Viral Respiratory Infections and asthma: How does vitamin D deficiency interact? Robert C. Strunk, MD Strominger Professor of Pediatrics Washington University School of Medicine St. Louis Children’s Hospital Division of Allergy, Immunology, and Pulmonary Medicine

Disclosures Employment Washington University School of Medicine Research Interests NHLBI Financial Interests None Chair, Pediatric Adjudication Committee, GSK study of safety and benefit of FP/salmeterol vs. FP

Role of viral infection in asthma: The Paradigm Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

The Paradigm: The role of vitamin D deficiency Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

The Paradigm: The role of vitamin D deficiency Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

Vitamin D deficiency and incidence of viral infection “Rachitic Lung”: children with rickets have more respiratory infections – Lung abnormalities included: lobar atelectasis, interstitial pneumonitis, pulmonary edema with cardiomegaly – Respiratory infections increased in children with “sub-clinical rickets” Khajavi and Amirhakimi Clin Ped 1977;16:1 Rehman J Trop Pediatr 1994;40:58

Vitamin D deficiency and incidence of viral infection “Rachitic Lung”: children with rickets have more respiratory infections Data from NHANES – Rate of URTI varied by vit D level Ginde et al. Arch Inern Med 2009;169:384

Vitamin D deficiency and incidence of viral infection “Rachitic Lung”: children with rickets have more respiratory infections Data from NHANES Seasonal variation of symptomatic respiratory infections, particularly influenza A epidemics.

Season and Influenza A: Do vitamin D levels play a role? Review by Cannell et al. Epidemiol Infect 2006;134:1129

What is the level of proof that vitamin D sufficiency would be protective? Increased rate of respiratory infectins in non-rachitic children with vit D deficiency returned to control levels after 6 weeks of high dose vit D RCT in 334 school children in Japan – Intervention group: 1200 IU/d, control 200 IU/d – Outcome of Inf A infection Intervention 18/167, 10.8% Placebo 31/167, 18.6% RR of 0.36 (p=0.006) Rehman J Tropical Pediatrics 1994 Urashima et al. Am J Clin Nutr 2010;91:1255

What is the level of proof that vitamin D sufficiency would be protective? Secondary outcome of a trial for bone loss – Women in intervention group (2,000 IU/d) had fewer respiratory infections than in control group: 7.7% vs. 25.0% Aloia and Li-Ng Correspondence to Epidemiol Infect 2007;135:1095

What is the level of proof that vitamin D sufficiency would be protective? Summary of evidence for protective effect – Letter by Rehman (J Tropical Pediatrics 1994) – School children in Japan, N=334 – Secondary outcome of a trial for bone loss RCTs need to be done

Mechanisms by which vitamin D decreases viral infection Limits production of pro-inflammatory cytokines, suppressing inflammation Increases factors that inactivate viral pathogens: e.g., cathelicidin, beta-defensin Primary airway epithelium generate active D that decreases inflammatory response to viral infection Enhances T regulatory cell suppression Hansdorrir et al. J Immunol 2008;181:7090 Hansdorrir et al. J Immunol 2010;184:965

The Paradigm: The role of vitamin D deficiency Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

Vitamin D levels and incidence of viral infection in young children Cord-blood levels associated with resp infection – Lower levels associated with higher risk of resp infection by 3 months of age after adjusting for season of birth OR 25(OH)D concentration, nmol/L Camargo et al. Pediatrics 2011;127:e180

Vitamin D levels and incidence of viral infection in young children Cord-blood levels associated with resp infection Low levels associated with increased probability of a viral co-infection (more than 1 concurrent viral infection Most notable for RSV and RV Deficient Camargo et al. JACI 2010;126:1074

Are vitamin D levels associated with severity of viral infections in young children? Pro – Case control study of 15 newborns with LRTI admitted to NICU 15 healthy controls matched for GA, birth weight, age, gender Levels in LRTI group vs. controls , p=0.012 Plus/minus – Deficiency noted in bronchiolitis only in those admitted to ICU, not to general pediatric ward vs. well controls Con – Maternal D evel not assciated with infant bronchiolitis score Karatekin et al. Eur J Clin Nutrution 2009;63:473 McNally et al. Ped Pulm 2009;44:981 Carroll et al. AJOG 2011;215:e1

The Paradigm: The role of vitamin D deficiency Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

Vitamin D deficiency and viral infection-induced exacerbations Higher levels associated with decrease markers of allergy and asthma severity Brehm et al. AJRCCM 2009;179:765 P=0.20 P=0.004 P=0.05 P=0.03

Vitamin D deficiency and viral infection-induced exacerbations Lower levels associated with increase markers of allergy and asthma severity Insufficient levels associated with risk of severe exacerbation, particularly when not on ICS

Brehm et al. JACI 2010;126:52

Risk of exacerbation over 4 years increased by a combination of ICS use and vit D status ExacerbationNoYesPercentageOR (95% CI) ICS, D suff (reference) ICS, D insuff ( ) No ICS, D suff ( ) No ICS, D insuff ( ) Brehm et al. JACI 2010;126:52

Conclusions Viral infections play a prominent role in: – Affecting asthma incidence in young children Prominent role of rhinovirus – Precipitating asthma exacerbations – Leading to loss of lung function Vitamin D deficiency associated with: – Increased rate of infections overall, particularly viral respiratory and in young children – Increased pro-inflammatory cytokines and decreased factors for viral inactivation on airway epithelium – Increased markers of allergy and asthma severity, and exacerbations Need for RCTs to document improvement in outcomes with vit D supplementation

Ancillary slides Evidence for viral infections: – Affecting asthma incidence in young children Prominent role of rhinovirus – Precipitating asthma exacerbations – Leading to loss of lung function

The Paradigm Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation, Decreased lung function Present asthma

Viral infection and asthma incidence RSV bronchiolitis liked to development of wheeze and asthma at age 5 years – Related to episode severity – Interaction with family history of asthma Rhinovirus (RV) plays a role more important than RSV – OR for development of asthma 2.6 for RSV 9.8 for RV – Improvement in detection via molecular techniques allowed determination of role for RV

Carroll et al. JACI 2009;123:1055

RSV bronchiolitis and asthma outcome: Role of family history Sigurs et al. Thorax 2010; 65:1045

Role of viral infection early in life on asthma development Risk of asthma at age 6 years in children who wheezed during the first 3 years of life with rhinovirus (RV), respiratory syncytial virus (RSV), or both (*P, 0.05 vs. Neither; +P, 0.05 vs. RSV only). OR = odds ratio. Jackson et al. AJRCCM 2008;178:667

Viruses that exacerbate asthma by year of age, by asthma outcome Jackson et al. AJRCCM 2008;178:667 RV – rhinovirus RSV – resp syn virus PIV – para influenza virus Flu – influenza A and B CV – coronovirus MPV – metapneumo virus AdV – adenovirus EnV – enterovirus

The Paradigm Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation Decreased lung function Present asthma

Viruses Trigger Most Asthma Exacerbations in Children Viruses were detected in: – 80% of reported episodes of reduced peak expiratory flow – 80% of reported episodes of wheeze – 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow Johnson SL et al. BMJ 1995;310:1225

Viral Detection During 292 Respiratory Episodes Picornavirus = Rhinovirus or enterovirus Johnson et al. BMJ 1995;310:1225

The Paradigm Viral infection Recurrent wheeze, Incident asthma Young children Exacerbation Decreased lung function Present asthma

Viral infection and decrease in lung function Severe exacerbations (severe asthma-related event, SARE) are associated with decline in lung function – Protective effect of regular ICS use – Direct link to virus as inducing exacerbations not studied, but feasible O’Byrne et al. AJRCCM 2009;179:18

Viral infection and decrease in lung function Severe exacerbations are associated with decline in lung function Decreased lung function after preschool wheezing RV, but not RSV, illnesses Guilbert et al. JACI 2011;128:532