the effects of viral & atypical infections in asthmatics

The effects of

viral & atypical infections

in asthmatics

İ.Kıvılcım OğuzülgenGazi University School of Medicine Dept. of Pulmonary Medicine, Ankara

The aim of this presentation is to provide

an update about the effect of respiratory

infections caused by either viruses or

atypical bacteria on asthma.

2

Atypical and viral infections in asthma exacerbations

Pathogen Asthma Control p valueViral agent (%) Influenza A 11 2 0.01

Influenza B 5 1 NS

Parainfluenza type 1 3 0 NS



Adenovirus 6 1 NS

RSV 2 0 NS

One or more of the above 30 4 <0.00001

Atypical bacterial agents (%) Legionella spp. 5 3 NS

Mycoplasma pneumonia 18 3 0.0006

Coxiella burnetii 0 0 NS

Chlamydia pneumonia 8 6 NS

One or more of the above 26 10 0.003

No infectious etiologies found 51 85 <0.00001Lieberman D et al. Am J Respir Crit Care Med 2003; 167:406-

10.

3

Asthma and viral infections

Tan WC. Curr Opin Pulm Med 2005; 11:21-6.

Clinical and epidemiological observarions

strongly link viral infections with acute

worsening of asthma in as many as 80% of

cases in children and 60% in adults.

5

Tan WC et al. Am J Med 2003;115:272-7.

Patient GroupVirus Near-fatal

asthma (n:17)Acute asthma

(n:29)p

Number (%)

Picornavirus (RV) 8 (47) 8 (28) 0.15

Adevovirus 4 (24) 1 (3) 0.05

Picornavirus or adenovirus

12 (71) 9 (31) 0.01

Influenza A 1 (6) 5 (17) 0.27

Influenza B 0 1 (3) 0.63

Inflenza A+B 1 (6) 6 (21) 0.18

RSV 0 0 0.99

Parainfluenza virus 0 0 0.99

Any virus 10 (59) 12 (41) 0.36

Spectrum of viruses detected by PCR in asthma attacks

6

Link between asthma and viral infections

URT/LRT symptoms

+PEFR

Microbiological samples

The seasonal patterns of upper respiratory infections correlated strongly with hospital admissions for asthma (r = 0.72; p < 0.0001).

This relationship was stronger for pediatric (r = 0.68; p < 0.0001) than for adult admissions (r = 0.53; p < 0.01).

Upper respiratory viral infections are strongly associated in time with hospital admissions for asthma in children and

adults.Johnston SL et al. Am J Respir Crit Care Med. 1996;154:654-60.

108 school age children

7


Relation between symptomatic colds

and asthma exacerbations

Nicholson KG et al. BMJ 1993;307:982-6.

Colds were reported in 80%

(223/280) of episodes with

symptoms of wheeze, chest

tightness, or breathlessness,

and 89% (223/250) of colds

were associated with asthma

symptoms.

138 adult asthmatics (19-46 yr)

Mean wheese duration 19.6 yr

8

Pathogen found

No pathogen found

0

20

40

60

80

100

120Dec

reas

e in

pea

k ex

pira

tory

flow

(l/m

in)

1 3 6 9 12 14Days after onset of symptoms

Mean daily decrease in PEFR for episodes with objective evidence of asthma exacerbations


Nicholson KG et al. BMJ 1993;307:982-6. 9


Patients recorded symptom scores for

asthma and peak expiratory flow rate daily

for 11 months

Microbiological samples (every 4 wk & as soon as possible after the onset of worsening asthma or symptoms suggesting a

respiratory tract infection)

Baesly R et al. Thorax 1988;43:679-83.

30 viral infection 60% asthma exacerbation

178 asthma exacerbation 10% viral RTI

28 severe exacerbation 36% viral RTI

31 atopic asthmatics (15-56 yr)

10


Daily URT and LRT symptoms&

PEFR records&

Nasal aspirates for rhinovirus (every 2 wk)

Corne JM et al. Lancet 2002;359:831-4.

Rhinovirus was detected in 10.1% of asthmatics and 8.5% of healthy participants.

Frequency, severity, or duration of URT infections were similar.

Symptoms of LRT associated with RV infection were significantly more severe (p=0.001) and longer-lasting in participants with asthma than in healthy participants (p=0.005).

Atopic asthma

Healthy control

76 couples

11

Asthma and Rhinovirus

Pelaia G et al. Respir Med 2006;100:775-84.

During the following periods of childhood

and adolescence, as well as in adults,

about 60% of the viral, upper respiratory

tract infections involved in asthma

exacerbations, are caused by Rhinovirus.

12

Lemanske RF Jr et al. J Clin Invest 1989;83:1-10.

Baseline

URI

Recovery

*p<0.05 Compared to baseline**p<0.05 Compared to URI

Effects of RV to lower respiratory tract

In 10 experimentally infected (with RV) patients with allergic rhinitis, comparison of the airway response to histamine and ragweeg antigen at baseline, during an acute RV illness, and 4 wk later at recovery.

Histamin(Pre-antigen)

Antigen Histamin(Post-antigen)

PD20

(Cum

ulat

ive

Bre

ath

Uni

ts) F

EV1 125

100

75

50

25

0

*

*,**

*

*

* *

13

BAL eosinopils before, 48 hr after and 4 weeks after segmental antigen challenge in subjects with experimentally infected with rhinovirus 16

PreInfection

Allergic RhinitisNormal

AcuteInfection

PostInfection

PreInfection

AcuteInfection

PostInfection

BA

L Eo

sino

phils

(Mili

ons)

125

100

75

50

25

0

125

100

75

50

25

0

Calhoun WJ et al. J Clin Invest 1994;94:2200-8.


14

PreInfection

Allergic RhinitisNormal

AcuteInfection

PostInfection

PreInfection

AcuteInfection

PostInfection

BA

L TN

Fα (n

g/m

l)

50

40

30

20

10

0

50

40

30

20

10

0

BAL TNF α concentrations before, 48 hr after and 4 weeks after segmental antigen challenge in subjects with experimentally infected with rhinovirus 16

Calhoun WJ et al. J Clin Invest 1994;94:2200-8.


15

Mechanisms of RV-asthma interaction

ICAM-1

NF-кBIL-4

IL-16 IL-8 IL-6 FGF-2, Eotaksin, RANTES


RV

16

Mechanisms of RV-asthma interaction

Exacerbation of asthma

symtoms

Increase in bronchial hyper-

responsiveness

Structural changes responsible

for airway remodelling


RV

17

Asthma and influenza & parainfluenza viruses


The airway immune inflammation occurring in

many asthmatic patients can be further

amplified by acute viral infections caused by

influenza viruses.

Influenza viruses often exacerbate respiratory

symptoms and bronchial responsiveness to

allergic stimuli.

18

Mechanisms of influenza-asthma interaction

ACh

ACh

M2


IL-8. RANTES, MIP1-α

19

Mechanisms of influensa-asthma interaction

Enhance celluler response to

allergen sensitization

Exaggeration of reflex

parasympathetic

bronchoconstriction

Pelaia G et al. Respir Med 2006;100:775-84.20

TGF-β

NO

Mechanisms of parainfluenza-asthma interaction


Mechanisms of parainfluenza-asthma interaction

Increase in bronchial hyper-

responsiveness

Bronchiolar fibrosis

Structural changes responsible

for airway remodelling


23

Conlusions: Viruses & Asthma

The importance of common respiratory viruses,

especially the rhinovirus, in the pathogenesis of

exacerbations of asthma is well recognized.

There is now evidence that viral respiratory tract

infections affect existing asthma by increasing the

intensity of (allergic) inflammation.There is good

clinical and epidemiologic evidence that a

synergistic effect with pre-existing allergen

sensitization occurs.

24

Conlusions: Viruses & Asthma

Currently, there is no effective method for

the prevention of these virus-provoked

asthma attacks.

Rate of atypical infections in asthma exacerbations

Pathogen Asthma(n:100)

Control(n:100)

p value

Atypical bacterial agents (%)

Legionella spp. 5 3 NS

Mycoplasma pneumonia 18 3 0.0006

Coxiella burnetii 0 0 NS

Chlamydia pneumonia 8 6 NS

One or more of the above 26 10 0.003

Viruses 30 4 <0.00001

No infectious etiologies found 51 85 <0.00001

Lieberman D et al. Am J Respir Crit Care Med 2003; 167:406-10.

26

Martin RJ et al. J Allergy Clin Immunol 2001;107:595-601.

45

9

13

56

0

Mycoplasma Chlamydia50

30

10

% o

f sub

ject

s

Asthma Control Asthma Control Asthma Total

Percent of subjects with positive PCR results for Mycoplasma and Chlamydia species among asthmatic patients and normal control subjects.

Rate of atypical infections in stable asthma

27

It is not known whether M. pneumoniae or C.

pneumoniae were allowed to persist after an

infection, or were present prior to the development

of asthma. There is evidence to support both

possibilities, the effects of infection with this

organism can persist for months, resulting in

decreased expiratory flow rates, and increased

airway hyperresponsiveness in normal individuals.

Kraft M et al. Chest 2002; 121:1782-88.28

Bacterial infection of resident airway cells, such as

epithelial cells or macrophages, produces a

cascade of cytokines that recruit and activate

immune cells involved in bacterial destruction.

However, these cells may also lead to

inflammation —possibly thereby increasing

asthma severity—and tissue damage with airway

remodelling.

Proposed biological mechanisms

Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.29

TNF-α, IL-1β, IL-8 IL-6

Hsp60 Ag NF-кB

Mechanisms of Chlamydia-asthma interaction


Mechanisms of Chlamydia-asthma interaction

Increase airway susceptibility to

other environmental stimuli such as

allergens and viruses thereby

accelerate asthma progression

Structural changes responsible for

airway remodelling

Contributes to asthma severity


TNF-α, IL-1β, IL-8,IL-4, IL-5, IL-6, RANTES, TGF- β

Mechanisms of Mycoplasma-asthma interaction


B cell

IgE

32


Trigger Th2-like cytokine

responses, associated with

elevated serum IgE concentrations

Causes inflammatory and structural

changes


Sutherland ER et al. Chest 2007; 132:1962-6.

Airway collagen deposition in allergen sensitized

animals 6 weeks after experimental model of

Mycoplasma pneumonia infection (b) and control

group (a)


34

In addition to causing a decrement in

pulmonary function during acute infection, M.

pneumoniae might also be associated with the

long-term impairment of pulmonary function in

both asthmatic subjects and nonasthmatic

subjects.


35

Antibiotics in the treatment of asthma

Sutherland ER et al. Chest 2007; 132:1962-6.

Johnston SL. J Allergy Clin Immunol 2006;117:1233-6

Antibiotics do not currently play a major role in

the treatment of chronic asthma in stable

patients. There is emerging evidence, however, that

symptoms and markers of airway inflammation

may improve when patients who have atypical

bacterial infection as a cofactor in their asthma

are treated with antibiotics.36

A number of different antibacterial agents

have in vitro activity against C. pneumoniae

and M. pneumoniae, including tetracyclines,

macrolides (e.g., erythromycin,

roxithromycin, clarithromycin, and

azithromycin), the newer quinolones, and

the ketolide telithromycin.

Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

Antibiotics in the treatment of asthma

37

Modulate the functions of inflammatory cells, including

polymorphonuclear leukocytes, lymphocytes, and macrophages. Influence several pathways involved in the inflammatory

process, including the migration of neutrophils, the oxidative

burst in phagocytes, and the production of proinflammatory

mediators and cytokines. Inhibit the synthesis and/or secretion of proinflammatory

cytokines (e.g., TNF-, IL-8, IL-6, IL-1). Their effects on

antiinflammatory cytokines (IL-10, IL-4) are more variable.

Effects of macrolides in asthma


The most important molecular targets for the

antiinflammatory effects of the macrolides in

asthma appear to be the transcription factors

activator protein-1 and NF-кB.

Effects of macrolides in asthma


In 55 chronic stable asthmatics, M. pneumoniae or C.

pneumoniae were present in the airways by PCR in 55% of the

patients. In addition, treatment with clarithromycin improved the

FEV1 and reduced airway tissue expression of IL-5, but only in

the PCR-positive subjects.

Effect of clarithromycin in asthma

Kraft M et al. Chest 2002; 121:1782-88.

Baseline Clarithromycin Baseline Clarithromycin

3.0

2.5

2.0

FEV

1 (L

)p=0.47

p=0.05

PCR +

PCR -

40

41

7 studies recruiting a total of 416 participants Findings from studies comparing macrolide

treatment for at least 4 weeks in adult and pediatric

patients treated for chronic asthma. 4 studies showed a positive effect on symptoms

of macrolides in different types of asthmatic

patients.T here was no significant difference in FEV1 for

either parallel or crossover trials.However, there were significant differences in

eosinophilic inflammation and symptoms.One large parallel group trial reported significant

differences in peak flow but these differences

abated within six months of treatment.

Richeldi L et al. Cochrane Database of Systematic Reviews 2005, Issue 4 . Updated 2007

Fewer data are available concerning the

antiinflammatory properties of ketolides, although

telithromycin has demonstrated immunomodulatory

effects both in vitro and in vivo. Telithromycin has been shown to significantly

inhibit secretion of IL-1 and TNF-α in human

monocytes in vitro, and inhibit IL-1, IL-6, and IL-10

secretion in a murine model.

Johnston SL et al. Am J Respir Crit Care Med 2005; 172:1079-89.

Effects of ketolides in asthma

42

Johnston SL et al. N Engl J Med 2006;354:1589-600.

Patients in the telithromycin group (n:126) had a significantly greater improvement in asthma symptoms during the 10-day treatment period but did not have an improvement in peak expiratory flow rates as measured in the morning at home. There was no relationship between bacteriologic status and the response to asthma treatment.

Telithromycine in asthma

Cha

nge

in F

EV1

from

bas

elin

e (L

)

43

0 11-14 28 42Day

0.8

0.6

0.4

0.2

0.0

Telithromycine

Placebo

p=0.001

p=NS278 adults with acute

exacerbation of asthma (61%had microbiological evidence of Mycoplasma or Chlamydia infection)

Conclusions

Richeldi L et al. Cochrane Database of Systematic Reviews 2005, Issue 4.Updated 2007.

Sutherland ER et al. Chest 2007; 132:1962-6

Even though some clinical data indicate a positive

effect of macrolides in asthmatic patients in the

absence of relevant side effects, these data are

insufficient to recommend the routine use of

macrolides for control of asthma at present.

Current studies will further define the role of

macrolide antibiotics in the treatment of stable

asthma patients.

44

As a result, increasing evidence suggests

atypical bacterial and viral infections

contribute to exacerbation severity, as well

as stable asthma, particularly severe

asthma.

Johnston SL. J Allergy Clin Immunol 2006;117:1233-645

the effects of viral & atypical infections in asthmatics

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