TITOLO RELAZIONE Vitamina D ed infezioni respiratorie ricorrenti. DOCENTE Prof. Peroni Diego

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1 TITOLO RELAZIONE Vitamina D ed infezioni respiratorie ricorrenti DOCENTE Prof. Peroni Diego

2 Ruolo dell'ipovitaminosi D nelle infezioni respiratorie Diego Peroni U.O. Pediatria Università di Pisa Le basi immunologiche L associazione La supplementazione Le conclusioni diego.peroni@unipi.it

3 Multiple Functions of Vitamin D The vitamin D receptor (VDR), the nuclear hormone receptor that mediates most if not all of the functions of its preferred ligand 1,25 dihydroxyvitamin D [1,25(OH)2D] or calcitriol, is found in most tissues of the body. Indeed, many of these tissues also contain the enzyme, CYP27B1, which converts the major circulating metabolite of vitamin D, 25 hydroxyvitamin D (25OHD calcidiol), to 1,25(OH)2D (calcitriol). Thus, it has been suspected for some time that vitamin D exerts its actions not only on classic tissues regulating calcium homeostasis such as bone, gut and kidney but also on other tissues.

4 Overview of vitamin D and its interactions with cells of the immune system. Muehleisen B, JACI 2013;131:324-9.

5 Vitamin D and immune system. 1α,25(OH)2D appears to influence susceptibility to and severity of infection via multiple mechanisms via the innate and adaptive immune system. Gröber U, Dermatoendocrinol. 2013;5:331-47

6 Ruolo dell'ipovitaminosi D nelle infezioni respiratorie Diego Peroni U.O. Pediatria Università di Pisa Le basi immunologiche L associazione con: Le infezioni Wheezing e asma La supplementazione Le conclusioni diego.peroni@unipi.it

7 Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Vitamin D levels in participants 12 years in the Third National Health and Nutrition Examination Survey in the USA; Ginde AA Arch Intern Med. 2009;169: % patients with recent URTI 24% OR= % OR=1.24 P <0.001 for trend 17% OR=1.0 Symptoms suggestive of an URTI in the preceding few days. 0 < <30 25(OH)D level ng/ml 30

8 Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Ginde AA Arch Intern Med. 2009;169:384 Vitamin The D association levels in between participants 25(OH)D 12 level years and in the URTI seemed Third National to be stronger Health in individuals and Nutrition with asthma Examination (OR,5.67) Survey and in chronic the USA; obstructive Symptoms pulmonary suggestive disease of an (OR,2.26). URTI in the preceding few days % patients with recent URTI 24% OR= % OR=1.24 < <30 25(OH)D level ng/ml P <0.001 for trend 17% OR=1.0 30

9 Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection. JL Hurwitz, J Pediatr 2017;187:323 VAD and VDD were commonly detected among children aged <5 years in Memphis hospitalized with LRTI and RSV and/or hmpv detection. Low vitamin levels were correlated with severe disease, supporting the continued evaluation of both vitamin A and D levels in US children

10 Vitamin D status is associated with treatment failure and duration of illness in Nepalese children with severe pneumonia. Haugen J, Ped Res 2017 Our findings indicate that low vitamin D status (25(OH)Do50 nmol/l) is an independent risk factor for treatment failure and delayed recovery from severe lower respiratory infections in children

11 Ruolo dell'ipovitaminosi D nelle infezioni respiratorie Diego Peroni U.O. Pediatria Università di Pisa Le basi immunologiche L associazione con: Le infezioni Wheezing e asma La supplementazione Le conclusioni diego.peroni@unipi.it

12 Low cord-serum 25-hydroxyvitamin D levels are associated with poor lung function performance and increased respiratory infection in infancy. Shen-Hao Lai. 2017, PLoS ONE 12(3):e mother-infant pairs were enrolled Maternal and cord blood were collected for determining the 25(OH)D level. Questionnaires were recorded at birth and 6 months of age. Infant lung function, including tidal breathing analysis, respiratory mechanics, and forced tidal expiration, was tested at 6 months of age Infants with low cord serum 25(OH)D levels have poorer lung function at 6 months of age compared with those with high levels. They also have a higher risk of a respiratory tract infection before this age.

13 Serum Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa Rica Brehm Am J Respir Crit Care Med 2009;179: hydroxyvitamin D levels 616 asthmatic children Vitamin D levels deficient (<20 ng/ml), insufficient ( 20 and <30 ng/ml), and sufficient ( 30 ng/ml) Vitamin D levels were significantly and inversely associated with: 1) total IgE and eosinophil count 2) any hospitalization in the previous year (p=0.03), 3) any use of anti-inflammatory medications in the previous year (p=0.01), 4) increased airway responsiveness (p = 0.05).

14 Vitamin D Serum Levels and Markers of Asthma Control in Italian Children Chinellato J Pediatr 2011;158:437 p= asthmatic children p= hydroxyvitamin D Spirometry asthma control, according to GINA guidelines and with Childhood Asthma Control Test

15 Vitamin D over the first decade and susceptibility to childhood allergy and asthma. Hollams, JACI; 2017;139:472 Asthma-, allergy-, and respiratory tract infection associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years. Relationships with clinical outcomes

16 Vitamin D over the first decade and susceptibility to childhood allergy and asthma. Hollams, JACI; 2017;139:472 Asthma-, allergy-, and respiratory tract infection associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years. Relationships with clinical outcomes

17 Vitamin D over the first decade and susceptibility to childhood allergy and asthma. Hollams, JACI; 2017;139:472 Asthma-, allergy-, and respiratory tract infection associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years. Relationships with clinical outcomes

18 Vitamin D status through the first 10 years of life: A vital piece of the puzzle in asthma inception. Litonjua A, J Allergy Clin Immunol 2017;139:459 Adequate vitamin D status prenatally and throughout childhood in the prevention of asthma and allergies. FVC, Forced vital capacity.

19 Ruolo dell'ipovitaminosi D nelle infezioni respiratorie Diego Peroni U.O. Pediatria Università di Pisa Le basi immunologiche L associazione La supplementazione nella terapia Le conclusioni diego.peroni@unipi.it

20 Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia Camargo, Pediatrics 2012;130(3):e children who were assigned to daily ingestion of unfortified regular milk (control; n = 104) or milk fortified with 300 IU of vitamin D (n = 143) (Jan-March); number of parent-reported ARIs over the past 3 months. At baseline, the median serum 25(OH)D level was 7 ng/ml; The median 25(OH)D levels of children in the control versus vitamin D groups was significantly different (7 vs 19 ng/ml; P <.001);

21 Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia Camargo, Pediatrics 2012;130(3):e561-7 Vitamin D 247 children who were assigned to daily ingestion supplementation of unfortified regular milk (control; n = 104) or milk fortified with 300 IU of vitamin D (n = 143) (Jan- March); significantly reduced the risk of ARIs in number of parent-reported ARIs over the past 3 winter months. among Mongolian children with vitamin D deficiency. Compared with controls, children receiving vitamin D reported significantly fewer ARIs during the study period with rate ratio of 0.52 (95% confidence interval: ).

22 Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Manaseki-Holland, Lancet 2012;379:1419 Incidence of pneumonia (n per child per yr) 3046 children (1-11 mo); 1524 children Vitamin D IU); 1522 children placebo; (oral Administration once every 3 mo for 18 mo Vitamin D 3 n.s. Placebo

23 Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Urashima M, Am J Clin Nutr 2010;91: Vitamin D(3) supplements (1200 IU/d) (n= 167) with placebo (n= 167) in schoolchildren From December 2008 through March 2009 incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen RR for asthma attacks 0.17 P=0.006 in asthmatic children who had been vitamin D supplemented

24 Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. Bergman P, PLoS One 2013; 8:e65835 meta-analysis of 11 placebo-controlled studies 5660 patients included OR for respiratory tract infection P=0.01 daily doses vs bolus doses vitamin D supplemented in

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26 Yakoob MY, Salam RA, Khan FR, Bhutta ZA Authors conclusions: Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.

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28 Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Martineau AR, BMJ 2017;356:i6583

29 We think that they should be viewed as hypothesis generating only, requiring confirmation in well designed adequately powered randomised controlled trials. Several very large such randomised controlled trials of vitamin D supplements will report on the effects on respiratory infections within the next few years. These trials have not targeted individuals with very low serum concentrations of vitamin D, and there is still a need for trials in these population groups.

30 We think that they Should should these be viewed results as hypothesis generating only, requiring confirmation in well designed adequately powered randomised controlled change trials. clinical practice? Probably not. The results are heterogeneous Several very large such randomised controlled trials of vitamin D supplements will and report not on sufficiently the effects on respiratory infections within the next few years. applicable to the general population. These trials have not targeted individuals with very low serum concentrations of vitamin D, and there is still a need for trials in these population groups.

31 But..

32 Martineau added, Influenza vaccination programmes are motivated by the principle that, when a disease is common, even minor reductions in incidence can have significant public health benefits; vitamin D fortification programmes might well be motivated by the same principle, particularly given that ARI is a major cause of industrial absenteeism, health service use, and antibiotic prescribing. We acknowledge that the general population may not be motivated to take supplements this is why we highlight the importance of food fortification as an effective way to boost vitamin D status at a population level.

33 Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. Majak P, J Allergy Clin Immunol 2011;127: children (5-18 yrs) with newly diagnosed asthma and sensitive only to house dust mites budesonide 800 µg/d administered as a dry powder and vitamin D placebo (steroid group, n = 24), or budesonide 800 µg/d and vitamin D3-500 IU (steroid + vit D group n=24). Follow-up: 6 months

34 Improved control of childhood asthma with low-dose, short-term vitamin D supplementation: a randomized, double-blind, placebocontrolled trial. Tachimoto, Allergy placebo-controlled trial comparing vitamin D3 supplements (800 IU/day) with placebo for 2 months in schoolchildren with asthma. The primary outcomes were frequency and severity by GINA. Schoolchildren received vitamin D (n = 54) or placebo (n = 35).

35 Improved control of childhood asthma with low-dose, short-term vitamin D supplementation: a randomized, double-blind, placebocontrolled trial. Tachimoto, Allergy placebo-controlled trial comparing vitamin D3 supplements (800 IU/day) with placebo for 2 months in schoolchildren with asthma. The primary outcomes were frequency and severity by GINA. Schoolchildren received vitamin D (n = 54) or placebo (n = 35). Low-dose, short-term vitamin D supplementation in addition to standard treatment may improve levels of asthma control in schoolchildren.

36 Vitamin D Supplementation Reduces Airway Hyperresponsiveness and Allergic Airway Inflammation in a Murine Model. Agrawal, CEA 2013; 43:672 Mice were fed with VD-deficient or VD-sufficient (2,000 IU/kg) or VD-supplemented (10,000 IU/kg) diet for 13 weeks. Mice sensitized and challenged with ovalbumin. Effect of VD on lung histology, AHR, Tregulatory cells and BALF cytokines Lung histological examination: Hematoxylin and eosin showing differences in the airway remodeling

37 Ruolo dell'ipovitaminosi D nelle infezioni respiratorie Diego Peroni U.O. Pediatria Università di Pisa Le basi immunologiche L associazione La supplementazione Le conclusioni diego.peroni@unipi.it

38 Vitamin D levels optimal for overall health. The lower defined threshold value for bone health (25OHD 20 ng/ml [50 nmol/l]), Holick MF, J Clin Endocrinol Metab 2011;96: Rosen CJ, J Clin Endocrinol Metab 2012;97: Serum level of 25OHD ng/ml ( nmol/l) has been suggested as a lower threshold of an optimal serum level for the immune effects of vitamin D. Vieth R, Am J Clin Nut 2007;85: Bischoff-Ferrari HA, Am J Clin Nut 2006; 84: More than one-third of the population worldwide may have levels of vitamin D < 20 ng/ml (50 nmol/l). Hilger J. British J Nut 2014;111:23 45.