1.
Risks for infection in patients with asthma
(or other atopic conditions)
: Is asthma more than a chronic airway disease?
Young J. Juhn, MD, MPH
J ALLERGY CLIN IMMUNOL, VOL 134, NUMBER 2, AUGUST 2014
Presented by.. Suvanee Charoenlap , MD.

2.
Objective of this review
1. To provide examples of specific immune
dysfunction that might contribute to increased risk of
infection in patients with asthma.
2. To recognize asthma of all severities as a risk factor
for respiratory and nonrespiratory tract infections.

3.
The prevalence of
asthma, allergic rhinitis and atopic dermatitis
Adult Children
Asthma 4.3 – 8.6% 1 2.8 – 37% 2
Allergic rhinitis 7 – 24% 5-8 2 – 45% 2
Atopic dermatitis 8 – 18% 4 1 – 22% 2,3
1. To T, et al. BMC Public Health 2012;12:204.
2. Asher MI, et al. Lancet 2006;368:733-43.
3. Joseph AO,et al. J Allergy Clin Immunol 2009;124:1251-8.e23.
4. Vartiainen E, et al. J Allergy Clin Immunol 2002;109:643-8.
5. Zhang Y, et al. Allergy Asthma Immunol Res 2014;6:105-13.
8. Meltzer EO, et al. Allergy Asthma Proc 2012;33(suppl 1):S113-41.

4.
Worldwide time trends in the prevalence of
symptoms of asthma, allergic rhinoconjunctivitis,
and eczema in childhood: ISAAC Phases One and
Three repeat multicountry cross-sectional surveys

5.
World map showing direction of change in prevalence of
asthma symptoms for 6–7 year age-group
M Innes Asher, et al. Lancet 2006; 368: 733–43

6.
World map showing direction of change in prevalence of
asthma symptoms 13–14 year age-group
M Innes Asher, et al. Lancet 2006; 368: 733–43

7.
World map showing direction of change in prevalence of
allergic rhinoconjunctivitis symptoms for 6–7 year age-group
M Innes Asher, et al. Lancet 2006; 368: 733–43

8.
World map showing direction of change in prevalence of
allergic rhinoconjunctivitis symptoms for 13–14 year age-group
M Innes Asher, et al. Lancet 2006; 368: 733–43

9.
Time Trends of the Prevalence of Asthma, Rhinitis and Eczema
in Thai Children–ISAAC Phase Three
Prevalence of asthma, rhinitis, rhinoconjunctivitis and eczema
symptoms (percentage) in ISAAC Phase I and Phase III studies.
Trakultiwakorn M., et al. Journal of Asthma, 44:609–611, 2007

10.
Time Trends of the Prevalence of Asthma, Rhinitis and Eczema
in Thai Children–ISAAC Phase Three
Prevalence of asthma, rhinitis, rhinoconjunctivitis and eczema
symptoms (percentage) in ISAAC Phase I and Phase III studies.
Trakultiwakorn M., et al. Journal of Asthma, 44:609–611, 2007

11.
Relationship between
microbial colonization or infections
and atopic conditions.

12.
Microbial
colonization
or infections
Development of
atopic conditions
Protect
 Hygiene hypothesis

13.
Microbial
colonization
or infections
Development of
atopic conditions
Provoke
 Counter-Hygiene hypothesis
 Microbiome hypothesis

14.
Microbial
colonization
or infections
Development of
atopic conditions
Reverse causality hypothesis
atopic conditions alter susceptibility to
microbial colonization or infections.

15.
Atopic conditions and
risk of respiratory tract infections
• Gram-positive bacteria
• Gram-negative bacteria
• Other microbial infections

16.
Gram-positive bacteria
• The US Advisory Committee on Immunization
Practices (ACIP) issued a recommendation in 2008
• A single dose of PPV23 to Asthmatic patients aged
19 to 64 years
Asthma • Invasive pneumococcal disease
• Pneumococcal pneumonia
The Center for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2010;59:1102-6.
Juhn YJ, J Allergy Clin Immunol 2008;122:719-23.

17.
Gram-positive bacteria
Jung JA, J Allergy Clin Immunol 2010;125:217-21.
• AD
• AR
Increased risk of
serious pneumococcal disease
(Adjusted OR,2.13; 95%CI, 1.04-4.35)
Asthma
or other atopic
conditions
Higher rates of tympanostomy
tube placement than those
• without asthma
(RR 1.53; 95% CI, 0.93-2.53) or
• without other atopic conditions
(RR 1.70;95% CI, 1.01-2.86)
Bjur KA, et al. Allergy Asthma Proc 2012;33:289-96.

18.
• Streptococcus pyogenes
Gram-positive bacteria
Asthma Other atopic
condition
URI with
Streptococcus
pyogenes
Adjusted RR
(95%CI)
1.40
(1.12-1.74)
1.36
(1.07-1.66)
Frey D, Jacobson R, Poland G, Li X, Juhn Y. Allergy Asthma Proc 2009;30:540-5.
Juhn YJ, Frey D, Li X, Jacobson R. Prim Care Respir J 2012;21:153-8.

19.
• Asthma was associated with increased colonization with
Streptococcus pneumoniae and Staphylococcus aureus in
the nasopharynx.
• Increased risk of Staphylococcus aureus colonization of the
skin in patients with atopic dermatitis
Gram-positive bacteria
Cernelc D, Gerbec M, Cernelc P. Acta Allergol 1975;30:423-33.
Graham PL 3rd, Lin SX, Larson EL. Ann Intern Med 2006;144:318-25.
Halablab MA, Hijazi SM, Fawzi MA, Araj GF. Epidemiol Infect 2010;138:702-6.
Warner JA, McGirt LY, Beck LA. Br J Dermatol 2009;160:183-5.
Leung A, Schiltz A, Hall C, Liu A. Clin Exp Allergy 2008;38:789-93.
Leung DY. Curr Opin Pediatr 2003;15:399-404.

20.
Gram-negative bacteria
• Bordetella pertussis
Adjusted OR, 1.73;
95% CI, 1.12-2.67; P 5 .01
Asthma
Capili CR, et al. J Allergy Clin Immunol 2012;129:957-63.
• Legionella pneumophila
• Community-acquired
Escherichia coli bloodstream
infection (BSI)
• Pseudomonas aeruginosa
Boldur I, Beer S, Kazak R, Kahana H, Kannai Y. Isr J Med Sci 1986;22:733-6.
Bang DW, et al. BMJ Open 2013;3:1-8.
Beisswenger C, et al. J Immunol 2006;177:1833-7.

21.
Viral infections
• H1N1 Influenza virus
• Asthma = the most common comorbid condition among
patients with severeH1N1 infection (hospitalization or
death), with rates of asthma ranging from 10% to 32%.
Asthma Other atopic
condition
H1N1 Influenza
Adjusted RR
(95%CI)
4
(1.8-9.0)
1.89
(1.15-3.12)
Kloepfer KM, et al. Am J Respir Crit Care Med 2012; 185:1275-9.
Santillan S, Mehra S, Pardo Crespo MR, Juhn YJ. Allergy Asthma Proc 2013;34:459-66.

22.
• Respiratory syncytial virus (RSV)
• Rhinovirus
Viral infections
Increased risk of viral infections
• Type of virus
• Host’s immunogenetics
• Environmental factors
Atopic conditions
Holt PG, Sly PD. Nat Med 2012;18:726-35.

23.
Other microbial infections
• Mycoplasma pneumoniae
– Normal IgM responses
– Suboptimal IgG response
• Chlamydia pneumoniae
Asthma
The potential negative effect of a TH2-biased
response on immunity
 Leishmaniasis, Toxoplasmosis, Schistosomiasis,
and Candidiasis
Smith-Norowitz TA, et al. Pediatr Infect Dis J 2013;32:599-603.

24.
Atopic conditions and risk of
non–respiratory tract infections
• Genitourinary tract infection
• Reactivation of latent viral infection

25.
Genitourinary tract infection
• Community-acquired E. coli BSI
Asthma Food allergy
community-acquired
E coli BSI
Adjusted RR
(95%CI)
2.74
(1.11-6.76)
3.51
(0.94-13.1)
Bang DW, et al. BMJ Open 2013;3:1-8.

26.
Reactivation of latent viral infection
• Herpes zoster
• A large retrospective cohort study showed that
Asthma = The most common chronic condition
among children with herpes zoster
Asthma sensitization against
aeroallergens or food
allergens
Herpes zoster
infection
Adjusted RR
(95%CI)
2.09
(1.24-3.52)
3
(1.09-8.25)
Kim BS, et al. J Pediatr 2013;163:816-21.
Tseng HF, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Pediatr Infect Dis J 2009;28:1069-72.

27.
POTENTIAL FACTORS AFFECTING
THE ASSOCIATION BETWEEN ATOPIC CONDITIONS
AND THE RISK OF MICROBIAL INFECTION
• Corticosteroid therapies
• Control status or severity

28.
Influence of corticosteroid therapies on
infection risk
O’Byrne, et al
:ICSs  decreased the risk of pneumonia
HR = 0.52 (95% CI, 0.36-0.76) based on
pooled data from many clinical trials.
O’Byrne PM, et al.Am J Respir Crit Care Med 2011;183:589-95.

29.
Immune response to influenza vaccination
in children and adults with asthma
: Effect of corticosteroid therapy
Hanania NA, et al. J Allergy Clin Immunol 2004;113:717-24

30.
Asthma control status or severity
and risk of infections

31.
Worldwide severity and control of asthma in
children and adults
Rabe KF, et al. J Allergy Clin Immunol 2004;114:40-7.
Mild asthma are at an increased risk of infection

32.
Characteristics of asthmatics
with vs. without remission
Remission
(n = 59)
No
remission
(n = 58)
Adj. OR
(95% CI)
p-value
Freq. of viral infections
per person-years
0.3
[95% CI,
0.2-0.8]
0.4
[95% CI,
0.1-0.7]
0.60
(0.23-1.56)
0.29
Freq. of bacterial
infections per person-
years
0.5
[95% CI,
0.2-1.0]
0.5
[95% CI,
0.2-0.9]
0.94
(0.74-1.19)
0.49
Javed A,et al. J Asthma 2013;50:472-9
No significant differences

33.
Microbes and mucosal immune responses
in asthma

34.
Microbes and mucosal immune responses
in asthma
Genes
• Filaggrin gene (FLG)
• ORM-1 (yeast) like
protein3 (ORMDL3)
• A disintegrin and
metalloprotease-33
(ADAM33)
Host immune
response to
microbes
Environmental effects
epigenetic changes
• DNA methylation
• Histone acetylation
• Micro RNA activities

35.
Mucosal immune response to microbes
Professional APCs
cDCs T cells
pDCs IFN-α/β
Macrophages are phagocytic APCs
M1: inflammatory and T-cell activation
M2: patrolling and scavenging
AAM: IL-13 production in atopy
(M2 subtype)

36.
IL-25, IL-33, TSLP and chemokines
Circle of lymphoid cells and pathways
Innate lymphoid cells
Group 1 ILCs (ILC1 and NK cells) -> IFN-γ
Group 2 ILCs (ILC2, NH cells) -> IL-5 and IL-13
Group 3 ILCs (including ILC3) -> IL-17 and IL-22
Th2 pathway
IL-3, IL-4, IL-5, IL-9, IL-13
Th1 pathway
IFN-γ, TNF-β
IL-17 (Th17, Tγδ) pathway
IL-17A, IL-17F, IL-23 T follicular helper cells
B cell
Ig and IgE
Cytotoxicity/cell killing
• Tc
• NK cells
• NKT cells
Immune homoeostasis
and
remodelling (Th22, Treg)
IL-10, IL-22, TGF-β, IL-17

37.
PAMPs and mucosal immune response
PAMPs
PRRs:
• Plasma membrane
• Cytosol
• Endosome
Cytokine
Production
Trevor T Hansel, et al. Lancet 2013; 381: 861–73

38.
PAMPs and mucosal immune response
PAMPs
PRRs:
• Plasma membrane
• Cytosol
• Endosome
Cytokine
Production
Respiratory RNA viruses contain
ssRNA and generate dsRNA
replication intermediates:
• Rhinoviruses
• Influenza viruses
• Respiratory syncytial virus
Bacteria:
• Lipoproteins
• Lipoteichoic acid and
peptidoglycan
• Lipopolysaccharide
• Flagellin
TLRs
3, 7, 8, 9
RLRs
• Type I IFN production
(IFN-α types and IFN-β)
• Type III IFNs
(3 subtypes: IFN-λ1/IL-29, IFN-
λ2/IL-28A, and IFN-λ3/IL-28B)
TLRs 1/2, 2/6, 4, 5
NLR family
• Inflammosome complex,
Inactive
pro-proteins Active IL-1β and IL-18
Proinflammatory cytokines
Trevor T Hansel, et al. Lancet 2013; 381: 861–73

39.
PAMPs and mucosal immune response
Allergens:
• House dust mite binds TLR4
and dectin-2
• Peanut allergen binds CTLR
CTLR
Dectin-1
: fungal PAMPs
Dectin-2
Trevor T Hansel, et al. Lancet 2013; 381: 861–73

40.
POTENTIAL MECHANISMS UNDERLYING
THE ASSOCIATION BETWEEN ATOPIC CONDITIONS
AND INCREASED RISK OF MICROBIAL INFECTIONS

41.
• Innate immunity
• Humoral immunity
• Cell-mediated immunity
POTENTIAL MECHANISMS UNDERLYING
THE ASSOCIATION BETWEEN ATOPIC CONDITIONS
AND INCREASED RISK OF MICROBIAL INFECTIONS

42.
Innate immunity
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Habibzay et
al, 2012
HDM-sensitized
mice
• Impaired TLR 2–
mediated signaling
transduction on
neutrophils
• Reduced neutrophil
recruitment in the
airways
S pneumoniae

43.
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Contoli et al,
2006
Asthma Impaired IFN-λ secretion Rhinovirus
Wark et al,
2005
Asthma Impaired IFN-β secretion Rhinovirus
Message et
al, 2008
Asthma • Impaired TH1 cytokine
secretion (IFN-γ, IL-10,
and IL-12) by PBMCs
• Augmented TH2 cytokine
secretion (IL-4, IL-5, and
IL-13) by PBMCs
Rhinovirus
Laza-Stanca
et al, 2011
Asthma Impaired IL-15 secretion Rhinovirus
Sykes et al,
2013
Asthma
Well controlled
No difference in
• rhinovirus replication or
• Induction of IFN-β or IFN-
λ secretion by epithelial
cells
between patients with well-
controlled asthma and
nonasthmatic subjects
Rhinovirus

44.
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Plummeridge
et al, 2000
Asthma Impaired IL-12 secretion LPS (E coli) and IFN-γ
Beisswenger
et al, 2006
TH2 cytokine–
preincubated
human bronchial
epithelial cells
Decreased antimicrobial
peptide (human β-
defensin 2) secretion
P aeruginosa
OVA-sensitized
mice
• Decreased
antimicrobial peptide
(CRAMP) and
proinflammatory
cytokine (IL-1b and IL-
6) secretion
• Increased TH2 cytokine
(IL-4 and IL-13)
secretion in the
airways and number of
bacteria in the lungs
(BAL)
P aeruginosa

45.
Humoral immunity
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Grove et al,
1975
Asthma (no
steroid)/atopic
dermatitis
(human)
Decreased
hemagglutinin antibody
response to
tetanus toxoid
Tetanus toxoid
vaccine

46.
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Lee et al,
1995
Asthma • Decreased antibody
level against studied
polysaccharide
antigens both before
and after vaccination
• No difference in mean
fold increase
PPV23
Lee et al,
1995
Eczema (human
[moderate/sev
ere])
Decreased antibody level
against pneumococcal
vaccine (PPV23)
PPV23
Jung et al,
2010
Asthma Decreased serotype-
specific pneumococcal
antibody levels against
PPV23 but not
pneumococcal surface
protein antibody
PPV23

47.
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Wiertsema
et al, 2007
Alleles
associated with
atopy and
asthma
(human)
• IL4 2589T, IL4 2979T,
and IL4RA 551Gln
associated with lower
serotype-specific
pneumococcal
antibody responses,
IgG
PCV7 followed by
PPV23
Zhao et al,
2013
Asthma • Inverse correlation
between anti-PspC
antibody levels and
TH2 immune profile (IL-
5 secretion by PBMCs
after stimulation with
staphylococcal
enterotoxin B)
• Correlation modified
by asthma status
pneumococcal
surface protein C

48.
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Noseworthy
et al, 2005
Asthma Seronegative for measles
(40% to 43%) and
mumps (25% to 39%)
Two doses of MMR
vaccine
Patel et al,
2013
Asthma Decreased mumps
virus–specific IgG levels
Single dose of MMR
vaccine
Yoo et al,
2014
Asthma More rapid waning of
measles vaccine virus–
specific IgG levels over
time than in nonasthmatic
subjects after 1 dose of
MMR vaccination
Measles vaccine
virus

49.
Asthma and Risk of Selective IgA Deficiency or
Common Variable Immunodeficiency
: A Population-Based Case-Control Study
Urm SH, et al. Mayo Clin Proc 2013;88:813-21.

50.
Mutations in the TNFRSF13B gene
(TACI gene transmembrane activator and calcium-
modulator and cyclophilin ligand interactor) are found
in
• 6.25% of patients with sIgAD
• 8% to 21% of patients with CVID
TNFRSF13B mutations
2.5-fold increased risk of asthma at 4 years
independent of IgE levels
Castigli E, et al. Nat Genet 2005;37:829-34.
Janzi M, Melen E, Kull I, Wickman M, Hammarstrom L. Genes
Immun 2012;13:59-65.

51.
Cell-mediated immune response
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Fischer et al,
1997
IL-4–
overexpressing
mice
Delayed clearance of
RSV from the lung
RSV
Grove et al,
1975
Asthma Decreased delayed-type
hypersensitivity (CMI)
response to any of 5
antigens (Aspergillus
fumigatus, Candida
albicans, mumps skin
test antigen, old
tuberculin,streptokinase
streptodornase)
5 antigens

52.
Cell-mediated immune response
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Kim et al,
2013
Asthma Increased risk of herpes
zoster against which
CMI has been known to
be the primary defense
mechanism
NA
Yoo et al, 2010 Asthma Decreased
lymphoproliferative
response
(MMR-specific T-cell
response) to MMR
vaccine virus
Two doses of
MMR
vaccine

53.
Cell-mediated immune response
Authors Atopic
conditions
Reported immunologic
abnormalities
and dysfunctions
Immune
stimulants
Otero et al,
2013
Asthma • Lower production of
TNF-α and IFN-γ and
higher production of
IL-5 by PBMCs (PMA)
• No differences in
CMI responses after
stimulating PBMCs
with intact
Mycobacterium
tuberculosis and
S pneumoniae
M tuberculosis,
S pneumoniae

54.
Summary of the mechanisms
• Impairments in innate immunity in the airways
• Decreased adaptive immune functions

55.
IMPLICATIONS

56.
Patient care
• Asthmatic patients aged 19 to 64 years should be
vaccinated with PPV23 regardless of their asthma
control status.
• Atopic conditions  Increase risk of infections
: Routine vaccinations and booster
• Atopic conditions  work up
: Immunoglobulin levels
sIgAD and CVID

57.
Research
Identify phenotypic clusters
of asthmatic patients
Susceptibility to infection
or immune dysfunction
Only a subgroup
 increased risk of
microbial infections and
immune incompetence
Need to identify
The effects of
atopic conditions
Not be limited to the airways
but might be systemic

58.
Public health
• Public health surveillance and the epidemiology of
a broad range of microbial infections.
• The effects of atopic conditions on emerging or re-
emerging infectious diseases at a population level
are unknown

59.
What do we know?
• Patients with asthma and
other atopic conditions
Increased risks of
Serious and Common
Infections
• Respiratory
• Nonrespiratory
• A subgroup of
patients with asthma
and other atopic
conditions
• Impaired innate
immunity in the airways
• Decreased adaptive
immune functions

60.
What is still unknown?
• The molecular mechanism for
How atopic conditions impair immune functions?
• Clinical features and biomarkers for
Identify patients with asthma or other atopic
conditions who have increased risk of infections
• Atopic conditions affect the epidemiology of
emerging and re-emerging infectious diseases???

61.
Thank you