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  • 1.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    High cord blood levels of the T-helper 2-associated chemokines CCL17 and CCL22 precede allergy development during the first 6 years of life2011In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 70, no 5, p. 495-500Article in journal (Refereed)
    Abstract [en]

    Exposure to a strong T-helper 2 (Th2)-like environment during fetal development may promote allergy development. Increased cord blood (CB) levels of the Th2-associated chemokine CCL22 were associated with allergy development during the first 2 y of life. The aim of the present study was to determine whether CB Th1- and Th2-associated chemokine levels are associated with allergy development during the first 6 y of life, allowing assessment of respiratory allergic symptoms usually developing in this period. The CB levels of cytokines, chemokines, and total IgE were determined in 56 children of 20 women with allergic symptoms and 36 women without allergic symptoms. Total IgE and allergen-specific IgE antibody levels were quantified at 6, 12, 24 mo, and 6 y of age. Increased CB CCL22 levels were associated with development of allergic sensitization and asthma and increased CCL17 levels with development of allergic symptoms, including asthma. Sensitized children with allergic symptoms showed higher CB CCL17 and CCL22 levels and higher ratios between these Th2-associated chemokines and the Th1-associated chemokine CXCL10 than nonsensitized children without allergic symptoms. A pronounced Th2 deviation at birth, reflected by increased CB CCL17 and CCL22 levels, and increased CCL22/CXCL10 and CCL17/CXCL10 ratios might promote allergy development later in life.

  • 2.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Helsingborg Hospital, Helsingborg.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity2015In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 73, no 5, p. 445-459Article in journal (Refereed)
    Abstract [en]

    PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.

    METHOD OF STUDY: Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring.

    RESULTS: Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development.

    CONCLUSIONS: Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

  • 3.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Gene expression in placenta, peripheral and cord blood mononuclear cells from allergic and non-allergic women2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: The influence of maternal allergy on the development of immune responses and allergy in the offspring is not understood.

    Objective: To investigate (i) if maternal allergy influences the gene expression locally in placenta, systemically in peripheral blood mononuclear cells (PBMC) and fetally in cord blood mononuclear cells (CBMC), (ii) if the gene expression in the placenta and PBMC influences the gene expression in CBMC and (iii) how the gene expression at birth relates to allergy development during  childhood.

    Methods: A real-time PCR array was used to quantify forty immune regulatory genes in placenta, PBMC (gestational week 39) and in CBMC from 7 allergic and 12 non-allergic women and their offspring. Furthermore, quantitative real-time PCR was used to measure mRNA expression of Tbx21, GATA-3, Foxp3, RORC and CCL22 in CBMC, selected based on present PCR array results and previous protein findings in cord blood, in 13 children who developed and 11 children who did not develop allergy during childhood.

    Results: The gene expression profile in the placenta revealed a T-helper (Th) 2-/anti-inflammatory environment as compared with gene expression systemically, in PBMC. Maternal allergy was associated with increased expression of p35 in PBMC and CBMC and p40 in placenta. Placental p35 expression correlated with fetal Tbx21 expression (Rho=-0.88, p<0.001) and maternal IL-5 expression in PBMC with fetal Galectin-1 (Rho=0.91, p<0.001) expression. Allergy development in the children was preceded by high mRNA expression of the Th2-associated chemokine CCL22 at birth.

    Conclusion and clinical relevance: Gene expression locally and systemically during pregnancy influenced the offspring’s gene expression at birth, indicating an interplay between maternal and fetal immunity. Children developing allergy during childhood had an increased expression of the Th2-associated chemokine CCL22 at birth, indicating a Th2 skewing before disease onset. Maternal allergy was not associated with a Th2-dominance in placenta, PBMC or CBMC.

  • 4.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Lempinen, Esma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Lindblad, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy2014In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 25, no 4, p. 387-393Article in journal (Refereed)
    Abstract [en]

    Background: The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring’s chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children.

    Methods: The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2- associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10–12, 15–16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 yr of age. Total IgE levels were measured using ImmunoCAP Technology.

    Results: The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pregnancy (irrespectively of maternal allergy status) as compared to post-partum. In the whole group, the Th1-like chemokine levels were higher at gw 39 than during the first and second trimester and post-partum. Maternal CXCL11, CCL18 and CCL22 levels during and after pregnancy correlated with the corresponding chemokines in the offspring during childhood. Increased CCL22 and decreased CXCL10 levels in the children were associated with sensitisation and increased CCL17 levels with allergic symptoms during childhood. Maternal chemokine levels were not associated with maternal allergic disease.

    Conclusions: Allergic symptoms and sensitisation were associated with decreased Th1-and increased Th2-associated chemokine levels during childhood, indicating a Th2 shift in the allergic children, possibly influenced by the maternal immunity during pregnancy.

  • 5. Annus, T
    et al.
    Björkstén, Bengt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Mai, Xiaomei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Riikjärv, MA
    Sandin, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Bråbäck, L
    Wheezing in relation to atopy and environmental factors in Estonian and Swedish schoolchildren2001In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 31, no 12, p. 1846-1853Article in journal (Refereed)
    Abstract [en]

    Background: The prevalence of asthma and allergic diseases is significantly lower in post socialist Eastern Europe than in Western industrialized countries. The reason for this difference is largely unknown. Different types of childhood wheezing could be related to different risk factors. Objective: To compare the prevalence of respiratory symptoms, asthma and atopic diseases among Estonian and Swedish schoolchildren and to evaluate characteristics for wheezing in the two countries. Methods: In a prevalence study, population-based random samples of 10-11-year-old schoolchildren in Tallinn (n = 979), Estonia and in Link÷ping (n = 911) and ╓stersund (n = 1197), Sweden were studied by a parental questionnaire and skin prick tests (SPT). All 275 children with wheeze in the past 12 months and 710 randomly selected controls within the original cohorts were invited to a case-control study involving a parental questionnaire, examination for flexural dermatitis and bronchial challenge with hypertonic saline. The study adhered to the International Study of Asthma and Allergies in Childhood (ISAAC) Phase II protocol. Results: The prevalence of current wheezing was similar (8-10%) in the three centres, while diagnosed asthma and atopic symptoms were more common in Sweden and cold-related respiratory symptoms were more prevalent in Estonia. Frequent wheezing was more common in Sweden than in Estonia (but significantly so only in ╓stersund). Wheezing children in Sweden had a high rate of positive SPT (49% in Link÷ping and 58% in ╓stersund) bronchial hyper-responsiveness (BHR) (48% in Link÷ping and ╓stersund) and anti-asthmatic treatment (63% in Link÷ping and 81% in ╓stersund). In Estonia, the proportion of wheezing children with positive SPT, BHR and anti-asthmatic treatment was only 26%, 13% and 17%, respectively. Domestic crowding was inversely related to wheezing in one of the study areas (╓stersund). The mean baseline forced expiratory volume in one second (FEV1) was higher in Estonia than in Sweden, both in wheezing and non-wheezing children. Conclusions: Our study suggested that although wheezing symptoms were equally common in Estonia and Sweden, they were less severe in Estonia. More frequent symptoms and a high rate of atopy, BHR and anti-asthmatic medication characterized wheezing children in Sweden. In contrast, BHR, atopy and medication were uncommon among wheezing children in Estonia.

  • 6. Bråbäck, L
    et al.
    Plaschke, P
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Boman, G
    Jansson, C
    Stora geografiska skillnader i förekomst av astma och allergi. Internationella befolkningsstudier har sökt sambandsfaktorer2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, p. 5322-5326Article in journal (Other academic)
  • 7.
    Böttcher, Malin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Bjurström, Jenny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Mai, Xiaomei
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Allergen-induced cytokine secretion in atopic and non-atopic asthmatic children2003In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 14, no 5, p. 345-350Article in journal (Refereed)
    Abstract [en]

    Atopic asthma is characterized by excessive T helper 2 (Th2)-like immunity to allergens in the bronchial mucosa. The Th2-cytokine interleukin (IL)-4 induces IgE production, while the Th2-cytokine IL-5 promotes eosinophilic inflammation in the airways of asthmatics. Most asthmatics are atopic, but a subgroup is non-atopic. We hypothesize that allergen-induced Th2, particularly IL-5, responses can be observed in peripheral blood in both atopic and non-atopic asthmatic children but not in healthy control children. The aim of the present study was to determine IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-γ secretion induced from peripheral blood mononuclear cells (PBMC) by a broad panel of inhalant allergens (timothy, cat, birch, dog and house dust mite) in asthmatic children with and without sensitization. The study included 13 atopic asthmatic, 5 non-atopic asthmatic, and 12 non-atopic non-asthmatic children. PBMC were stimulated with allergens and cytokine production was measured with enzyme-linked immunosorbent assay (ELISA). Higher levels of cat and dog antigen-induced IL-5 release were more commonly observed in both atopic and non-atopic asthmatics than in controls. Children with atopic, but not non-atopic, asthma produced higher levels of allergen-induced IL-4 and IL-9 than controls. Non-atopic asthmatics produced more IL-10 than atopic asthmatics after cat stimulation. High levels of eosinophilia-associated IL-5 responses are induced by cat and dog allergen in both atopic and non-atopic asthmatic children. The Th2 cytokines IL-4 and IL-9 were associated only with atopic asthma, probably due to their IgE-inducing properties.

  • 8.
    Carlsson, R. M.
    et al.
    Public Health Agency Sweden, Sweden; Sahlgrens University Hospital, Sweden; Gothenburg University, Sweden.
    Gustafsson, L.
    Public Health Agency Sweden, Sweden.
    Hallander, H. O.
    Public Health Agency Sweden, Sweden.
    Ljungman, M.
    Public Health Agency Sweden, Sweden.
    Olin, P.
    Public Health Agency Sweden, Sweden.
    Gothefors, L.
    Public Health Agency Sweden, Sweden; Umeå University, Sweden.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Allergy Center. Linköping University, Faculty of Medicine and Health Sciences. Public Health Agency Sweden, Sweden.
    Netterlid, E.
    Public Health Agency Sweden, Sweden; Lund University, Sweden; Skåne University Hospital, Sweden.
    Two consecutive randomized controlled pertussis booster trials in children initially vaccinated in infancy with an acellular vaccine: The first with a five-component Tdap vaccine to 5-year olds and the second with five- or monocomponent Tdap vaccines at age 14-15 years2015In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 33, no 31, p. 3717-3725Article in journal (Refereed)
    Abstract [en]

    Prior study children from a DTaP efficacy trial were recruited at ages 5 and 15 years to randomized booster trials addressing immunogenicity and reactogenicity; 475 preschool children received mixed or separate injections of a reduced antigen vaccine (Tdap5, Sanofi Pasteur MSD) and an inactivated polio vaccine, and 230 adolescents received the same or another booster vaccine (Tdap1, SSI, Denmark). Pre-vaccination antibody concentrations against pertussis antigens were significantly higher at 15 than 5 years of age, probably due to natural boosting between the studies. Tdap5 induced comparable anti-PT concentrations at both ages, but antibody responses were significantly higher to filamentous haemagglutinin, pertactin and fimbriae 2/3 in adolescents. As expected, a higher amount of PT (Tdap1, 20 mu g) induced a stronger anti-PT response than a lower amount (Tdap5, 2.5 mu g). The frequency of adverse events was low and there were no serious adverse reactions. All local reactions had an early onset and a short duration. A large swelling or redness of more than half of the upper arm circumference was reported in 8/475 5-year-olds and in 6/230 15-year-olds. Children vaccinated with Tdap5 reported more moderate pain in adolescence than at preschool age, whereas itching was only reported in preschool children. Sweden introduced DTaP vaccines in 1996 after a 17-year hiatus with no general pertussis vaccination and pertussis was still endemic at the time of the studies. The frequency of adverse events was nevertheless low in both preschool children and adolescents and antibody responses were adequate. These studies document immunogenicity and reactogenicity in a trial cohort consecutively vaccinated with acellular pertussis vaccines from infancy to adolescence. (C) 2015 Elsevier Ltd. All rights reserved.

  • 9.
    Carlsson, R. M.
    et al.
    Public Health Agency Sweden, Sweden; Sahlgrens University Hospital, Sweden.
    von Segebaden, K.
    Public Health Agency Sweden, Sweden.
    Bergstrom, J.
    Public Health Agency Sweden, Sweden.
    Kling, A. M.
    Public Health Agency Sweden, Sweden.
    Nilsson, Lennart J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Surveillance of infant pertussis in Sweden 1998-2012; severity of disease in relation to the national vaccination programme2015In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 20, no 6, article id 21032Article in journal (Refereed)
    Abstract [en]

    In Sweden, pertussis was excluded from the national vaccination programme in 1979 until acellular vaccination was introduced in a highly endemic setting in 1996. The general incidence dropped 10-fold within a decade, less in infants. Infant pertussis reached 40–45 cases per 100,000 in 2008 to 2012; few of these cases were older than five months. We present an observational 15-year study on the severity of infant pertussis based on 1,443 laboratory-confirmed cases prospectively identified from 1998 to 2012 in the national mandatory reporting system and followed up by telephone contact. Analyses were made in relation to age at onset of symptoms and vaccination history. Pertussis decreased in non-vaccinated infants (2003 to 2012, p < 0.001), indicating herd immunity, both in those too young to be vaccinated and those older than three months. The hospitalisation rates also decreased (last five-year period vs the previous five-year periods, p <0.001), but 70% of all cases in under three month-old infants and 99% of cases with apnoea due to pertussis were admitted to hospital in 1998 to 2012. Median duration of hospitalisation was seven days for unvaccinated vs four days for vaccinated infants aged 3–5 months. Nine unvaccinated infants died during the study period.

  • 10.
    Fagerås Böttcher, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hmani-Aifa, Mounira
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Lindström Lundberg, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria Christina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Mai, Xiao-Mei
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Aniansson Zdolsek, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Björkstén, Bengt
    Centre for Allergy Research and Institute of Environmental Medicine, Karolinska Institute, Stockholm;.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children2004In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 114, no 3, p. 561-567Article in journal (Refereed)
    Abstract [en]

    Background

    Bacterial signals play an important role in the maturation of the immune system. Polymorphisms in genes coding for receptors to bacterial components can alter the immune responsiveness of the host to microbial agents and may indicate the development of aberrant immune responses that are associated with immune-mediated diseases such as atopic diseases.

    Objective

    The study's objective was to investigate the relationship between TLR4 and CD14 gene polymorphisms, the LPS responsiveness of PBMCs, and the presence of asthma and allergic rhinoconjunctivitis in children.

    Methods

    The TLR4 (Asp299Gly) and CD14/−159 polymorphisms were determined in 115 Swedish children aged 8 and 14 years. LPS-induced IL-12(p70), IL-10, and IFN-γ responses of PBMCs from 69 of the children were analyzed by means of ELISA. The levels of soluble CD14 in serum samples were analyzed by means of ELISA, and the total IgE levels were analyzed by means of UniCAP Total IgE (Pharmacia Diagnostics, Uppsala, Sweden).

    Results

    Decreased LPS-induced IL-12(p70) and IL-10 responses were associated with the TLR4 (Asp299Gly) polymorphism and independently with asthma, especially atopic asthma. The TLR4 (Asp299Gly) polymorphism was associated with a 4-fold higher prevalence of asthma in school-aged children (adjusted odds ratio 4.5, 95% CI 1.1-17.4) but not to allergic rhinoconjunctivitis.

    Conclusion

    A TLR4 polymorphism modifies innate immune responses in children and may be an important determinant for the development of asthma. This may influence the outcome of intervention studies that use microbial stimuli as immune modulators.

  • 11.
    Gehring, U
    et al.
    University of Utrecht.
    Strikwold, M
    University of Utrecht.
    Schram-Bijkerk, D
    University of Utrecht.
    Weinmayr, G
    University of Ulm.
    Genuneit, J
    University of Ulm.
    Nagel, G
    University of Ulm.
    Wickens, K
    Wellington School of Medical & Heallth Science.
    Siebers, R
    Wellington School of Medical & Heallth Science.
    Crane, J
    Wellington School of Medical & Heallth Science.
    Doekes, G
    University of Utrecht.
    Di Domenicantonio, R
    Rome E Health Authority.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Priftanji, A
    University Hospital Centre Mother Teresa.
    Sandin, A
    Umeå University.
    El-Sharif, N
    AL Quds University.
    Strachan, D
    St Georges University London.
    van Hage, M
    Karolinska Institute.
    von Mutius, E
    University Childrens Hospital.
    Brunekreef, B
    University of Utrecht.
    Asthma and allergic symptoms in relation to house dust endotoxin: Phase Two of the International Study on Asthma and Allergies in Childhood (ISAAC II)2008In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 38, no 12, p. 1911-1920Article in journal (Refereed)
    Abstract [en]

    Background: Several studies have consistently reported inverse associations between exposure to endotoxin in house dust and atopy. With regard to the association between house dust endotoxin and asthma, the results are inconsistent.

    Objectives: To study the association between house dust endotoxin levels and respiratory symptoms and atopy in populations from largely different countries.

    Methods: Data were collected within the International Study on Asthma and Allergies in Childhood Phase Two, a multi-centre cross-sectional study of 840 children aged 9-12 years from six centres in the five countries of Albania, Italy, New Zealand, Sweden and the United Kingdom. Living room floor dust was collected and analysed for endotoxin. Health end-points and demographics were assessed by standardized questionnaires. Atopy was assessed by measurements of allergen-specific IgE against a panel of inhalant allergens. Associations between house dust endotoxin and health outcomes were analysed by logistic regression. Odds ratios (ORs) were presented for an overall interquartile range increase in exposure.

    Results: Many associations between house dust endotoxin in living room floor dust and health outcomes varied between countries. Combined across countries, endotoxin levels were inversely associated with asthma ever [adjusted OR (95% confidence interval (CI)) 0.53 (0.29-0.96) for endotoxin levels per m(2) of living room floor] and current wheeze [adjusted OR (95% CI) 0.77 (0.64-0.93) for endotoxin levels per gram of living room floor dust]. There were inverse associations between endotoxin concentrations and atopy, which were statistically significant in unadjusted analyses, but not after adjustment for gender, parental allergies, cat and house dust mite allergens. No associations were found with dust quantity and between endotoxin exposure and hayfever.

    Conclusion: These findings suggest an inverse association between endotoxin levels in living room floor dust and asthma in children.

  • 12. Grüber, C
    et al.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Björkstén, Bengt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Do early childhood immunizations influence the development of atopy and do they cause allergic reactions?2001In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 12, no 6, p. 296-311Article in journal (Refereed)
    Abstract [en]

    Concerns about allergic side-effects of vaccines and about a possible promotion of allergic diseases contribute to incomplete vaccination rates in childhood. This article reviews the current understanding of these issues. There is evidence that pertussis and diphtheria/tetanus antigens elicit immunoglobulin E (IgE) antibody formation as part of the immune response. In murine models, pertussis toxin is an effective adjuvant for IgE formation against simultaneously administered antigens. In children, however, sensitization to unrelated antigens or development of allergic diseases do not seem to be augmented. In contrast, bacille Calmette-GuΘrin (BCG) and measles vaccination have been proposed as suppressors of allergy because of their T helper 1 (Th1)-fostering properties. In the murine system, BCG inhibits allergic sensitization and airway hyper-reactivity. Some epidemiological studies in humans suggest an inhibitory effect of tuberculosis on allergy. BCG vaccination in children, however, has no or merely a marginal suppressive effect on atopy. Other vaccine components such as egg proteins, gelatin, and antibiotics are a potential hazard to children with severe clinical reactions to these allergens. These rare children should be vaccinated under special precautions. In conclusion, vaccination programs do not explain the increasing prevalence of allergic diseases, but individual children may uncommonly develop an allergic reaction to a vaccine. The risks of not vaccinating children, however, far outweigh the risk for allergy. Therefore, childhood vaccination remains an essential part of child health programs and should not be withheld, even from children predisposed for allergy.

  • 13.
    Hallander, H
    et al.
    Swedish Institute for Communicable Disease Control, Stockholm.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Gustafsson, L
    Swedish Institute for Communicable Disease Control, Stockholm.
    Is adolescent perutssis vaccination prefrable to natural booster infections?2011In: Expert Review of Clinical Pharmacology, ISSN 1751-2433, Vol. 4, no 6, p. 705-711Article, review/survey (Refereed)
    Abstract [en]

    Pertussis is still poorly controlled in both adolescents and adults. As a result, an adolescent pertussis booster vaccine dose has already been implemented or decided on in many countries. The reasons for this have been twofold: a worrying increase of infections in the target group of adolescents and a wish to prevent serious pertussis disease among young yet unvaccinated, and partly vaccinated, infants. Currently, it is still too early to evaluate the effect of the late booster on the circulation of Bordetella pertussis owing to the lack of relevant follow-up data. A universal adolescent booster vaccination will reduce the incidence of pertussis in the target group but the duration of immunity is uncertain. It is an open question as to what extent boosters should be offered to older age groups or if natural infections would be preferable. On the one hand, circulating B. pertussis may be hazardous to the youngest unvaccinated infants. On the other hand, subclinical natural boosters might be beneficial to population immunity. As the duration of immunity is shorter after vaccination than after natural infections, an unwanted consequence of adolescent boosters might shift the infection peak to older child-bearing adults. It is therefore recommended that recurrent serosurveys are used to follow the influence of vaccination on the antigenic pressure, as well as the duration of protective immunity. For this purpose, standardization of symptoms and laboratory criteria used for notification, as well as the methodology for seroepidemiology, must be established. Adverse reactions after adolescent vaccination and outbreaks owing to new B. pertussis variants must also be carefully monitored. In this article, we have used Swedish surveillance data and the results from Swedish seroepidemiology to illustrate these problem areas.

  • 14.
    Hallander, Hans O.
    et al.
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Ljungman, Margretha
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Jahnmatz, Maja
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Storsaeter, Jann
    Norwegian institute of Public Health, Oslo, Norway.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Gustafsson, Lennart
    Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden.
    Should fimbriae be included in pertussis vaccines? Studies on ELISA IgG anti-Fim2/3 antibodies after vaccination and infection2009In: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, Vol. 117, no 9, p. 660-671Article in journal (Refereed)
    Abstract [en]

    The anti-Fim response and long-term persistence after vaccination and infection may be of importance in understanding population immunity. Longitudinal serum samples (n = 1330) from 542 non-infected children related to a Swedish vaccine trial showed that the post vaccination (DTPa5) antibody decay curve for pertussis ELISA IgG anti-fimbriae2/3 (anti-Fim2/3) was bi-phasic. A slower one followed an initial rapid decay approximately 5-6 months after the third dose at 12 months of age. After 71 months, however, 60% still had concentrations above > or =5 EU/ml, a level that had been shown to correlate with decreased risk of disease. Booster responses after re-vaccination with DTPa5 at 4, 5 and 6 years of age were strong and appeared within 1 week after vaccination, indicating immune memory. Ninety-six young children with verified pertussis infection, for whom we had serum samples both before, during and after the infection, showed a high response if they had been primed with fimbriae (either DTPa5 or DTPwc). In contrast, 76% of infected children not primed with fimbriae (a DTPa2 or DT group) only had concentrations below the minimum level of detection in all samples taken during and after the infection. In two Swedish seroepidemiological surveys, one from 1997 just after reintroduction of universal childhood vaccination against pertussis and one from 2007, the proportion of children 2-3 years with anti-Fim2/3 concentrations <5 EU/ml was similar and above 90%. This reflects that the two- or three-component pertussis vaccines (DTPa2 and DTPa3) that were introduced in Sweden in 1996 do not induce anti-Fim2/3 antibodies. In previous studies it was shown in multivariate analyses that levels of IgG anti-Fim2/3 > or =5 EU/ml reduced short-term risk of pertussis in small children. As the antibody response to Fim2/3 after infection is poor in children who have not been primed earlier in life, inclusion of immunogenic Fim2/3 in future pertussis vaccines should be considered.

  • 15.
    Hedin-Skogman, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Croner, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Kampanj för TBE vaccination av små barn oetisk och felaktig2004In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 101, no 37, p. 2832-2832Article in journal (Other academic)
  • 16.
    Hedin-Skogman, Barbro
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Croner, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    TBE-vaccinera barn över 7 år i endemiska områden, men låt de små barnen slippa.2004In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 101, no 43, p. 3367-3367Article in journal (Other (popular science, discussion, etc.))
  • 17.
    Hällgren, Anita
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology.
    Burman, L
    Olsson-Liljequist, B
    Isaksson, Barbro
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Saedi, B
    Walther, Sten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Anaesthesiology. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hanberger, Håkan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Hög frekvens an korskolonisering med resistenta enterokocker hos "långliggare" på IVA2004In: Hygiea,2004, 2004, p. 57-57Conference paper (Other academic)
  • 18.
    Jahnmatz, Maja
    et al.
    Public Health Agency Sweden, Sweden; Karolinska Institute, Sweden.
    Ljungman, Margaretha
    Public Health Agency Sweden, Sweden.
    Netterlid, Eva
    Public Health Agency Sweden, Sweden.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center. Public Health Agency Sweden, Sweden.
    Thorstensson, Rigmor
    Public Health Agency Sweden, Sweden.
    Pertussis-Specific Memory B-Cell and Humoral IgG Responses in Adolescents after a Fifth Consecutive Dose of Acellular Pertussis Vaccine2014In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 9, p. 1301-1308Article in journal (Refereed)
    Abstract [en]

    In order to impede the increase in pertussis incidence in the adolescent group, a school-leaving booster dose administered at the age of 14 to 16 years will be introduced in Sweden in 2016. Preceding this introduction, an open-label, randomized, multicenter, clinical trial without a control group and with blinded analysis was performed, investigating both safety and immunogenicity. Reported here are the memory B-cell and serological responses detected in a smaller cohort (n = 34) of the 230 subjects recruited to the study. All subjects had received primary vaccination consisting of three doses of diphtheria-tetanus-5-component pertussis (DTaP5) vaccine, at 3, 5, and 12 months of age, and a tetanus-low-dose diphtheria-5-component pertussis (Tdap5) vaccine booster at 5.5 years. In this study, the subjects were randomly assigned and received either a Tdap1 or Tdap5 booster. Of the 230 participants, 34 subjects had samples available for evaluation of IgG-producing memory B-cell responses. Both vaccine groups had significant increases in pertussis toxin-specific serum IgG levels, but only the 1-component group showed significant increases in pertussis toxin-specific memory B cells. The 5-component group had significant increases in filamentous hemagglutinin- and pertactin-specific memory B-cell and serum IgG levels; these were not seen in the 1-component group, as expected. In conclusion, this study shows that a 5th consecutive dose of an acellular pertussis vaccine induces B-cell responses in vaccinated adolescents.

  • 19.
    Kilpi, Terhi M
    et al.
    National Public Health Institute, Finland.
    Arne Silfverdal, Sven
    University of Örebro.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Syrjanen, Ritva
    San Matteo Hospital.
    Desole, Maria
    AUSL 1, Italy.
    Triban, Chiara
    GlaxoSmithKline.
    Storsaeter, Jann
    GlaxoSmithKline.
    Soila, Maaria
    GlaxoSmithKline.
    Jacquet, Jeanne-Marie
    GlaxoSmithKline.
    Immunogenicity and reactogenicity of two diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccines administered at 3, 5 and 11-12 months of age2009In: HUMAN VACCINES, ISSN 1554-8619, Vol. 5, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    The use of combination vaccines in the routine childhood program reduces distress to the recipients and is likely to improve uptake rates and timeliness of vaccination but requires careful evaluation and surveillance. The aim of this study was to evaluate the immunogenicity and reactogenicity of two commercial diphtheria-tetanus-acellular pertussis-hepatitis b-inactivated polio virus-Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) combination vaccines when administered to infants at 3, 5 and 11-12 months of age. A total of 494 infants were randomized to receive three doses of either Infanrix hexa T (GlaxoSmithKline Biologicals; N = 246) or Hexavac (TM) (Sanofi Pasteur MSD; N = 248) in 10 centers in Italy, Finland and Sweden. After the third dose, antibodies to diphtheria, tetanus, polio and Hib were at the protective level in nearly all infants in both groups whereas the proportion of subjects who had achieved the protective concentration of = 10 mIU/ml to hepatitis B surface antigen was 99.1% (95% CI 96.7-99.9) in the Infanrix hexa T group as compared to 94.4% (95% CI 90.4-97.1) in the Hexavac T group. Antibody titers to all three polio antigens were highest in Italy and lowest in Finland. Clinically relevant general reactions (such as fever of >39.5 degrees C) were mostly reported in less than 5% of the vaccinees. Three doses of DTaP-HBV-IPV/Hib combination vaccines produced sufficient immune responses in nearly all vaccinees.

  • 20.
    Kivling, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Allergy Centre UHL.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    How and when to pick up the best signals from markers associated with T-regulatory cells?2009In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 345, no 1-2, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Regulatory T (Treg) cells are important tools with the purpose to control and regulate the immune system. These cells use FOXP3, TGF-beta, CTLA-4 and sCTLA-4 to regulate other T-cells. Since cryopreservation of peripheral blood mononuclear cells (PBMC) is a convenient way to handle samples, we investigated whether these cells will change their mRNA expression of Treg associated markers, as well as secretion of TGF-beta1, after cryopreservation. Additionally, we aimed to investigate the mRNA expression after two different time intervals of in vitro antigen stimulation. PBMC from healthy adults were stimulated either fresh (48/96 h) or after cryopreservation (48 h), with PHA, tetanus toxoid, beta-lactoglobulin, ovalbumin or in culture medium exclusively (spontaneous). The mRNA expression of FOXP3, TGF-beta, CTLA-4 and sCTLA-4 were studied with multiplex real-time RT-PCR and TGF-beta1 with ELISA. Cryopreserved PBMC were appropriate for detection of the Treg associated markers FOXP3, TGF-beta, CTLA-4 and sCTLA-4 expressed spontaneously. Also antigen-induced mRNA expression of CTLA-4, sCTLA-4 and TGF-beta and secreted TGF-beta1, with the exception of FOXP3, preserved a stable transcription activity after cryopreservation. Further, a stimulation period of 48 h in general revealed the highest mRNA expression of the markers studied. In conclusion, cryopreserved cells are in general suitable for studying Treg associated markers.

  • 21.
    Kivling, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Sollvander, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Johanson, Calle
    Ryhov Jonkoping City Hospital.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, p. 273-277Article in journal (Refereed)
    Abstract [en]

    Imbalance between different types of T lymphocytes, such as T helper (Th) and regulatory T cells (Tregs), has been reported to play a part in the pathogenesis behind such autoimmune diseases as type 1 diabetes (T1D) and celiac disease (CD). Defects in Tregs are proposed to at least partly explain the imbalance of Th cells found in children with immunologic diseases. Peripheral blood mononuclear cells from 24 children with T1D and/or CD, and reference children (that is, those without any of these diseases) were stimulated with disease-associated antigens (insulin, gluten, transglutaminase [tTG]), and phytohemagglutinin (PHA). The mRNA expression of the Treg-associated marker FOXP3 was analyzed with multiplex real-time RT-PCR. Children with T1D showed both a low spontaneous (P < 0.05) and PHA-induced (P < 0.01) expression of FOXP3 mRNA compared to children with CD. Children with T1D also had a low PHA-induced FOXP3 mRNA expression compared to the group of children diagnosed with both T1D and CD (P < 0.05). Spontaneous (P < 0.05) and PHA-induced (P < 0.05) FOXP3 mRNA expression was high in children with CD compared to reference children. In contrast, stimulation with insulin tended to induce high FOXP3 mRNA expression in T1D children compared to reference children (P = 0.057). In conclusion, children with only T1D generally showed a lower FOXP3 mRNA expression than did children with CD, or with T1D in combination with CD, which suggests impaired regulation of the immune system in children with T1D.

  • 22.
    Kivling, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Åkesson, Karin
    Clinic of Paediatrics, Ryhov County Hospital, Jönköping, Sweden 4.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Diverging immune responses when allergy, type 1 diabetes and celiac disease coexistManuscript (preprint) (Other academic)
    Abstract [en]

    An imbalance between different immune cells, among them T-cells and inflammatory cells, has been proposed to be part of the disease process in type 1 diabetes (T1D), celiac disease and allergy. T-cells and inflammatory cells exert their actions through cytokines and chemokines, and the secretion of those can be used to describe the cell milieu during an immune response.

    This study included seventy-two children, diagnosed with T1D, celiac disease, allergy, or a combination of two of these diseases and compared to reference children. The study aimed to evaluate the secretion of 27 different cytokines and chemokines in cell culture supernatant after in vitro stimulation with disease-associated antigens (birch, gluten, insulin) detected by Luminex technique.

    Combination of allergy with either T1D or celiac disease gave diverging results. Children with combination of T1D and allergy showed an increased secretion of several cytokines (IL-2, IL-4, IL-5, IL-7, IL-9, IL-10, IL-12, IL-15, IL-17 and CCL11), in comparison to almost all groups from birch stimulation. In contrast, when allergy was combined with celiac disease, the spontaneous secretion of IL-1β, IL-5, IL-6, IL-9, IL-10, IL-12 and CCL3 was decreased compared to children with T1D or allergy, as well as children with celiac disease alone, children with combination of T1D and allergy and reference children.

    In conclusion, our results shed some light on the immune responses in children with common immunological diseases. Our study indicates diverging immune responses when allergy, type 1 diabetes and celiac disease coexist.

  • 23.
    Kivling, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkesson, Karin
    Clinic of Paediatrics, Ryhov County Hospital, Jönköping, Sweden 4.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Combined type 1 diabetes and celiac disease in children give raise to a pronounced Treg populationManuscript (preprint) (Other academic)
    Abstract [en]

    Regulatory T-cells (Treg) suppress the immune response in order to avoid harmful effects. A wide range of highly expressed markers are associated to Treg, among them are CD4, CD25, CD39 and forkhead box p3 (FOXP3). Others are expressed in a low number on Tregs, for example CD45RA and CD127. Type 1 diabetes (T1D) and celiac disease are both autoimmune diseases, caused by an unwanted immune response, and Treg cells have been associated to both diseases. As T1D and celiac disease share same risk genes, patients have the risk of developing the other disease subsequently. Treg cells have been implicated to be associated with development of T1D combined with celiac disease.

    This pilot study aimed to investigate the expression of Treg associated markers in both CD4+CD25+ and CD4+CD25high cells by flow cytometry. In order to evaluate the involvement of Treg cells, CD39, CD45RA, CD127 and FOXP3 were studied in children with combination of T1D and celiac disease, in comparison to children with either T1D or celiac disease, and healthy children.

    Our data point out that children with combination of T1D and celiac disease have higher expression of FOXP3 as well as CD39, together with a decreased expression of both CD127 and CD45RA, in comparison to children with exclusively T1D or celiac disease. Even though none of the groups differed from the reference group, our data indicates that children with combination of T1D and celiac disease have a more pronounced Treg population, both in frequency and MFI, compared to children with either T1D or celiac disease.

  • 24.
    Kjellman, Max
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Is allergy prevention realistic and beneficial? 1999In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 10, p. 11-17Article in journal (Refereed)
  • 25.
    Käyhty, Helena
    et al.
    Dept of Vaccines, National Public Health Institute, Helsingfors, Finland.
    Åman, Heidi
    Wyeth Finland, Vantaa, Finland .
    Eriksson, Karin
    Wyeth Lederle Nordiska AB, Solna, Stockholm .
    Sörberg, Mikael
    Infectious Diseases Unit, Dept of Medicine, Karolinska sjukhuset, Stockholm.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Immunogenicity and tolerability of a heptavalent pneumococcal conjugate vaccine administered at 3, 5 and 12 months of age2005In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 24, no 2, p. 108-114Article in journal (Refereed)
    Abstract [en]

    Background: The recommended vaccination schedule for the pneumococcal conjugate vaccine (PCV) includes 4 immunizations, according to the national programs in the United States and some European countries. Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses. Aims: The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life (a 2+1 dose schedule) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b (Hib) vaccine. Methods: A total of 101 healthy Swedish infants were enrolled in an open, nonrandomized, multicenter study. PCV was administered concomitantly with (at separate sites) a diphtheria-tetanus toxoids-acellular pertussis vaccine, inactivated polio vaccine and Hib conjugate vaccine combination at 3, 5 and 12 months of age. IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum samples taken at 3, 6, 12 and 13 months were determined with enzyme immunoassays. Local and systemic reactions were monitored for 3 days after each immunization, and serious adverse reactions were monitored for the whole study period. Results: Two doses of PCV induced satisfactory antibody responses, with the exception of serotypes 6B and 23F. The third dose evoked strong responses for all serotypes, which suggests good immunologic priming with the primary series of 2 doses. The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children. The PCV was well tolerated. Conclusion: The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule. The results suggest that the implementation of a 2+1 dose schedule for PCV should be considered.

  • 26.
    Lahdenperä, Anne
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Regnström, Karin
    Farmakologen Uppsala.
    Kinetics of asthma- and allergy-associated immune response gene expression in peripheral blood mononuclear cells from vaccinated infants after in vitro re-stimulation with vaccine antigen2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 14, p. 1725-1730Article in journal (Refereed)
    Abstract [en]

    The global expression of immune response genes in infants after vaccination and their role in asthma and allergy is not clearly understood. Pharmacogenomics is ideally suited to study the involved cellular responses, since the expression of thousands of genes can be assessed simultaneously. Here, array technology was used to assess the expression kinetics of immune response genes with association to asthma and allergy in peripheral blood mononuclear cells (PBMC) of five healthy infants after vaccination with Infanrix-Polio + Hib. At 12 h after in vitro re-stimulation of the PBMC with pertussis toxin (PT) antigen, 14 immune response pathways, 33 allergy-related and 66 asthma-related genes were found activated. © 2008 Elsevier Ltd. All rights reserved.

  • 27.
    Mai, Xiao-Mei
    et al.
    Canada.
    Almqvist, Catarina
    Astrid Lindgrens barnsjukhus Stockholm.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Wickman, Magnus
    Karolinska Institutet Stockholm.
    Birth anthropometric measures, body mass index and allergic diseases in a birth cohort study (BAMSE)2007In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 92, no 10, p. 881-886Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to assess increased birth weight or birth length in relation to allergic diseases at 4 years of age, taking body mass index (BMI) at age 4 as a covariate in the adjustment. Methods: The parents of a large prospective birth cohort answered questionnaires on environmental factors and allergic symptoms when their children were 2 months and 1, 2 and 4 years old. Perinatal data on weight and length at birth were received from the child care health centres. The children were clinically examined at 4 years of age and height and weight recorded. Blood was drawn for analysis of specific IgE antibodies to common inhalant allergens. Risk associations between birth anthropometric measures and wheeze, allergic diseases or sensitisation were estimated in multivariate logistic regression analyses (n = 2869). Results: There were no clear overall associations between birth weight and allergic diseases at 4 years of age. Birth length ≥90th percentile was inversely associated with any wheeze at age 4 (adjusted OR 0.64, 95% Cl 0.44 to 0.92) but was significantly associated only with late-onset wheeze (adjusted OR 0.40, 95% Cl 0.21 to 0.77). No such associations were seen for persistent or transient wheeze, eczema, rhinitis or allergic sensitisation. Transient wheeze during the first 2 years of age tended to be associated with increased BMI at age 4. Conclusion: Increased birth weight was not associated with wheeze or allergic disease. Increased birth length may play a protective role in late-onset wheeze in early childhood.

  • 28.
    Mai, Xiaomei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Fagerås Böttcher, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Bruhammar, M
    Allergicentrum US, Linköping.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Zetterström, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Allergy Centre. Östergötlands Läns Landsting, Centre for Medicine, Allergy Centre UHL.
    Urinary inflammatory mediators and inhalation of hypertonic saline in children2005In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 60, no 1, p. 60-64Article in journal (Refereed)
    Abstract [en]

    Background: The inflammatory mechanisms of hypertonic saline-induced bronchoconstriction are not well understood. Methods: Seventeen asthmatics with (n = 11) and without bronchial hyperresponsiveness (BHR) (n = 6) and 18 randomly selected nonatopic nonasthmatic controls without BHR were evaluated by urine samples collected before and 1 h after hypertonic saline provocation test. Histamine, 11β-PGF2α, and LTE4 were analysed by enzyme immunoassay (EIA) and eosinophil protein X (EPX) by radioimmunoassay (RIA). Results: The levels of leukotriene E4 (LTE4) increased significantly after the challenge tests, both in the asthmatics (median: 354 pg/mg pre-challenge vs. 628 pg/mg post-challenge, P = 0.05) and in the controls (median: 294 pg/mg pre-challenge vs. 460 pg/mg post-challenge, P < 0.01). The levels of histamine also increased significantly in the latter (median: 299 μmol/mg pre-challenge vs. 569 μmol/mg post-challenge, P = 0.03). However, the levels of 11β-PGF2α and EPX did not change significantly after the challenge tests either in the asthmatics or in the controls. Conclusions: The inhalation of hypertonic saline increased urinary excretion of LTE4 both in the asthmatics and in the controls. The slight increase of leukotrienes was enough to induce airway obstruction in some of the asthmatics, because of the hyperresponsiveness in their airways.

  • 29.
    Mai, Xiaomei
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Fagerås Böttcher, Malin
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Holmberg, Mikaela
    Linköping University, Department of Molecular and Clinical Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Zetterström, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences.
    Inflammatory mediators monitored in urine in asthmatic children with hypertonic saline-induced bronchoconstriction and in healthy controlsManuscript (preprint) (Other academic)
    Abstract [en]

    Hypertonic saline provocation tests have been validated to be useful in the International Study of Asthma and Allergies in Childhood, but the inflammatory mechanisms of hypertonic saline-induced bronchial hyperresponsiveness (BHR) have not been well understood in asthmatic children. Of the 127 children who participated in hypertonic saline provocation tests, all asthmatics with (n = 13) and without BHR (n = 7) as well as all healthy controls without BHR (n = 37) were evaluated with urine samples collected before and one hour after the provocation test. Paired samples were analyzed in 11 asthmatics with and 6 asthmatics without BHR and 18 healthy controls. Urinary histamine, 11ß-PGF and LTE4 were analyzed by EIA and urinary EPX by RIA. The levels of LTE4 increased after the challenge tests, both in the asthmatics (median value: 354.2 pg/mg pre-challenge vs. 628.3 pg/mg post-challenge, p = 0.05) and in the healthy controls (median value: 294.4 pg/mg pre-challenge vs. 460.0 pg/mg post-challenge, p = 0.008). The levels of histamine also increased in the latter (median value: 299.3 µmol/rug pro-challenge vs. 568.8 µmol/mg post-challenge, p = 0.03). However, the levels of 11ß-PGF and EPX were similar before and after the challenge tests both in the asthmatics and in the healthy controls. The inhalation of hypertonic saline induced the secretion of LTE4 and histamine even in healthy children, but the bronchoconstriction did not seem to be induced by the analyzed inflammatory mediators, such as LTE4, 11ß-PGF, histamine and EPX.

  • 30.
    Mai, Xiaomei
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Gäddlin, Per-Olof
    Central Hospital, Jönköping, Sweden.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Finnström, Orvar
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Björkstén, Bengt
    Centre for Allergy Research and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Jenmalm, Maria C.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Leijon, Ingemar
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study2003In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 14, no 3, p. 184-192Article in journal (Refereed)
    Abstract [en]

    We assessed the relationship between very low birth weight (VLBW) (≤1500 g) and the development of asthma, lung function and atopy. The study groups comprised 74 of all 86 (86%) VLBW and 64 of all 86 (74%) matched term children who were prospectively followed for 12 years. A questionnaire on asthmatic and allergic symptoms was completed and skin prick tests, spirometry and hypertonic saline provocation tests were performed at 12 years of age. Cytokine secretion was analysed in stimulated blood leukocyte cultures in 28 VLBW and 23 term children. A history of asthma was more frequent among the VLBW children, as compared with the term children at age 12 (22% vs. 9%, p = 0.046). Among the VLBW children, very preterm birth (gestational age: week 25 to 29) (RR 2.5, 95%CI 1.1–5.8), neonatal mechanical ventilation (RR 2.8, 95%CI 1.2–6.4) and neonatal oxygen supplementation (RR 4.3, 95%CI 1.3–14.0) were significantly associated with a history of asthma by the age of 12 years in univariate analyses. In multivariate logistic regression, neonatal oxygen supplementation ≥ 9 days was the only remaining significant risk factor for a history of asthma (adjusted OR 6.7, 95%CI 1.0–44). The VLBW children who required mechanical ventilation during the neonatal period were more likely to have bronchial hyperresponsiveness than those not requiring mechanical ventilation (60% vs. 28%, p = 0.050). The spirometric values were similar among the VLBW and the term children at 12 years. Very low birth weight was not significantly related to allergic rhinoconjunctivitis, eczema or positive skin prick tests. Furthermore, the levels of IL-4, IL-5 and IFN-γ in stimulated cell cultures were similar in the VLBW and the term children. A history of asthma by 12 years of age was twice as common among the VLBW as the term children, and neonatal oxygen supplementation seemed to be associated with the increased risk. Furthermore, mechanical ventilation during the neonatal period was associated with bronchial hyperresponsiveness at age 12. Very low birth weight per se was not, however, related to atopy.

  • 31.
    Mai, Xiaomei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Gäddlin, Per-Olof
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Leijon, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Early rapid weight gain and current overweight in relation to asthma in adolescents born with very low birth weight2005In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 16, no 5, p. 380-385Article in journal (Refereed)
    Abstract [en]

    Early catch-up growth and subsequent overweight are suggested to be associated with later cardiovascular diseases and later type II diabetes. However, the impact of early catch-up growth and childhood overweight on the development of asthma has been less studied, particularly in children born with very low birth weight (VLBW). A birth cohort of 74 VLBW children (birth weight ≤ 1500 g) was followed from birth and investigated on asthma at 12 yr of age. Early rapid weight gain was in one way defined as an increase of weight ≥1 standard deviation score (SDS) at 6 months of corrected postnatal age. Current overweight was defined by body mass index (BMI) exceeding 21.2 and 21.7 kg/m2, respectively, for boys and girls at 12 yr of age. Current asthma was diagnosed by a pediatrician, according to asthma ever in combination with a positive response to hypertonic saline bronchial provocation test and/or wheeze at physical examination at 12 yr old. Being overweight at 12 yr of age was associated with an increased risk for current asthma in the VLBW children [crude odds ratio (OR): 5.5, 95% confidence interval (CI): 1.3-22.2]. After adjustment for early weight gain and neonatal risk, the OR of overweight increased nearly three times (adjusted OR: 15.3, 95% CI: 2.5-90.6). Early rapid weight gain seemed to be inversely associated with current asthma (adjusted OR: 0.49 for an increase of weight equal to 1 SDS, 95% CI: 0.23-1.02, p = 0.06). In addition, early rapid weight gain was inversely associated with the magnitude of bronchial responsiveness at 12 yr (coefficient -1.15, p < 0.01). There was a strong and positive association between overweight and asthma at 12 yr of age in the VLBW children. This strong association had been reduced by early rapid weight gain, possibly via the reduction of bronchial responsiveness. © 2005 Blackwell Munksgaard.

  • 32.
    Mai, Xiaomei
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelson, Olav
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Bråbäck, Lennart
    Mid-Sweden Research and Development Centre, Sundsvall Hospital, Sweden.
    Sandin, Anna
    Department of Paediatrics, Östersund Hospital, Sweden.
    Kjellman, Max
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Björkstén, Bengt
    Centre for Allergy Research and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: phase II2003In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, no 10, p. 1144-1148Article in journal (Refereed)
    Abstract [en]

    Aim: To assess the relationship between high body mass index (BMI) and asthma and atopic manifestations in 12-y-old children.

    Methods: The relationship between high BMI and asthma symptoms was studied in 457 sixth-grade children, with (n= 161) and without (n= 296) current wheeze. High BMI was defined as ±75th percentile of gender-specific BMI reference values for Swedish children at 12 y of age; overweight as a subgroup of high BMI was defined as ±95th percentile. Children with a BMI >75th percentile served as controls. Questionnaires were used to assess asthmatic and allergic symptoms, and bronchial hyperresponsiveness was assessed by hypertonic saline provocation tests.

    Results: Current wheeze was associated with high BMI after adjustment for confounding factors (adjusted OR 1.7, 95% CI 1.0–2.5) and overweight had an even more pronounced effect (adjusted OR 1.9, 95% CI 1.0–3.6). In addition, asthma severity was associated with high BMI, as evaluated by the number of wheezing episodes during the previous 12 mo among the wheezing children (adjusted OR 2.0, 95% CI 1.0–4.0). There was also an association between high BMI and the presence of eczema in wheezing children (adjusted OR 2.2, 95% CI 1.0–4.6). However, high BMI was not significantly associated with hay fever, positive skin prick tests or bronchial hyperresponsiveness.

    Conclusion: The study confirms and extends a previously observed relationship between BMI and the presence of wheezing and asthma.

  • 33.
    Mai, Xiaomei
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Kjellman, Max
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Björkstén, Bengt
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hypertonic saline challenge tests in the diagnosis of bronchial hyperresponsiveness and asthma in children2002In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 13, no 5, p. 361-367Article in journal (Refereed)
    Abstract [en]

    The hypertonic saline challenge test is the recommended method to assess bronchial hyperresponsiveness in the International Study of Asthma and Allergies in Childhood (ISAAC). The sensitivity of this procedure to assess asthma symptoms, however, has been reported to vary among study centers. The purpose of our study was to evaluate the value of this provocation test in an epidemiological survey in children, and to relate the degree of bronchial hyperresponsiveness to the severity of asthma symptoms. All 11–13-year-old children from 16 randomly selected schools in Linköping, Sweden received a questionnaire regarding respiratory symptoms and allergic disease. Skin prick tests with eight inhalant allergens were performed. In addition, all children with wheeze over the past 12 months (current wheeze) and a random sample of children without current wheeze were invited to perform hypertonic saline provocation tests. A complete data set was available for 170 children, including 50 with and 120 without current wheeze. Bronchial hyperresponsiveness (BHR) was defined as at least 15% decline in FEV1. The degree of BHR was represented by the response/dose ratio, i.e. the fall in FEV1 divided by total dose of inhaled saline. The severity of asthma symptoms was classified by the number of wheezing episodes over the past 12 months. ‘Asthma ever’ was defined by a combination of symptoms in the questionnaires. Children with ‘asthma ever’ and current wheeze were considered as having current asthma. Current atopic asthma was defined as current asthma with at least one positive skin prick test. The sensitivity of the procedure to detect ‘asthma ever’, current asthma and current atopic asthma was 62, 61 and 83%, and the specificity 83, 81 and 60%, respectively. The positive challenge rate was 52, 34, 13 and 7% among current wheezers, previous wheezers, non-wheezers with a history of allergy and healthy children. The degree of bronchial hyperresponsiveness increased with the number of wheezing episodes. Thus, the median and range of the response/dose ratio were 4.8%/ml (2.1–14.8), 2.6%/ml (0.7–8.6) and 1.3%/ml (0.8–2.7), respectively, for children with ≥ 4 episodes, 1–3 episodes and no wheezing episodes over the past 12 months (p<0.001). In conclusion, hypertonic saline provocation test is useful as a tool to detect asthma in epidemiological studies in children. The degree of bronchial hyperresponsiveness, as represented by the response/dose ratio, reflects the severity of asthma symptoms.

  • 34.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Allergiutveckling hos barn. Går den att förhindra?Del A Sensibilisering i spädbarnsåldern och riskfaktorer.2001In: Vetrinärmötet 2001, ISSN 1402-9324, Vol. 1, p. 103-103Article in journal (Other (popular science, discussion, etc.))
  • 35.
    Nilsson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Risk factors for atopic disease in childhood1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: It is important to assess risk factors for the development of allergic diseases, primarily because these diseases are so common and affect one third of all children in the western world, sometimes with serious manifestations, and also because these diseases have continued to increase over the last few decades.

    Aims: To study the difference between the cumulative incidence of allergic diseases in 7-ycarold children in 1974 and 1994. To ascertain whether a/ urban as opposed to rural living, b/ maternal allergy, cl season of birth, and particularly, dl pertussis vaccination influence the development of allergic diseases.

    Material & methods: Two cross-sectional and two prospective studies were evaluated in regard to allergic diseases and their relation to various risk factors. Diagnoses of allergic diseases were obtained from questionnaires and intensive prospective clinical evaluations. Skin prick tests and analyses of IgE to common allergens and pertussis toxin were performed.

    Results: Allergic diseases increased from 15.1% to 26.1% with a relative risk of 1.7 (95% C.!. 1.4-2.1). The increase was attributed to the children having a heredity of allergic disease. Today, it is more common to have a family member with an allergic disease than not to have allergy in the immediate family. Bronchial asthma and allergic rhinoconjunctivitis in 7-year-old girls increased more than fourfold between 1974 and 1994 but the increase in 7-year-old boys was only 50%.

    Urban as opposed to rural living during the first two years of life was a moderate risk factor for allergic disease up to 13-14 years of age. The risk was particularly high for bronchial asthma with a relative risk of 2.1 (95% C.!. 1.2-3.7) associated with urban living during the first year of life and 2.1 (1.2-3.6) with urban living the second year. The increase in risk remained after adjustment for family history of allergy, gender, environmental tobacco smoking, smoking during pregnancy, pets indoors, damp indoors and living area. Smoking during pregnancy was an independent risk factor for asthma in the child. The two crosssectional studies both showed significant increase (I 0%) in children if the mother had an allergic disease. Allergic diseases were associated with birth during the winter and negatively associated with birth during spring time. The acellular pertussis vaccines did not influence the development of allergy significantly more than the whole cell pertussis vaccines, or placebo (with diphtheria and tetanus only).

    Discussion/Conclusions: The increased risk of allergic disease over the last few decades cannot be explained by genetic factors. The most plausible explanation is that there is some factor or factors that influence children with a genetic pre-disposition to allergy. Differences in microbial exposure and infections are conceivable reasons for the increase and may contribute to the difference seen between urban and rural areas. Other possible causes may be exposure to different adjuvants, e.g. nitrogen dioxide and diesel exhausts.

    The increase in family size in families with an allergic mother, would be a survival advantage of being atopic. This could explain a long-term accumulation but not the dramatic increase during the second half of the 20th century.

    The seasonal effect is moderate. One plausible explanation of the effect in relation to pollen allergy may be that the levels of maternal IgG to inhalants are dependent on the pollen season. However, the seasonal effects of IgE to egg in infancy may be attributable to the indoor environment.

    In spite of the fact that acellular vaccines induced more IgE to pertussis toxin and that the Th2-type cytokines increased more than Thl-type cytokines after acellular pertussis vaccines, these vaccines did not significantly increase the risk of allergic disease in the children. Acellular vaccines are therefore recommended owing to their documented safety as well as effectiveness. All in all, several risk factors for allergic diseases have been found but none of them is strong enough to explain the increase over the last few decades.

  • 36.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Blennow, Margareta
    Sachsska barn- och ungdomssjukhuset, Södersjukhuset (KI SÖS), Stockholm.
    Storsaeter, Jann
    Biverkningsgruppen, Avdelning för Vacciner, Nasjonalt Folkehelseinstitutt i Norge, .
    Lepp, Tiia
    Folkhälsomyndigheten, Östersund.
    Att förebygga kikhosta hos spädbarn: Systematisk litteraturöversikt2015Report (Other academic)
    Abstract [sv]

    Allmän barnvaccination mot kikhosta återinfördes i Sverige 1996 och sedan dess har antalet rapporterade fall av kikhosta minskat dramatiskt. Sjukdomen förekommer dock fortfarande bland ovaccinerade spädbarn och bland ungdomar och vuxna. Den högsta sjukdomsincidensen i Sverige ses bland spädbarn under sex månaders ålder. Kikhosta är en allvarlig och livshotande sjukdom för spädbarn och hårdast drabbas de allra yngsta som inte har fått sin första vaccindos vid tre månaders ålder. Drygt 70 procent av dem som insjuknar behöver sjukhusvård.

    Flera länder har under de senaste åren rapporterat en ökning av kikhostefall i befolkningen och dödsfall på grund av kikhosta hos spädbarn. För att minska sjukdomsbördan hos spädbarnen har rekommendationer i dessa länder innefattat vaccination av vuxna runt det nyfödda barnet (kokongvaccination), vaccination av modern under sista trimestern av graviditeten och vaccination av hälso- och sjukvårdspersonal. Dessutom har man i vissa länder rekommenderat vaccination av vuxna vart tionde år.

    Folkhälsomyndigheten har gjort en systematisk litteraturöversikt med syfte att finna evidens enligt GRADE-metodiken för preventiva strategier som minskar förekomsten av kikhosta hos barn yngre än sex månader. De preventiva strategier som har utvärderats är a) striktare följsamhet till tidpunkten för eller tidigareläggning av första vaccindosen, b) neonatal vaccination, c) kokongvaccination, d) vaccination av gravida, e) vaccination vid 4–7 års ålder, f) vaccination vid 13–19 års ålder, och g) postexpositionsprofylax med antibiotika.

    Litteraturöversikten visar någon grad av evidens för att alla de utvärderade strategierna bidrar till att skydda spädbarn mot kikhosta, förutom tonårsvaccination. Det finns två vårdinsatser som redan stöds av befintliga föreskrifter och rekommendationer men som bör följas mer strikt.

    • Tidpunkten för första vaccindosen har betydelse för skydd mot kikhosta hos spädbarn. Uträkningar från bland annat det svenska uppföljningsprogrammet talar för en väsentlig minskning av kikhosta hos barn under sex månaders ålder om första vaccindosen ges strikt vid angiven tid enligt vaccinationsschemat eller inom två veckor före den tidpunkten.
    • Det är viktigt att vara uppmärksam på hosta i närfamiljen under barnets första levnadsmånader. Frikostig provtagning, snabb diagnostik och behandling kan förhindra dödsfall i kikhosta hos spädbarn. Tidigt insatt postexpositionsprofylax med antibiotika till spädbarn ger ett gott skydd mot klinisk kikhosta.

    Dessutom finns två strategier som ytterligare kan minska förekomsten av kikhosta hos spädbarn under 6 månader:

    • Kokongvaccination
    • Vaccination av gravida.

    Kokongvaccination har i några länder visat effekt vid hög anslutning och kostnadsfri vaccination. Vaccination mot kikhosta under graviditet rekommenderas i flera länder. I England har vaccination av gravida erbjudits i cirka tre års tid i vaccinationsprogram och visat god effekt bland spädbarn till vaccinerade mödrar. Uppföljning av programmet och utvärdering av långtidseffekterna pågår och resultaten publiceras allteftersom.

  • 37.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Allergy Centre UHL.
    Carlsson, Rose-Marie
    Smittskyddsinstitutet, Solna.
    Hallander, Hans Olof
    Konsult.
    Ljungman, Margaretha
    Smittskyddsinstitutet, Solna.
    Hallberg, Mårten
    Centrallasarettet, Västerås.
    Storsaeter, Jann
    GlaxoSmithKline, Solna.
    Bra immunsvar av vaccination mot difteri, stelkramp och kikhosta i årskurs 4: Lokala reaktioner mycket vanliga – och förväntade2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 38, p. 2357-2361Article in journal (Refereed)
    Abstract [sv]

    Acellulärt kikhostevaccin, difterivaccin och stelkrampsvaccin gav bra serologiska svar vid påfyllnadsvaccination vid 10 års ålder. Även skolbarn som aldrig fått kikhostevaccin svarade med antikroppar mot kikhosta efter endast en dos acellulärt kikhostevaccin.

    Lokala biverkningar som ont i armen, rodnad/svullnad och klåda var mycket vanliga, och dessa lokalreaktioner höll i sig vanligtvis 3–4 dagar.

    Större lokala reaktioner om minst fem centimeters rodnad eller svullnad drabbade mellan vart tredje till vart sjätte barn.

    Dessa reaktioner är ofarliga, men det är viktigt att korrekt informera skolelever och föräldrar om vilka vanliga reaktioner som kan förväntas vid påfyllnadsvaccination mot difteri, stelkramp och kikhosta i denna ålder.

  • 38.
    Nilsson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Castor, O
    Löfman, O
    Magnusson, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Kjellman, Max
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Allergic disease in teenagers in relation to urban or rural residence at various stages of childhood.  1999In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 54, p. 716-721Article in journal (Refereed)
  • 39.
    Nilsson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faldella, Giacomo
    Instituto Clinico di Pediatri,a Bologna, Spanien.
    Jacquet, Jeanne-Marie
    GlaxoSmithKline Belgium.
    Storsaeter, Jann
    GlaxoSmithKline Solna, Sverige.
    Silfverdahl, Sven-Arne
    Barnkliniken, Örebro.
    Ekholm, Leif
    BVC, Örebro.
    A fourth dose of DTPa-IPV vaccine given to 4-6 year old children in Italy and Sweden following primary vaccination at 3, 5 and 11-12 months of age2005In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 37, no 3, p. 221-229Article in journal (Refereed)
    Abstract [en]

    Healthy 4-6 y old children from Italy and Sweden immunized with DTPa and inactivated or oral polio vaccines at 3, 5 and 11-12 months of age, received 1 dose of combined DTPa-IPV (n = 211) or DTPa+IPV as separate doses (n = 205) in a randomized trial. The pre-booster seroprotection rates were similar in each group and were above 60% against all antigens except diphtheria (31.3% and 37.0%) and PT (21.5% and 25.9%) in the DTPa-IPV and DTPa+IPV groups, respectively. At least 99.5% of subjects had seroprotective antibody levels against diphtheria, tetanus and polioviruses and ≥96% showed a vaccine response to each pertussis antigen after vaccination. Post-booster antibody levels increased at least 51-fold for anti-diphtheria and anti-tetanus, at least 18-fold for anti-pertussis antibodies and at least 32-fold for antibodies against all 3 poliovirus types, compared to prior levels. DTPa-IPV was comparable to DTPa+IPV in terms of seroprotection rates and mean antibody levels against each vaccine antigen. Similar reactogenicity profiles were observed between groups including swelling >50 mm [13% (9.1, 18.7) vs 17% (12.4, 23.4)] or involving an adjacent joint [0% (-,-) vs 1.5% (0.3, 4.3)] and were consistent with previous reports. The combined DTPa-IPV vaccine could be used to add DTP valences to the IPV vaccine currently given to children in Scandinavia and Italy at 4-6 y of age and reinforce protection against 4 diseases. © 2005 Taylor & Francis.

  • 40.
    Nilsson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Kivling, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Jalmelid, M
    Fälth-Magnusson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Combinations of common chronic paediatric diseases deviate the immune response in diverging directions2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 146, no 3, p. 433-442Article in journal (Refereed)
    Abstract [en]

    The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-γ and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, β-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-γ response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response. © 2006 The Author(s).

  • 41.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Kjellman, N.-I. Max
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Björksten, Bengt
    Center for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Allergic Disease at the Age of 7 Years after Pertussis Vaccination in Infancy: Results from the Follow-up of a Randomized Controlled Trial of 3 Vaccines2003In: Archives of Pediatrics & Adolescent Medicine, ISSN 1072-4710, E-ISSN 1538-3628, Vol. 157, no 12, p. 1184-1189Article in journal (Refereed)
    Abstract [en]

    Objective: To prospectively assess sensitization rates and the development of allergic diseases in a follow-up of a randomized controlled pertussis vaccine trial. Setting: Two-month-old infants were the subject of this double-blind study in 1992 in a collaboration between the Pediatric Clinic and the Primary Care Centers in Linköping. Patients and Intervention: Allergic diseases were evaluated in 667 children, who were randomized to 1 of 4 vaccine groups: a 2-component, a 5-component, or a whole cell pertussis vaccine (all of which were administered with the diphtheria and tetanus toxoids vaccine) and the diphtheria and tetanus toxoids vaccine alone. Allergy development was assessed by questionnaires (n = 667) and skin prick tests (n= 538) at the age of 7 years. Main Outcome Measures: Allergic diseases and skin prick test results at the age of 7 years. Results: The cumulative incidence of allergic diseases was 34.9%, and was similar in the 4 groups (33.3%-37.3%, P =.89), even after adjusting for family history, sex, pets, dampness, environmental smoking at home, and other living conditions. Positive skin prick test results were more prevalent, however, after vaccination with the 2-component acellular vaccine (19.4%) than in the other 3 groups (11.1%-13.5%, adjusted for confounding factors, P=.01). Furthermore, allergic rhino-conjunctivitis was more common in children who were initially immunized with the 2-component pertussis vaccine and received a booster dose with an acellular vaccine compared with those who received no booster vaccination (relative risk, 3.6, 95% confidence interval, 1.1-12.0). Conclusion: Pertussis vaccination in infancy with any of these vaccines was not associated with allergic manifestations at the age of 7 years, apart from a higher prevalence of positive skin prick test results after an experimental 2-component vaccine, which is no longer in use.

  • 42.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Allergy Centre UHL.
    Lepp, Tiia
    Swedish Institute Communicable Disease Control.
    von Segebaden, Kerstin
    Swedish Institute Communicable Disease Control.
    Hallander, Hans
    Swedish Institute Communicable Disease Control.
    Gustafsson, Lennart
    Swedish Institute Communicable Disease Control.
    Pertussis vaccination in infancy lowers the incidence of pertussis disease and the rate of hospitalisation after one and two doses: Analyses of 10 years of pertussis surveillance2012In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, no 21, p. 3239-3247Article in journal (Refereed)
    Abstract [en]

    Objectives: Shortly after pertussis vaccination was reintroduced in Sweden in 1996, an intensified pertussis disease surveillance programme was set up. In this study, we report on in-depth analyses of age-dose-number-specific incidences and the rate of pertussis hospitalisation for children with no, 1 or 2 doses of an acellular pertussis vaccine before pertussis disease. Vaccine coverage, the timeliness of childhood vaccination and the effect of later than scheduled pertussis vaccination(s) are also examined. less thanbrgreater than less thanbrgreater thanStudy design: Children with notified laboratory-confirmed (culture or PCR) pertussis disease were evaluated among the surveillance population of about 1 million infants, born between 1996 and 2007 and followed for pertussis disease from October 1997 to December 2007, for nearly 6 million person-years. Birth and vaccination dates of the diseased children are known from the surveillance programme. To estimate denominators of the age-dose-number-specific pertussis incidences, we used birth and vaccination dates from a vaccine trial with more than 72,000 infants combined with national pertussis vaccine coverage data for children in the surveillance population. less thanbrgreater than less thanbrgreater thanResults: For infants from 3 to andlt;5 months of age, the incidence of pertussis disease with at least 14 days of cough decreased from 264/100,000 for unvaccinated infants to 155/100,000 for infants with one dose of a pertussis vaccine prior to onset of the disease. In the age range 5 to andlt;12 months, the age-dose specific incidences were 526, 95, and 24/100,000 for infants with no, 1 and 2 doses, respectively. The rate of hospitalisation for infants with 1 dose of a pertussis vaccine prior to onset of the disease was significantly lower than for unvaccinated infants of the same age. less thanbrgreater than less thanbrgreater thanFor many infants, there is a delay in administration of the vaccine doses according to the regular 3-5-12 month schedule (which has been the case for many years). Hypothetically, if all infants had been vaccinated exactly on schedule, we would expect about 28% fewer pertussis cases with at least 14 days of cough and 38% fewer hospitalisations due to pertussis, of cases possible to influence by vaccinations on schedule. less thanbrgreater than less thanbrgreater thanConclusion: Pertussis vaccination had a significant effect among infants already after the first dose. This is particularly important for premature infants and infants with severe respiratory and cardiac diseases. A moderate decrease in the incidence of pertussis disease in infants and rate of hospitalisation could be expected if primary vaccinations were carried out closer to the scheduled time than is currently the practice in Sweden.

  • 43.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Regnström, Karin J.
    School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA.
    Pharmacogenomics in the Evaluation of Efficacy and Adverse Events During Clinical Development of Vaccines2008In: Pharmacogenomics in Drug Discovery and Development: From Bench to Bedside / [ed] Yan, Qing, New York, NY, United States: Humana Press, 2008, 1, p. 469-479Chapter in book (Other academic)
    Abstract [en]

    The field of pharmacogenomics arose to develop personalized medicine, or medicine that deals with the complexity of the human body. In this book, leading experts present methodical, state-of-the-art contributions covering topics from individual molecules to systemic diseases, examining both fundamental concepts and advanced technologies. The volume begins by exploring cutting-edge technologies used to pursue systems-based pharmacogenomics, followed by extensive chapters on gene-drug interactions and the use of pharmacogenomics in therapeutics of diseases. This book is ideal for scientists striving to transform disease treatment into disease prevention.

  • 44.
    Nilsson, Lennart
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Von Segebaden, Kerstin
    Blennow, Margareta
    Linde, Annika
    Uhnoo, Ingrid
    [Whooping cough is a risk to infants. The disease is circulating among adolescents and adults].2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 37, p. 1599-1602Article in journal (Refereed)
  • 45.
    Regnström, K.J.
    et al.
    School of Pharmacy, University of Connecticut, Storrs, CT, USA.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Pharmacogenomics in the evaluation of efficacy and adverse events during clinical development of vaccines2008In: Pharmacogenomics in Drug Discovery and Development: From Bench to Bedside / [ed] Qing Yan, Humana Press, 2008, Vol. 448, p. 469-479Chapter in book (Other academic)
    Abstract [en]

    The understanding of vaccine-induced immune responses in adults and infants is limited. Current vaccination schedules for infants are frequently debated. Especially, the relationship among the timing, the frequency of the dosing, and the generation of an immunological memory are debated. Vaccine antigen-induced cytokine responses to vaccinations given in infancy are of particular interest because little is known about cellular responses in this age, and the information available is based on antibody responses. Pharmacogenomics is ideally suited to study cellular responses related to immune response, in addition, toxicity, inflammation, apoptosis, stress, and oncogenesis can be monitored, since the expression of thousands of genes can be measured in a single experiment. © 2008 Humana Press, a part of Springer Science + Business Media, LLC.

  • 46. Ryan, EJ
    et al.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Kjellman, N-IM
    Gothefors, L
    Mills, KHG
    Booster immunization of children with an acellular pertussis vaccine enhances Th2 cytokine production and serum IgE responses against pertussis toxin but not against common allergens2000In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 121, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    Acellular pertussis vaccines (Pa) protect against severe pertussis in children. However, serum antibody responses decline quickly after immunization. Studies in animal models suggest that cell-mediated immunity also contributes to protection against Bordetella pertussis, and it has already been demonstrated that Pa induce T cells that secrete type-1 and type-2 cytokines in children. In this study we examined the persistence of the T cell response and the effect of booster immunization in 4-6-year-old children. Cell-mediated immunity to B. pertussis antigens was detected in a high proportion of children more than 42 months after their last immunization. Peripheral blood mononuclear cells (PBMC) from the majority of children secreted interferon-gamma (IFN-?) and a smaller proportion IL-5, in response to specific antigen stimulation in vitro. However, following booster immunization, significantly higher concentrations of IL-5, but not IFN-?, were produced by PBMC in response to B. pertussis antigens. Furthermore, plasma IL-4 and IL-5 concentrations were increased, whereas IFN-? concentrations were reduced following booster immunization. It has been suggested that childhood immunization with Th2-inducing vaccines may predispose some children to atopic disease. Although we found that pertussis toxin (PT)-specific IgE was significantly increased after booster immunization in both atopic and non-atopic children, the levels of IgE to common allergens and the prevalence of positive skin prick test were unaffected by the booster vaccination. Thus, despite the enhancement of type-2 responses to B. pertussis antigens, booster vaccination with Pa does not appear to be a risk factor for allergy.

  • 47.
    Sandberg, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Frykman, Anne
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Cord blood cytokines and chemokines and development of allergic disease2009In: PEDIATRIC ALLERGY AND IMMUNOLOGY, ISSN 0905-6157, Vol. 20, no 6, p. 519-527Article in journal (Refereed)
    Abstract [en]

    Exposure to ubiquitous allergens early in life, even before birth, may influence the incidence of allergic diseases later in life. During pregnancy, the fetomaternal interface is surrounded by high levels of T-helper (Th)2-like cytokines, possibly favouring the development of Th2-like immune responses in the offspring. The aim of this study was to evaluate the relation between cord blood (CB) IgE antibodies, Th1- and Th2-like cytokines and chemokines, maternal allergy and development of allergic disease during the first 2 yr of life in the offspring. The CB cytokine and chemokine levels from children of 20 allergic and 36 non-allergic women were determined by a multiplexed Luminex assay and ELISA. Total CB and maternal IgE antibody concentrations were quantified using ImmunoCAP technology. The maternal IgE levels during and after pregnancy correlated with CB IgE and Th2-associated macrophage-derived chemokine [MDC (CCL22)] levels. Development of allergic disease and sensitization was associated with increased CB IgE and MDC (CCL22) levels, as well as high ratios of MDC (CCL22) to Th1-associated interferon-gamma inducible protein 10 [IP-10 (CXCL10)] and interferon-gamma inducible T-cell alpha-chemoattractant [I-TAC (CXCL11) (n = 7 allergic vs. n = 25 non-allergic)]. The correlations between maternal IgE and CB IgE and MDC (CCL22) levels possibly indicate that the maternal immunity can affect the Th1/Th2 profile in the neonate. Development of allergic disease is associated with a more marked Th2-like deviation already at birth, shown as increased levels of CB IgE and MDC (CCL22) and higher ratios of MDC (CCL22) to IP-10 (CXCL10) and I-TAC (CXCL11).

  • 48.
    Sandin, Anna
    et al.
    Barnkliniken, Umeå lasarett.
    Annus, T
    Tartu University Childrens Hospital, Tartu, Estonia.
    Björkstén, Bengt
    Institute of Environment, Karolinska Institute, Stockholm.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Riikjärv, M-A
    Tallin Childrens Hospital, Tallin, Estonia.
    van Hage-Hamsten, M
    Medicinkliniken, Klinisk immunologi och allergi, Karolinska institutet, Stockholm.
    Bråbäck, Lennart
    Dept of Public Health and Research, Sundsvall.
    Prevalence of self-reported food allergy and IgE antibodies to food allergens in Swedish and Estonian schoolchildren2005In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 59, no 3, p. 399-403Article in journal (Refereed)
    Abstract [en]

    Objective: To compare the prevalence of self-reported food allergy and IgE antibodies to food allergens in wheezing and non-wheezing Estonian and Swedish schoolchildren, in the light of the disparities in the standard of living, food consumption and prevalence of respiratory allergies that still exist between Estonia and the Scandinavian countries. Design and setting: As a part of the ISAAC Phase II study, children from a random sample of schools in Tallinn in Estonia and Linköping and Östersund in Sweden participated in skin prick tests to inhalant allergens and the parents replied to questionnaires. IgE antibodies against a panel of food allergens (egg white, milk, soy bean, fish, wheat and peanut) were taken from children with questionnaire-reported wheezing and a random sample of nonwheezing children. Subjects: Children aged 10-11 y. Results: The prevalence of self-reported food allergy was similar in Estonia and Sweden and about twice as high in wheezing children than in nonwheezing children. In Estonia, however, 3% of the children with perceived food allergy reported reactions from at least four different foods, as compared to 31% in Sweden. The prevalence of sensitisation to food allergens was similar in wheezing and nonwheezing children in Estonia (8%) while, in Swedish children, IgE antibodies to food allergens were more likely among wheezing children (Linköping 38 vs 11%, crude OR 5.1, 95% CI 2.2-11.6, and Östersund 24 vs 7%, crude OR 4.1, 95% CI 1.9-8.5). Conclusion: Our study suggests that IgE-mediated food reactions were less likely in Estonian schoolchildren. Moreover, the perception of food allergy and thereby the meaning of self-reported food allergy appears to be different in the two countries. © 2005 Nature Publishing Group. All rights reserved.

  • 49.
    Silfverdal, Sven-Arne
    et al.
    Umea University.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    Blennow, Margareta
    Stockholm S General Hospital.
    Carlsson, Rose-Marie
    Swedish Armed Forces.
    Hanson, Lars A
    Gothenburg University.
    Lindberg, Anders
    County Council Halland.
    Lindquist, Lars
    Karolinska University Hospital.
    Magnusson, Margaretha
    Uppsala Akademic Hospital.
    Norlund, Anders
    Karolinska Institute.
    Nyren, Olof
    Karolinska Institute.
    Olcen, Per
    Orebro University Hospital.
    Olin, Patrick
    Swedish Institute Infectious Disease.
    Sawe, Juliette
    Swedish Council Technology Assessment Health Care.
    Soderstrom, Ann
    Department Communicable Disease Control, Gothenburg.
    Trollfors, Birger
    Sahlgrenska University Hospital .
    Ortqvist, Ake
    Karolinska Institute.
    Vaccination of children - summary and conclusions from a systematic reviewThe full review can be found in Acta Paediatrica 2010; 99: s4612010In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 99, no 9, p. 1287-1289Article in journal (Other academic)
  • 50.
    Synnerstad, Ingrid
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Fredrikson, Mats
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine.
    Rosdahl, Inger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of dermatology and venereology. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Fewer melanocytic nevi found in children with active atopic dermatitis than in children without dermatitis2004In: Archives of Dermatology, ISSN 0003-987X, Vol. 140, no 12, p. 1471-1475Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the effects of atopic diseases on nevus development during childhood. Design: A descriptive survey of nevi in a cohort of 8- and 9-year-old children combining a skin examination and a validated questionnaire regarding atopic dermatitis, allergic rhinoconjunctivitis, and bronchial asthma. Setting: Fifty-one primary schools in Sweden. Participants: A total of 788 children born in 1992 participated in 1999 in a prevalence study of allergic diseases. The present study was restricted to the 545 children from that study who were still living in the community, and 515 (94%) of them participated. The cumulative incidence of atopic dermatitis, allergic rhino-conjunctivitis, and bronchial asthma was 24%, 12%, and 13%, respectively, from birth to age 7 years as reported by questionnaire, 3% reported all 3 diagnoses. Results: Children with reported atopic dermatitis and findings of active dermatitis on examination had fewer nevi (median, 4, mean, 7.4) than children with no reported atopic disease and no active dermatitis found on examination (median, 9, mean, 11.2) (P<.001). Children who developed active atopic dermatitis after the questionnaire was filled out (ie, during the last 2 years) had fewer nevi than children with no atopic disease (median, 3, mean, 5.3) (P<.001). There was no difference in nevus number between the children with bronchial asthma or allergic rhinoconjunctivitis and children with no atopic disease. Conclusion: Children with atopic dermatitis had few melanocytic nevi, which suggests that the proinflammatory cytokine network in the atopic skin might inhibit melanocyte growth and/or progression to nevi.

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