The relationship of 25-hydroxyvitamin D values and risk of fracture: a population-based retrospective cohort study.

Our study investigates 25-hydroxyvitamin D levels and fracture risk using population-level data. 25-Hydroxyvitamin D values < 12, 12-19, and > 50 ng/mL were not associated with increased risk of fractures overall compared with values 20-50 ng/mL. Severely low levels may be associated with increased risk of osteoporotic fracture, particularly of the wrist. INTRODUCTION: Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and fracture risk have been inconsistent. We hypothesized that high 25(OH)D concentrations (> 50 ng/mL) would be associated with increased risk of fracture. METHODS: We identified all adult patients living in Olmsted County, Minnesota, between January 1, 2005 and December 31, 2011, who had at least one 25(OH)D measurement. Fracture outcomes were retrieved starting 30 days after 25(OH)D measurement and until patients' final clinical visit as an Olmsted County resident, December 31, 2014, or death. Data were analyzed using Cox proportional hazard regression. RESULTS: Of 11,002 individuals with a 25(OH)D measurement, 5.8% had a 25(OH)D value ˂ 12 ng/mL, and 5.1% had a value > 50 ng/mL. Compared with subjects with 25(OH)D values 20-50 ng/mL (reference group), values < 12, 12-19, and > 50 ng/mL displayed no association with overall fracture risk. After adjusting for a prior diagnosis of osteoporosis/osteopenia, only individuals with values ˂ 12 ng/mL had increased risk of any osteoporotic fracture (aHR = 1.41; 95% CI 1.05-1.89) and wrist fracture (aHR = 2.11; 95% CI 1.27-3.48) compared with the reference group. Compared with the reference group, values ˂ 12 ng/mL were associated with increased risk of any fracture (aHR = 1.35; 95% CI 1.01-1.80), osteoporotic fracture (aHR = 2.18; 95% CI 1.44-3.31), and wrist fracture (aHR = 2.39; 95% CI 1.19-4.81) in subjects without a prior diagnosis of osteoporosis/osteopenia, but not in those with a prior diagnosis of osteoporosis/osteopenia. CONCLUSION: Severely low 25(OH)D levels may be associated with increased risk of osteoporotic fracture, particularly of the wrist, but 25(OH)D values > 50 ng/mL were not associated with increased fracture risk.

Usefulness of asthma predictive index in ascertaining asthma status of children using medical records: An explorative study.

BACKGROUND: Frequent wheezing in original asthma predictive index (API) was defined by parental report of recurrent wheezing within 1 year during the first 3 years of life. The nature of frequent wheezing in children, particularly aged over 3 years, has not been studied. We aimed to assess the frequency and interval of wheezing to define frequent wheezing in ascertaining asthma for children using medical records. METHODS: Among children who participated in a previous study (n = 427), all wheezing episodes documented in medical records were collected for children who had ≥2 wheezing episodes PLUS met one major criterion or two minor criteria of API. We compared the distribution of known risk factors for asthma between subjects having two consecutive wheezing episodes with shorter interval (≤1 year) compared to those with longer interval (1 to 3 years). RESULTS: A total of 62 children met API at median age of 2.3 years. During follow-up period (median age: 11.3 years), a total of 198 wheezing episodes were observed. 81% of wheezing intervals were within 3 years from the earlier wheezing episode, including 60% within 1 year. Children who met API based on 1-year interval (n = 40) vs 1- to 3-year interval (n = 13) appeared to be similar in regard to the known risk factors for asthma. CONCLUSIONS: Our exploratory study finding suggests that children who had frequent wheezing episodes with longer interval (<3 years) need to be considered to be determined as asthma cases when API is applied to retrospective medical records. Prospective studies with a larger sample size need to replicate this finding.

Influence of HLA-DR polymorphism and allergic sensitization on humoral immune responses to intact pneumococcus in a transgenic mouse model.

Asthma is independently associated with HLA-DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA-DR polymorphism (HLA-DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti-pneumococcal polysaccharide and anti-surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA-DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat-killed Pn14 at day 24. Serum titers of anti-phosphorylcholine (PC) IgM and IgG, anti-pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti-pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM-sensitized and 22 control mice). HDM-sensitized mice, irrespective of HLA-DR polymorphism, had significantly lower humoral immune responses. HLA-DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti-PC IgG response. In contrast, the anti-PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti-PPS14 IgG and anti-PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA-DR polymorphism.

External validation of bloodstream infection mortality risk score in a population-based cohort.

A risk score was recently derived to predict mortality in adult patients with Gram-negative bloodstream infection (BSI). The aim of this study was to provide external validation of the BSI mortality risk score (BSIMRS) in a population-based cohort. All residents of Olmsted County, Minnesota, with Escherichia coli and Pseudomonas aeruginosa BSI from 1 January 1998 to 31 December 2007 were identified. Logistic regression was used to examine the association between BSIMRS and mortality. Area under receiver operating characteristic curve (AUC) was calculated to quantify the discriminative ability of the BSIMRS to predict a variety of short-term and long-term outcomes. Overall, 424 unique Olmsted County residents with first episodes of E. coli and P. aeruginosa BSI were included in the study. Median age was 68 (range 0-99) years, 280 (66%) were women, 61 (14%) had cancer and 9 (2%) had liver cirrhosis. The BSIMRS was associated with 28-day mortality (p <0.001) with an AUC of 0.86. There was an almost 56% increase in 28-day mortality for each point increase in BSIMRS (OR 1.56, 95% CI 1.40-1.78). A BSIMRS ≥ 5 had a sensitivity of 74% and a specificity of 87% to predict 28-day mortality with a negative predictive value of 97%. The BSIMRS had AUC of 0.85, 0.85 and 0.81 for 7-, 14- and 365-day mortality, respectively. BSIMRS stratified mortality with high discrimination in a population-based cohort that included patients of all age groups who had a relatively low prevalence of cancer and liver cirrhosis.

Asthma and antibodies to pneumococcal virulence proteins.

PURPOSE: We previously reported that asthmatics had lower anti-serotype-specific pneumococcal polysaccharide antibody levels than non-asthmatics, and the T-helper 2 (Th2) immune profile was associated with suboptimal pneumococcal polysaccharide antibody. Our objective was to determine the influence of asthma status on anti-pneumococcal protein antigen antibody levels. METHODS: We conducted a cross-sectional study, which enrolled 16 children and adults with asthma and 14 subjects without asthma. Asthma was ascertained by predetermined criteria. Serum IgG antibody levels to pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal choline-binding protein A (PcpA), and pneumolysin (PLY) were measured by enzyme-linked immunosorbent assays (ELISA). These antibody levels were compared between asthmatics and non-asthmatics. The Th2 immune profile was determined by IL-5 secretion from PBMCs cultured with house dust mite (HDM) and staphylococcal enterotoxin B (SEB) at day 7. The correlation between the anti-pneumococcal antibody levels and the Th2-HDM and SEB-responsive immune profile was assessed. RESULTS: Of the 30 subjects, 16 (53%) were male and the median age was 26 years. There were no significant differences in anti-PspA, anti-PspC, anti-PcpA, and anti-PLY antibody levels between asthmatics and non-asthmatics. The Th2 immune profile was inversely correlated with the anti-PspC antibody levels (r = -0.53, p = 0.003). This correlation was significantly modified by asthma status (r = -0.74, p = 0.001 for asthmatics vs. r = -0.06, p = 0.83 for non-asthmatics). Other pneumococcal protein antibodies were not correlated with the Th2 immune profile. CONCLUSION: No significant differences in the anti-pneumococcal protein antigen antibody levels between asthmatics and non-asthmatics were found. Asthma status is an important effect modifier determining the negative influence of the Th2 immune profile on anti-PspC antibody levels.

Housing data-based socioeconomic index and risk of invasive pneumococcal disease: an exploratory study.

We previously developed and validated an index of socioeconomic status (SES) termed HOUSES (housing-based index of socioeconomic status) based on real property data. In this study, we assessed whether HOUSES overcomes the absence of SES measures in medical records and is associated with risk of invasive pneumococcal disease (IPD) in children. We conducted a population-based case-control study of children in Olmsted County, MN, diagnosed with IPD (1995-2005). Each case was age- and gender-matched to two controls. HOUSES was derived using a previously reported algorithm from publicly available housing attributes (the higher HOUSES, the higher the SES). HOUSES was available for 92·3% (n = 97) and maternal education level for 43% (n = 45). HOUSES was inversely associated with risk of IPD in unmatched analysis [odds ratio (OR) 0·22, 95% confidence interval (CI) 0·05-0·89, P = 0·034], whereas maternal education was not (OR 0·77, 95% CI 0·50-1·19, P = 0·24). HOUSES may be useful for overcoming a paucity of conventional SES measures in commonly used datasets in epidemiological research.

HLA-DR polymorphism modulates response to house dust mites in a transgenic mouse model of airway inflammation.

We and others have reported that HLA-DRB1*03 is associated with childhood asthma. To extend this observation and to prove this association, we sensitized and challenged either HLA-DR2 (HLA-DRB1*1502) or HLA-DR3 (HLA-DRB1*0301) transgenic mice with house-dust mite extract. Inflammatory cell counts and cytokine levels in the bronchoalveolar lavage (BAL) fluid between HLA-DR3 and DR2 mice were compared. HLA-DR3 transgenic mice had significantly elevated eosinophil counts, Interleukin-4 and Interleukin-13 levels in the BAL fluid but not interferron gamma-γ. Thus, our study suggests that HLA-DRB1*0301 plays an important role in mounting a Th2-predominant immune response to house dust mite and Th2-type inflammation in the lung.

An assessment of the association between childhood asthma and HLA DRB1*03 using extended haplotype analysis.

Ancestral haplotypes between human leukocyte antigen (HLA) class I and class II alleles are well-recognized in the literature. We previously published a positive association between the class II HLA allele DRB1*03 and the subsequent development of asthma in a retrospective cohort of 383 children. To refine this association, we investigated whether DRB1*03-specific haplotypes extending across the HLA are associated with asthma incidence. We found evidence of strong HLA DRB1*03-dependent linkage disequilibrium across the region, but no association between DRB1*03 ancestral haplotypes and childhood asthma. We did, however, observe a trend toward a positive association between HLA DRB1*03 and asthma by adding non-ancestral DRB1*03 positive haplotypes. Our results suggest that the role of the HLA DRB1*03 in asthma susceptibility is independent of ancestral-haplotype-mediated linkage disequilibrium.

Allergic airway inflammation and susceptibility to pneumococcal pneumonia in a murine model with real-time in vivo evaluation.

The relationship between allergic airway inflammation and pneumococcal pneumonia is not well understood. We assessed susceptibility to experimental pneumococcal pneumonia in mice with and without allergic airway inflammation. Susceptibility to pneumococcal pneumonia was evaluated by challenging mice with a bioluminescent Streptococcus pneumoniae strain after sensitization with ovalbumin (OVA), with subsequent monitoring of pneumococcal infection using real-time photonic imaging. Of 46 OVA-sensitized mice challenged with pneumococci, 13 (28%) developed imaging findings consistent with pneumococcal pneumonia. In comparison, 28 (57%) of 49 non-sensitized control mice developed pneumococcal pneumonia (P = 0.005). While none of the control group developed meningitis (0%, none of 28), two mice in the OVA-sensitized group developed meningitis (15.4%, two of 13) (P = 0.09). The mean bacterial count in the lung was significantly lower in the OVA-sensitized than the non-sensitized group (8.26 +/- 0.69 versus 9.21 +/- 0.67 log(10) colony-forming units (CFU)/g, P = 0.002). There was a trend towards the mean bacterial count in the spleen being higher in the OVA-sensitized versus the non-sensitized group (8.14 +/- 0.89 versus 7.45 +/- 1.07 log(10) CFU/g, P = 0.071). A high level of interleukin (IL)-4 in lung homogenates was associated with risk of pneumococcal infection independent of sensitization with OVA (odds ratio: 49.7, 95% confidence interval 2.92-846.5, per increment of 1.0 pg/ml). In the murine model studied, acute allergic airway inflammation reduced susceptibility to pneumococcal pneumonia. IL-4 may increase the risk of pneumococcal pneumonia independently of allergic airway inflammation.

Timeliness of diagnosis of asthma in children and its predictors.

BACKGROUND: There is a paucity of literature using medical records to evaluate the timeliness of asthma diagnosis in children and the predictors associated with timeliness of asthma diagnosis. METHODS: Subjects were obtained from a convenience sample of 839 children, aged 5-13 years. We conducted comprehensive medical record reviews for these children to determine their asthma status by applying predetermined criteria for asthma. Predictors were evaluated for an association with timeliness of asthma diagnosis. RESULTS: Of 839 children, 276 children met the criteria for asthma before 18 years of age. Of these subjects, 97 had timely diagnosis of asthma while 179 did not have timely diagnosis of asthma with the median delay of 3.3 years. Children with definite asthma at the time of index date was three times more timely to be diagnosed with asthma [hazard ratios (HR) 3.3, 95% CI: 2.43-4.47, P < 0.001], compared to those with probable asthma. Children with a family history of asthma were more timely to be diagnosed with asthma (HR 1.36, 95% CI: 1.03-1.8, P = 0.031). Children with exercise-induced wheezing or bronchospasm were more timely to be diagnosed with asthma (HR 1.79, 95% CI: 0.95-3.36, P = 0.07), compared to those with spasmodic (or bronchospastic) cough. CONCLUSIONS: Many asthmatic children are not diagnosed with asthma in a timely manner, especially in those without the commonly recognized factors associated with asthma. Health care providers need to be reminded that asthma can still occur in those without commonly recognized risk factors. Asthma guidelines need to emphasize this aspect.

Childhood asthma and human leukocyte antigen type.

Little is known about the relationship between human leukocyte antigen (HLA) class II genes and family history of asthma or atopy in relation to the incidence of childhood asthma. The objective of the study was to determine whether specific HLA class II genes (e.g., DRB1*03) are associated with asthma and whether such association explains the influences of family history of asthma or atopy on asthma incidence. A stratified random sample of 340 children who had HLA data available from the Rochester Family Measles Study cohort (n= 876) and a convenience sample of healthy children aged 5-12 years were the participants. We conducted comprehensive medical record reviews to determine asthma status of these children. The associations between the presence of specific HLA alleles and development of asthma and the role of family history of asthma or atopy in the association were evaluated by fitting Cox models. The cumulative incidence of asthma by 12 years of age among children who carry HLA DRB1*03 was 33%, compared to 24.2% among those who did not carry this allele. Adjusting for family history of asthma or atopy, gender, low birth weight, season of birth, HLA DRB1*04, and HLA DQB1*0302, the hazards ratio for HLA DRB1*03 carriers was 1.8 (95% confidence interval: 1.1-2.9, P= 0.020). We concluded that the HLA DRB1*03 allele is associated with asthma. However, the HLA class II gene does not explain the influences of family history of asthma or atopy on development of asthma. The mechanism underlying the association between asthma and HLA genes needs to be elucidated.

Willingness of directors of child care centers to care for children with chronic infections.

Directors of 150 child care centers were surveyed about their willingness to accept children with HIV or hepatitis B infection. Among 100 respondents 58% agreed to accept HIV-positive children and 23% would accept hepatitis B-positive children.

Facial nerve palsy as an early manifestation of relapse in T-cell acute lymphoblastic leukemia.

We describe a 14-year-old girl with T-cell acute lymphoblastic leukemia (ALL) who developed peripheral type facial palsy alternately on each side during remission. The cerebrospinal fluid examination and imaging studies of the brain including the temporal area failed to identify the etiology. Fully 10 weeks after the onset of the facial nerve palsy, she showed cytological findings of meningeal and bone marrow relapse. Review of the literature revealed that an isolated facial nerve palsy due to leukemic cell infiltration is a rare occurrence. Nonetheless one needs to keep in mind that it may represent the initial sign of a relapse in a patient with leukemia, particularly with T-cell ALL.