Transcript Viral Respiratory Infections

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


Research Interests


NHLBI
Financial Interests


Washington University School of Medicine
None
Chair, Pediatric Adjudication Committee, GSK
study of safety and benefit of FP/salmeterol
vs. FP
Role of viral infection in asthma:
The Paradigm
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
The Paradigm:
The role of vitamin D deficiency
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
The Paradigm:
The role of vitamin D deficiency
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
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
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
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
2.5
2
1.5
respiratory infection
OR
any infection
1
0.5
0
>75
25-74
<25
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 9 + 9 vs. controls 16 + 13, 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
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
Vitamin D deficiency and viral
infection-induced exacerbations
• Higher levels associated with decrease
markers of allergy and asthma severity
0.25
P=0.20
0.2
P=0.004
0.15
P=0.05
OR
0.1
P=0.03
0.05
0
ICS or LM
ICS or LM
PD20
Hosp
Brehm et al. AJRCCM 2009;179:765
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
Exacerbation
No
Yes
Percentage
OR (95% CI)
ICS, D suff
162
52
24
1.0 (reference)
ICS, D insuff
58
31
35
1.7 (1.0-2.9)
No ICS, D suff
289
158
35
1.7 (1.2-2.5)
No ICS, D insuff 166
105
39
2.0 (1.3-2.0)
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
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation,
Decreased lung
function
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
RV – rhinovirus
RSV – resp syn virus
PIV – para influenza virus
Flu – influenza A and B
CV – coronovirus
MPV – metapneumo virus
AdV – adenovirus
EnV – enterovirus
Jackson et al. AJRCCM 2008;178:667
The Paradigm
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation
Decreased lung
function
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
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Number of episodes
Viral Detection During 292
Respiratory Episodes
Picornavirus = Rhinovirus or enterovirus
Johnson et al. BMJ 1995;310:1225
The Paradigm
Recurrent wheeze,
Incident asthma
Young children
Viral
infection
Present asthma
Exacerbation
Decreased lung
function
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