Liisa Kröger

Development of bone mass and bone density of the spine and femoral neck — a prospective study of 65 children and adolescents

The bone mineral density (BMD, g/cm2) of the lumbar spine (L2-L4) and femoral neck was measured twice with a 1-year interval by dual energy X-ray absorptiometry (DEXA) in 65 healthy children and adolescents aged 7-20 years. In addition, the BMD values were corrected for the size of bones to obtain the bone volumetric density (BMDvol, g/cm3) using a method developed previously. The annual increases of BMD and BMDvol in both spine and femoral neck were most marked in females at the time of menarche (during the age of 11-13 years), and in males between the ages of 13 and 17 years. The males showed significantly higher values in their mean annual increment rates of femoral bone mineral content (BMC) and femoral neck width, whereas no differences in spinal parameters were found. The acquisition of bone mass and bone density stopped or markedly diminished before the age of 20 years, supporting the theory that the major portion of the peak bone mass is attained in late adolescence. We could not find any significant relationship between the increment rate of bone density, and physical activity or calcium intake. This study emphasizes the significant effect of puberty and genetic factors on the development of bone mass and density.

Aggressive Combination Drug Therapy in Very Early Polyarticular Juvenile Idiopathic Arthritis (ACUTE–JIA): a multicentre randomised open-label clinical trial

Objectives In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating recent‑onset polyarticular JIA. Methods In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4–15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. Results In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare. Conclusion In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.

C-Reactive Protein in Viral and Bacterial Respiratory Infection in Children

C-reactive protein (CRP) was studied in 209 children treated in hospital due to middle or lower respiratory tract infection with serologically demonstrated viral or bacterial aetiology. Of the 110 patients with serological evidence of bacterial infection, either alone or in association with viral infection, 52% had CRP > 20 mg/l, 35% > 40 mg/l and 15% > 80 mg/l. Of the 99 patients with serological evidence of viral infection alone, 35% had CRP > 20 mg/l, but only 12% > 40 mg/l and 5% > 80 mg/l. Nearly all, 88%, of the 25 patients with CRP > 40 mg/l in association with viral infection had either an infectious focus, specific microbial or non-specific laboratory evidence suggestive of bacterial infection. By calculating diagnostic parameters at 3 cut-off levels of CRP, the level 40 mg/l seemed more useful than 20 mg/l or 80 mg/l for differentiation between viral and bacterial infections. By using a CRP value of 40 mg/l as a screening limit sensitivity was 0.55, specificity 0.88, positive predictive value 0.76, negative predictive value 0.55, and likelihood ratios of a positive and negative test result 2.9 and 0.74, respectively. It is concluded that low CRP values do not rule out bacterial aetiology of respiratory infection in children. On the other hand viral infection without bacterial involvement is very improbable if CRP is > 40 mg/l. Our results suggest that high CRP values rule out viral infection as a sole aetiology of infection; bacterial infection and antibiotic treatment should be considered in these cases.

Osteitis after newborn vaccination with three different Bacillus Calmette-Guérin vaccines : twenty-nine years of experience

Newborns in Finland have been vaccinated with Bacillus Calmette-Guérin (BCG) since the 1950s. Until the end of 1970 the vaccine was made from BCG strain Gothenburg by the Swedish BCG laboratory in Gothenburg and from 1971 on from the same strain in Copenhagen, Denmark. It was replaced by the Glaxo vaccine in 1978. Complications caused by BCG vaccination have been under follow-up, and the data have been collected from nationwide registers. In this study we analyzed the incidence rates of BCG osteitis between the years 1960 and 1988. From 1960 to 1970 the incidence rate was from 2.7 to 13.0/100 000 BCG-vaccinated infants (mean, 7.3; median, 6.9). The incidence increased during the years 1971 to 1978 when it varied between 15.3 and 72.9/100 000 BCG-vaccinated infants (mean, 36.9; median, 30.4). Since 1978 the incidence has varied between 1.7 and 10.1/100 000 BCG-vaccinated infants (mean, 6.4; median, 7.2). In Britain no reports of BCG osteitis have been published despite the use of the same Glaxo vaccine. Our results indicate that the incidence of BCG osteitis in a given population depends on the BCG vaccine used. The follow-up of BCG complications is an essential part of BCG vaccination program.

White Blood Cell and Differential Counts in Acute Respiratory Viral and Bacterial Infections in Children

White blood cell (WBC) and differential counts were studied in 201 children hospitalized for acute viral or bacterial respiratory infection. The aetiology of infection was studied with a comprehensive set of serological tests. WBC and granulocyte counts were higher in patients with bacterial infection than in those with viral infection. Lymphocyte counts, by contrast, had no such aetiological association. The 95% confidence limits for WBCs and granulocytes distinguished bacterial and pneumococcal cases completely from viral cases with no bacterial involvement. The sensitivity of WBC counts, as well as granulocyte or lymphocytes counts, for distinguishing bacterial from viral cases was low at all cut-off levels. Specificity, in contrast, was 86% and 95% for WBCs at the cut-off levels 15.0 and 20.0 x 10(9)/l, and 84% and 97% for granulocytes at the cut-off levels 10.0 and 15.0 x 10(9)/l, respectively. It is concluded that high WBC and granulocyte counts are clear evidence of the bacterial aetiology of respiratory infection, but low or normal values do not rule it out. Lymphocyte counts are of no value for distinguishing between viral and bacterial infections.

Repeated Exposure to Antibiotics in Infancy: A Predisposing Factor for Juvenile Idiopathic Arthritis or a Sign of This Group’s Greater Susceptibility to Infections?

Objective. Previous exposure to antibiotics has been associated with the pathogenesis of several autoimmune diseases. Our objective was to explore whether childhood exposure to antibiotics would be associated with the risk of developing juvenile idiopathic arthritis (JIA). Methods. The material was collected from national registers containing all children born in 2000–2010 in Finland and diagnosed with JIA by the end of December 2012 (n = 1298) and appropriate controls (n = 5179) matched for age, sex, and place of birth. All purchases of antibiotics were collected from birth until the index date (i.e., the date of special reimbursement for JIA medications). A conditional logistic regression was performed to evaluate the association between the exposure to antibiotics and the risk of JIA. Results. The risk of JIA increased with the number of antibiotic purchases from birth to the index date: for ≥ 1 purchases versus none, OR 1.6, 95% CI 1.3–1.9 with an upward trend in OR (p < 0.001). Antibiotic groups lincosamides and cephalosporins showed the strongest association with JIA (OR 6.6, 95% CI 3.7–11.7, and OR 1.6, 95% CI 1.4–1.8, respectively). Overall exposure to antibiotics before 2 years of age was associated with an increased risk of JIA (OR 1.4, 95% CI 1.2–1.6), with the trend test of OR (p < 0.001). Conclusion. Previous early and repeated exposure to antibiotics may predispose individuals to develop JIA. Alternatively, the apparent association may reflect shared susceptibility to infections and JIA.

Rapid decrease in tuberculin skin test reactivity at preschool age after newborn vaccination

A study of tuberculin sensitivity was performed in 353 children aged 4–6 years, all vaccinated at birth with British BCG vaccine. Significant waning of tuberculin reactions with increasing age was found (p < 0.05). In the age group < 4.5 years, the mean tuberculin reaction was 6.6 mm, in the age group 4.5–5.5 years 5.2 mm and in the age group of > 5.5 years 3.5 mm. The number of children with positive reactions ( 5 mm) was 165 (40%) and those with strong reactions ( 10 mm) 49 (14%). None of the latter children had active tuberculosis during a follow‐up period of 12 months. Eighty‐three (24%) of the children had no reaction. The children who had been revaccinated with the MPR vaccine against measles, rubella and parotitis (n= 31) had significantly larger tuberculin reactions than the non‐revaccinated children. Atopic dermatitis or infections during the preceding six months did not have any significant influence on reaction sizes. Our results demonstrate that the variation in size of tuberculin reactions after BCG vaccination at birth is large. We conclude that tuberculin sensitivity wanes rapidly by the age of 4.0–6.3 years.

Associations of genetic lactase non-persistence and sex with bone loss in young adulthood

Some studies have reported that after attainment of peak bone mass (PBM), slow bone loss may occur in both men and women; however, findings are inconsistent. Genetic factors play a significant role in bone loss, but the available evidence is conflicting. Genetic lactase non-persistence (lactase C/C(-13910) genotype) is suggested to increase risk for inadequate calcium intake predisposing to poorer bone health. We investigated whether this genotype is associated with PBM and bone loss in young Finnish adults. Subjects belong to the Cardiovascular Risk in Young Finns Study that is an ongoing multi-centre follow-up of atherosclerosis risk factors. From the original cohort, randomly selected subjects aged 20-29 participated in baseline bone mineral density (BMD) measurements (n=358), and in follow-up measurements 12 years later (n=157). Bone mineral content (BMC) and BMD at lumbar spine (LS) and femoral neck (FN) were measured at baseline and follow-up with dual energy X-ray absorptiometry (DXA). Lactase C/T(-13910) polymorphism was determined by PCR and allele-specific fluorogenic probes. Information on lifestyle was elicited with questionnaires. During the follow-up, bone loss at both bone sites was greater in males (LS BMD: -1.1%, FN BMD: -5.2%) than in females (LS BMD: +2.1%, FN BMD: -0.7%) (both bone sites p=0.001). Younger age predicted greater loss of FN BMC and BMD in females (p=0.013 and p=0.001, respectively). Increased calcium intake predicted FN BMD gain in both sexes (in females B=0.007 g/cm(2)/mg, p=0.002; in males B=0.006, p=0.045), and increased physical activity LS BMD gain in females (B=0.091 g/cm(2)/physical activity point, p=0.023). PBM did not differ between the lactase genotypes, but males with the CC(-13910) genotype seemed to be prone to greater bone loss during the follow-up (LS BMD: C/C vs. T/T p=0.081). In conclusion, bone loss in young adulthood was more common in males than in females and seemed to occur mainly at the femoral neck. Young males with the lactase CC(-13910) genotype may be more susceptible to bone loss; however, calcium intake predicts changes in bone mass more than the lactase genotype.

Inhaled corticosteroids and bone mineral density at school age: A follow‐up study after early childhood wheezing

The aim of the study was to evaluate the association between previous use of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood wheezing.

Toll-like receptor 2 subfamily gene polymorphisms are associated with Bacillus Calmette-Guerin osteitis following newborn vaccination

Toll‐like receptor (TLR) 1, 2, 6 and 10, the TLR2 subfamily, are known to be associated with immunity against tuberculosis. We evaluated whether polymorphisms in genes encoding TLR1, TLR2 and TLR6 were associated with osteitis in infants who received the Bacillus Calmette‐Guérin (BCG) vaccination soon after birth.