risks for infection in patients with asthma

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.

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.

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.

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

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

World map showing direction of change in prevalence of asthma symptoms 13–14 year age-group


World map showing direction of change in prevalence of allergic rhinoconjunctivitis symptoms for 6–7 year age-group


World map showing direction of change in prevalence of allergic rhinoconjunctivitis symptoms for 13–14 year age-group


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

Relationship between microbial colonization or infections

and atopic conditions.

Microbial

colonization or infections

Development of atopic conditions

Protect Hygiene hypothesis

Microbial



Provoke Counter-Hygiene hypothesis Microbiome hypothesis

Microbial



Reverse causality hypothesis atopic conditions alter susceptibility to microbial colonization or infections.

Atopic conditions and risk of respiratory tract infections

• Gram-positive bacteria

• Gram-negative bacteria

• Other microbial infections

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.


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.

• Streptococcus pyogenes


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.

• 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


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.

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.

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.

• 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.

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.

Atopic conditions and risk of non–respiratory tract infections

• Genitourinary tract infection

• Reactivation of latent viral infection

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.

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.

POTENTIAL FACTORS AFFECTING THE ASSOCIATION BETWEEN ATOPIC CONDITIONS

AND THE RISK OF MICROBIAL INFECTION

• Corticosteroid therapies

• Control status or severity

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.

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

Asthma control status or severity and risk of infections

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

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

Microbes and mucosal immune responses in asthma

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

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)

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

PAMPs and mucosal immune response

PAMPs

PRRs: • Plasma membrane • Cytosol • Endosome

Cytokine

Production

Trevor T Hansel, et al. Lancet 2013; 381: 861–73


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



Allergens: • House dust mite binds TLR4 and dectin-2 • Peanut allergen binds CTLR

CTLR Dectin-1 : fungal PAMPs Dectin-2


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

• Innate immunity

• Humoral immunity

• Cell-mediated immunity

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

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



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



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

Humoral immunity



and dysfunctions

Immune stimulants

Grove et al, 1975

Asthma (no steroid)/atopic dermatitis (human)

Decreased hemagglutinin antibody response to tetanus toxoid

Tetanus toxoid vaccine



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/severe])

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



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



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

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.

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.

Cell-mediated immune response



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




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




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

Summary of the mechanisms

• Impairments in innate immunity in the airways

• Decreased adaptive immune functions

IMPLICATIONS

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

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

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

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

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???

Thank you

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