levels Associated With Severity of Bronchiolitis and Viral Etiology.

BACKGROUND: LL-37 is a host defense peptide with antimicrobial and immunomodulatory properties. We examined the relation of serum LL-37 levels to the severity of bronchiolitis and viral etiology. METHODS: We performed a 17-center prospective cohort study in infants hospitalized with bronchiolitis over 3 winters (2011-2014). Site teams collected clinical data, nasopharyngeal aspirates and serum. We used real-time polymerase chain reaction to test nasopharyngeal aspirates for 16 viruses. We tested serum for LL-37. Severity of bronchiolitis was defined by intensive care use and hospital length of stay. Viral etiology was defined as respiratory syncytial virus (RSV) or rhinovirus (RV), including coinfections with other viruses. RESULTS: The median age of the 1005 enrolled infants was 3 months (interquartile range, 2-6 months). After adjustment for 12 variables, LL-37 levels in the lowest quartile, compared with the highest, were associated both with intensive care use (adjusted odds ratio [aOR], 1.97; P = .01) and longer hospital stay (1.34; P < .001). In separate multivariable models, infants with LL-37 levels in the lowest 3 quartiles, compared with the highest, were more likely to have RSV (eg, aOR, 2.6 [lowest quartile]; P < .001 [all quartiles]). By contrast, infants with the lowest 3 LL-37 quartiles were less likely to have RV (eg, aOR, 0.5 [lowest quartile]; Pall quartiles ≤ .03 [all quartiles]). CONCLUSIONS: In a large multicenter study of infants hospitalized with bronchiolitis, lower levels of serum LL-37 were associated with increased severity of illness. There was also an inverse relationship between LL-37 levels and the most common virus causing bronchiolitis, RSV. These findings highlight the role of LL-37 in the pathogenesis of bronchiolitis.

Distinct antibody repertoires against endemic human coronaviruses in children and adults.

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these "common cold" viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2' cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.

Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold.

We determined the dynamics of CD8(+) T cells specific for influenza virus and respiratory syncytial virus in blood and tracheostoma aspirates of children during the course of respiratory infections. We showed that during localized respiratory infections the ratio of activated effector CD8(+) T cells to resting memory/naive CD8(+) T cells in peripheral blood increased significantly. Furthermore, the number of effector/memory T cells specific for respiratory viruses declined in blood and increased in the airways, suggesting that these T cells redistributed from blood to airways. T cells specific for the infecting virus were present in the airways for longer periods at increased levels than nonspecifically recruited bystander T cells. After clearance of the infection, the ratio of resting memory and naive CD8(+) T cells normalized in peripheral blood and also memory T cell numbers specific for unrelated viruses that declined during the infection due to bystander recruitment were restored. Taken together, these results showed a significant systemic T cell response during relatively mild secondary infections and extensive dynamics of virus-specific and nonspecific Ag-experienced T cells.

25-Hydroxyvitamin D variability within-person due to diurnal rhythm and illness: a case report.

BACKGROUND: Vitamin D nutrition research requires accurate measures of circulating 25-hydroxyvitamin D. Our objectives were to test whether a diurnal fluctuation in blood-spot concentrations of 25-hydroxyvitamin D can be demonstrated statistically in a single individual, and whether such fluctuation is affected by the pre-dose versus post-dose timing of the blood draw. CASE PRESENTATION: The participant in this case study was a generally healthy Caucasian woman in her 40s who has taken 5000 IU vitamin D3 supplement at midday for over 1 year. Each blood sample was drawn individually from a finger prick onto filter paper at morning, midday, or night, on 4 days (three groups of five individual blood samples per collection day). On days 1 and 2, the midday samples were collected approximately 1 hour after the supplement was taken; on days 3 and 4, the midday samples were collected within an hour prior to supplementation (the classical, daily "trough" value for a drug). There was a significant daily pattern of variation in 25-hydroxyvitamin D concentrations (analysis of variance p ≤ 0.02 for 3 of the 4 days): peak midday mean 25-hydroxyvitamin D was approximately 20% higher than in the morning, and approximately 13% higher than in the evening. Trough sampling produced no significant difference in 25-hydroxyvitamin D compared to sampling an hour after the dose. An incidental finding was that acute illness during the study was related to acutely lower 25-hydroxyvitamin D at every sampling time in the day (p < 0.00001). CONCLUSIONS: There was a consistent diurnal variation in 25-hydroxyvitamin D, with the peak at midday. There was no difference between trough versus post-dose blood draws. Acute illness may acutely lower serum 25-hydroxyvitamin D levels. Because within-person, within-day variability in 25-hydroxyvitamin D is approximately 20%, sampling time introduces systematic error in vitamin D nutritional assessment that is bigger than random analytical error or choice of assay method.

Associations of Serum 25(OH)D Concentrations with Lung Function, Airway Inflammation and Common Cold in the General Population.

Vitamin D is hypothesized to have a beneficial effect on lung function and respiratory infections. The aim of this study was to assess the relationship of serum 25-hydroxyvitamin D (25(OH)D) concentrations with lung function, airway inflammation and common colds. We performed a cross-sectional analysis in the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study. We included participants with measurements of serum 25(OH)D, Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), Fractional Exhaled Nitric Oxide (FeNO), and data on self-reported common colds (n = 6138). In crude associations, serum 25(OH)D was positively associated with FEV1 and FVC, and negatively with FeNO and the occurrence of a common cold. After adjustment for confounders, however, these associations disappeared. Stratified analyses showed that Body Mass Index (BMI) was an effect modifier in the relationship between serum 25(OH)D and FEV1, FVC and FeNO. In obese participants (BMI ≥ 30 kg/m²), 10 nmol/L higher 25(OH)D was associated with 0.46% predicted higher FEV1 (95% Confidence Interval: 0.17 to 0.75), 0.46% predicted higher FVC (0.18 to 0.74), and 0.24 ppb lower FeNO (-0.43 to -0.04). Thus, in the total study population, 25(OH)D concentrations were not associated with lung function, airway inflammation and common colds. In obese participants, however, higher 25(OH)D concentrations were associated with a better lung function and lower airway inflammation.

Capturing the onset of the common cold and its effects on iron absorption.

Hypoferremia is a well-known response to infections and inflammatory disorders. It seems to be managed by the key mediator of iron kinetics, hepcidin. There are several studies on induced-acute phase reactions. However, to our best knowledge there are no previous published reports on the outbreak of a common cold and its initial effect on iron kinetics. The objective of this case report is to describe such an observation. From an apparently healthy state in the morning we observed, in a 28-year-old male, every hour for 6 h the outbreak of a common cold and the modulations in the levels of serum iron (S-Fe) and interleukin-6 (IL-6). Despite a 100 mg oral iron loading there was a substantial reduction in S-Fe, which seemed to precede the IL-6 peak. Interestingly, this observed succession is in conflict with the proposed infection chain of order in which IL-6 stimulates hepcidin induction.

Inflammatory changes during the 'common cold' are associated with platelet activation and increased reactivity of platelets to agonists.

Epidemiologic studies have shown increased rates of myocardial infarction after upper respiratory tract infections. We hypothesized that changes in platelet activation and reactivity and inflammation occur during the 'common cold'. Previously healthy individuals with viral upper respiratory tract infections were studied (n = 18). Venous blood samples were obtained during the time of infection and again after 6 weeks. Platelet reactivity was higher during the 'common cold' as measured by low-dose ADP-induced aggregation (46 +/- 28 versus 27 +/- 21% 6 weeks after presentation, P = 0.003) and was higher than control individuals (22 +/- 8%, P = 0.003). Platelet P-selectin expression increased during illness (2.3 +/- 0.2% CD62-positive platelets versus 1.8 +/- 0.1% at 6 weeks after presentation, P = 0.017; and 1.7 +/- 0.2% in the control group, P = 0.03). C-reactive protein (3.7 +/- 1.3 versus 2.2 +/- 1.5 mg/l, P = 0.004) and tumor necrosis factor-alpha (27.6 +/- 28 versus 12.7 +/- 9 pg/ml, P = 0.03) were increased during the 'common cold'. There were no significant differences in levels of soluble P-selectin (P = 0.18), soluble vascular adhesion molecule-1 (P = 0.59) and soluble intercellular adhesion molecule-1 (P = 0.23). Increased platelet reactivity and activation during the 'common cold' are associated with inflammation as measured by increased levels of C-reactive protein and tumor necrosis factor-alpha, but not increased levels of endothelial markers. These findings support a pro-aggregatory state that, in part, explains the thrombotic events shown by epidemiological studies.

Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial.

BACKGROUND: Episodic wheeze triggered by viral colds is common in children aged between 1 and 5 years (preschool viral wheeze). Most affected children are asymptomatic by age 6 years. Persistence of wheeze is associated with above-average systemic eosinophil priming. Use of parental-initiated oral prednisolone is recommended at the first sign of preschool viral wheeze. However, evidence for this treatment strategy is conflicting. We therefore aimed to assess the efficacy of a short course of oral prednisolone for preschool viral wheeze, with stratification for systemic eosinophil priming. METHODS: Children aged 1-5 years admitted to hospital with viral wheeze were allocated to either a high-primed or low-primed stratum according to amounts of serum eosinophil cationic protein and eosinophil protein X, and randomised to parent-initiated prednisolone (20 mg one daily for 5 days) or placebo for the next episode. The primary outcomes were the 7-day mean daytime and night-time respiratory symptom scores, which were analysed by mean differences between treatment groups. FINDINGS: 108 children were randomised to placebo and 109 to prednisolone. Outcome data were available for 120 (78%) of 153 children who had a further episode of viral wheeze, of whom 51 received prednisolone and 69 placebo. Mean daytime (difference in means -0.01 [-0.22 to 0.20]) and night-time (0.10 [-0.12 to 0.32]) respiratory symptom scores and need for hospital admission did not differ between treatment groups. Within the high-primed (n=59) and low-primed (n=61) strata there was no difference in primary outcome between treatment groups. INTERPRETATION: There is no clear benefit of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years even in those with above-average eosinophil priming.

Effect of clarithromycin on experimental rhinovirus-16 colds: a randomized, double-blind, controlled trial.

PURPOSE: Macrolide antibiotics are frequently prescribed to patients with symptoms of a common cold. Despite their lack of proven antiviral activity, macrolide antibiotics may have anti-inflammatory actions, such as inhibition of mucus secretion and production of interleukins 6 and 8 by epithelial cells. Because the symptoms of rhinovirus colds are attributed to the inflammatory response to infection, we studied the effects of treatment with clarithromycin on the symptomatic and inflammatory response to nasal inoculation with rhinovirus. SUBJECTS AND METHODS: We performed a prospective, double-blind, controlled trial in 24 healthy subjects who were seronegative for antibodies to rhinovirus-16. Subjects were randomly assigned to receive either clarithromycin (500 mg) or trimethoprim-sulfamethoxazole (800/160 mg, as a control antibiotic) twice a day for 8 days, beginning 24 hours before inoculation with rhinovirus-16. RESULTS: All 12 subjects in each group were infected and developed symptomatic colds. The groups did not differ in the intensity of cold symptoms (median [25th to 75th percentile] score in the clarithromycin group of 25 [5 to 33] versus 21 [11 to 26] in the trimethoprim-sulfamethoxazole group, P = 0.86), weight of nasal secretions (25 g [8 to 56 g] versus 12 g [5 to 28 g], P = 0.27), or decline in nasal peak flow during the 8 days following viral inoculation. In both groups, similar and significant increases from baseline were observed in the numbers of total cells and neutrophils, and in the concentrations of interleukins 6 and 8, in nasal lavage fluid during the cold. The changes that we observed did not differ from those in an untreated historical control group. CONCLUSIONS: We conclude that clarithromycin treatment has little or no effect on the severity of cold symptoms or the intensity of neutrophilic nasal inflammation in experimental rhinovirus-16 colds.

Acute phase response of serum amyloid A protein and C reactive protein to the common cold and influenza.

C reactive protein (CRP) and serum amyloid A protein (SAA) are sensitive and rapid acute phase reactants, and their measurement for monitoring inflammatory disease and assessing the prognosis in secondary amyloidosis is gaining widespread acceptance. The changes in these proteins in eight subjects suffering from natural colds, 15 subjects with experimentally induced colds (rhinoviruses E1, 3, 9, 14, or 31), and eight with experimentally induced influenza (A/Eng/40/83) were studied. SAA concentration increased in 21 of the 23 subjects with natural or experimental rhinovirus colds (mean increase 95 mg/l); CRP concentration increased in 11 (mean increase 11 mg/l). All subjects with influenza showed pronounced increases in SAA concentrations (mean increase 642 mg/l) while six showed increases in CRP concentration (mean increase 22 mg/l). All these increases were highly significant (p less than 0.001). Asymptomatic excretors of both rhinovirus and influenza virus showed significant increases in SAA concentration (p = 0.015 for rhinovirus and p less than 0.001 for influenza virus) but not in CRP concentration. No changes in SAA or CRP values were seen in 12 volunteers after challenge with saline. These observations suggest that caution is required in the interpretation of estimations of SAA concentration and that it may be too sensitive an acute phase protein for clinical use as its concentration may be raised in both trivial and asymptomatic viral infections.

Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu.

OBJECTIVE: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations. STUDY DESIGN: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers. METHODS: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400 mg, pseudoephedrine 60 mg. RESULTS: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events. CONCLUSIONS: Blood levels would predict that the present slow-release formulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.

Effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide in volunteers.

The effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide (VIP) was studied in 7 healthy subjects and 8 subjects with the common cold. Before terfenadine administration, the mean plasma substance P concentration of the subjects with the common cold was significantly higher than that of the healthy subjects. The increased mean plasma substance P concentration of the subjects with the common cold was decreased after terfenadine administration. In the healthy subjects, the mean plasma substance P concentration was unchanged by terfenadine administration. The mean plasma VIP concentration of the subjects with common cold was slightly higher than that of the healthy subjects before and after terfenadine administration, with no significant difference.

[Iron reserves in the female body and susceptibility to colds]. / Zapasy zheleza v organizme zhenshchin i vospriimchivost' k zabolevaniiam.

Levels of temporary invalidity because of catching cold were analyzed in 101 working women over two years and these women's levels of serum iron, total iron-binding capacity of the serum, transferrin saturation with iron, serum ferritin, and red cell ferritin measured. Women with stable iron reserves in the body virtually have no sick leaves because of catching cold, whereas in those with iron deficiency susceptibility to catching cold is increased, and if iron metabolism intensity in the body grows, invalidity periods are much longer. Normalization of not only iron reserves in the body, but correction of iron metabolism as well should be regarded as a factor exerting a favorable effect on body resistance to catching cold.

Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial.

The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

Response to rhinovirus infection by human airway epithelial cells and peripheral blood mononuclear cells in an in vitro two-chamber tissue culture system.

Human rhinovirus (HRV) infections are associated with the common cold, occasionally with more serious lower respiratory tract illnesses, and frequently with asthma exacerbations. The clinical features of HRV infection and its association with asthma exacerbation suggest that some HRV disease results from virus-induced host immune responses to infection. To study the HRV-infection-induced host responses and the contribution of these responses to disease, we have developed an in vitro model of HRV infection of human airway epithelial cells (Calu-3 cells) and subsequent exposure of human peripheral blood mononuclear cells (PBMCs) to these infected cells in a two-chamber trans-well tissue culture system. Using this model, we studied HRV 14 (species B) and HRV 16 (species A) induced cytokine and chemokine responses with PBMCs from four healthy adults. Infection of Calu-3 cells with either virus induced HRV-associated increases in FGF-Basic, IL-15, IL-6, IL-28A, ENA-78 and IP-10. The addition of PBMCs to HRV 14-infected cells gave significant increases in MIP-1ß, IL-28A, MCP-2, and IFN-α as compared with mock-infected cells. Interestingly, ENA-78 levels were reduced in HRV 14 infected cells that were exposed to PBMCs. Addition of PBMCs to HRV 16-infected cells did not induce MIP-1ß, IL-28A and IFN-α efficiently nor did it decrease ENA-78 levels. Our results demonstrate a clear difference between HRV 14 and HRV 16 and the source of PBMCs, in up or down regulation of several cytokines including those that are linked to airway inflammation. Such differences might be one of the reasons for variation in disease associated with different HRV species including variation in their link to asthma exacerbations as suggested by other studies. Further study of immune responses associated with different HRVs and PBMCs from different patient groups, and the mechanisms leading to these differences, should help characterize pathogenesis of HRV disease and generate novel approaches to its treatment.

Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate.

BACKGROUND: Zinc lozenges have been used for treatment of the common cold; however, the results remain controversial. METHODS: Fifty ambulatory volunteers were recruited within 24 h of developing symptoms of the common cold for a randomized, double-blind, placebo-controlled trial of zinc. Participants took 1 lozenge containing 13.3 mg of zinc (as zinc acetate) or placebo every 2-3 h while awake. The subjective scores for common cold symptoms were recorded daily. Plasma zinc, soluble interleukin (IL)-1 receptor antagonist (sIL-1ra), soluble tumor necrosis factor receptor 1, soluble vascular endothelial cell adhesion molecule, and soluble intercellular adhesion molecule (sICAM)-1 were assayed on days 1 and 5. RESULTS: Compared with the placebo group, the zinc group had a shorter mean overall duration of cold (4.0 vs. 7.1 days; P < .0001) and shorter durations of cough (2.1 vs. 5.0 days; P < .0001) and nasal discharge (3.0 vs. 4.5 days, P = .02) Blinding of subjects was adequate, and adverse effects were comparable in the 2 groups. Symptom severity scores were decreased significantly in the zinc group. Mean changes in plasma levels of zinc, sIL-1ra, and ICAM-1 differed significantly between groups. CONCLUSION: Administration of zinc lozenges was associated with reduced duration and severity of cold symptoms. We related the improvement in cold symptoms to the antioxidant and anti-inflammatory properties of zinc.