Common colds, allergens, pollution, stress and asthma attacks

[Guest guest]

This is not really new material, but here are a few abstracts illustrating the

link between

common colds (most often rhinoviruses), allergens, pollution and stress, which

all add

their effects

like a band of thugs to exacerbate an asthma attack.

Asthmatics are more susceptible to common colds because the antiviral defenses

of their

epithelial bronchial cells function poorly. Once viruses are installed, they

further weaken

the lung's immunity, strongly amplify the effects of allergens and pollution,

and often

precipitate an asthma attack.

In genetically susceptible individuals, some viruses can even reprogram host

lung immune

behaviour, in what an article calls a " hit-and-run " fashion. In a 2006 article,

Prof Szczeklik

also mentioned the possibility that, in genetically predisposed individuals, a

virus could

trigger the onset of Samter's.

Stress is also a worsening factor of asthma attacks.

We already knew it was important to avoid respiratory viruses, but it seems

that, in the last

few years, research has increasingly pinpointed their negative role in Samter's

and asthma.

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Abstract 1 - Viruses

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Allergy. 2007 May;62(5):457-70. Epub 2007 Feb 27. Links

Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and

InterAirways document.

Papadopoulos NG, Xepapadaki P, Mallia P, Brusselle G, Watelet JB, Xatzipsalti M,

Foteinos

G, van Drunen CM, Fokkens WJ, D'Ambrosio C, Bonini S, Bossios A, Lötvall J, van

Cauwenberge P, Holgate ST, Canonica GW, Szczeklik A, Rohde G, Kimpen J,

Pitkäranta A,

Mäkelä M, Chanez P, Ring J, ston SL.

Allergy Research Center, 2nd Pediatric Clinic, University of Athens, Athens,

Greece.

===> Viral infections of the respiratory tract are the most common precipitants

of acute

asthma exacerbations. Exacerbations are only poorly responsive to current asthma

therapies and new approaches to therapy are needed.

Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium,

generate

local and systemic immune responses, as well as neural responses, inducing

inflammation

and airway hyperresponsiveness.

Using in vitro and in vivo experimental models the role of various

proinflammatory or

anti-inflammatory mediators, antiviral responses and molecular pathways that

lead from

infection to symptoms has been partly unravelled. In particular, mechanisms of

susceptibility to viral infection have been identified and the bronchial

epithelium appeared

to be a key player. Nevertheless, additional understanding of the integration

between the

diverse elements of the antiviral response, especially in the context of

allergic airway

inflammation, as well as the interactions between viral infections and other

stimuli that

affect airway inflammation and responsiveness may lead to novel strategies in

treating

and/or preventing asthma exacerbations. This review presents the current

knowledge and

highlights areas in need of further research.

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Abstract 2

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Curr Opin Pulm Med. 2005 Jan;11(1):21-6. Links

Viruses in asthma exacerbations.

Tan WC.

Department of Medicine, National University Hospital, Singapore.

mdctanwc@...

PURPOSE OF REVIEW: Respiratory viruses are well recognized as major triggers of

acute

exacerbations of asthma in children and adults, resulting in frequent

outpatients visits and

hospitalizations. Clinical and epidemiologic evidence supports this association.

The

application of molecular diagnostic methods has improved understanding of viral

epidemiology and the pathophysiological mechanisms involved in viral induced

acute

asthma. This article reviews publications since October 2002 for an update of

the role of

viruses in exacerbations of asthma.

RECENT FINDINGS: Respiratory viruses are present in most patients hospitalized

for life-

threatening asthma and acute non life-threatening asthma. Rhinovirus is the most

common, but coinfection with other viruses may be important.

Patients with asthma are not more susceptible to upper respiratory tract

rhinovirus

infections than healthy people but suffer from more severe consequences of the

lower

respiratory tract infection.

===> Recent epidemiologic studies suggest that viruses provoke asthma attacks by

additive or synergistic interactions with allergen exposure or with air

pollution. An

impaired antiviral immunity to rhinovirus may lead to impaired viral clearance

and hence

prolonged symptoms.

Respiratory viral infections cause asthmatic exacerbations by triggering

recruitment of

Th2-type cells into the lungs. There is no specific antiviral strategy for

prevention of

respiratory-triggered asthma exacerbations, although clinical trials of

potential antiviral

agents are ongoing. Indirect prevention strategies focus on the reduction of

overall airway

inflammation to reduce the severity of the host response to respiratory viral

infections.

SUMMARY: Respiratory viral infections are a major cause of morbidity and

mortality in

asthma. There is a lack of specific antiviral strategies in the prevention or

reduction of

viral-triggered asthma exacerbations. Recent advances in understanding of the

epidemiology and immunopathogenesis of respiratory viral infection in asthma

provide

opportunities or identification of specific targets for antiviral agents and

strategies for

management and prevention.

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Abstract 3

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Proc Am Thorac Soc. 2007 Jul;4(3):267-70. Links

Innate immunity in the pathogenesis of virus-induced asthma exacerbations.

ston SL.

Department of Respiratory Medicine, National Heart and Lung Institute,

Fleming

Institute of Infection and Immunity, Imperial College London, Norfolk Place,

London

W2 1PG, UK. s.johnston@...

The major asthma morbidity, mortality, and health care costs are a result of

acute

exacerbations. However, exacerbations are only partially responsive to current

therapies

and new approaches to treatment are needed.

===> The great majority of acute asthma exacerbations are associated with

respiratory

viral infections and, of viruses implicated, approximately 60% are human

rhinoviruses

(RVs).

The mechanisms of RV-induced asthma exacerbations are poorly understood. We have

previously shown that adults with asthma have increased susceptibility to

naturally

occurring RV infections. Our recent studies have investigated mechanisms of

innate host

defense against RV infection. First, primary bronchial epithelial cells from

subjects with

asthma were shown to replicate RV in vitro to several logs, whereas those of

normal

control subjects were resistant to infection. This resistance was a result of

rapid induction

of apoptosis and of interferon (IFN)-beta in the normal cells, whereas ===>

these

responses were deficient in asthmatic cells.

These studies were recently extended to a novel family of three related

proteins, the IFN-

lambdas 1-3, production of which was also deficient in vitro and related to

asthma

exacerbation severity in vivo. These studies identify novel mechanisms for the

increased

susceptibility of subjects with asthma to RV infection. Further studies are now

required to

investigate whether administration of IFN-beta or IFN-lambda may be beneficial

in the

treatment of asthma exacerbations, to determine whether similar deficiencies are

observed

in children and in subjects with nonatopic asthma, and to investigate the

mechanisms of

deficient IFN production in asthma to help identify better therapeutic

strategies for asthma

exacerbations.

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Abstract 4 (FREE ARTICLE VIA MEDLINE)

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Clin Microbiol Rev. 1999 Jan;12(1):9-18. Links

Association of rhinovirus infections with asthma.

Gern JE, Busse WW.

Division of Allergy and Immunology, Department of Pediatrics, University of

Wisconsin-

Madison, Madison, Wisconsin, USA. gern@...

Rhinoviruses are the most common cause of the common cold, but they can cause

more

severe illnesses in people with underlying lung disorders such as asthma,

chronic

obstructive pulmonary disease, or cystic fibrosis. Epidemiologic studies with

sensitive

detection methods such as PCR have identified rhinovirus infection as a major

source of

asthma exacerbations in both children and adults, especially during the spring

and fall.

==> Since rhinoviruses cause little tissue destruction, it is presumed that the

immune

response to the infection may play an important role in the pathogenesis of

rhinovirus-

induced exacerbations of asthma.

This review examines the epidemiologic association between rhinovirus infections

and

exacerbations of asthma and outlines current information on immune responses to

rhinovirus infection and potential connections between antiviral responses and

preexisting

allergic inflammation. Finally, current and future strategies for treating

rhinovirus

infections and virus-induced exacerbations of asthma are discussed.

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Abstract 5 - Stress and asthma (FREE ARTICLE VIA MEDLINE)

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Brain Behav Immun. 2007 Nov;21(8):993-9. Epub 2007 May 9. Links

Stress and inflammation in exacerbations of asthma.

Chen E, GE.

University of British Columbia, Department of Psychology, 2136 West Mall,

Vancouver, BC,

Canada V6T 1Z4. echen@...

In this mini-review, we outline a model depicting the immunologic mechanisms by

which

psychological stress can exacerbate clinical symptoms in patients with asthma.

This model

highlights the importance of both social and physical exposures in the

exacerbation of

asthma symptoms.

==> The basic premise of the model is that psychological stress operates by

altering the

magnitude of the airway inflammatory response that irritants, allergens, and

infections

bring about in persons with asthma.

The biological pathways for how stress amplifies the immune response to asthma

triggers

include the hypothalamic-pituitary-adrenal (HPA) axis, the

sympathetic-adrenal-medullary

(SAM) axis, and the sympathetic (SNS) and parasympathetic (PNS) arms of the

autonomic

nervous system. Empirical evidence for this model is reviewed, and conclusions

and future

research directions are discussed.

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Abstract 6

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Pulm Pharmacol Ther. 2006;19(5):320-34. Epub 2005 Nov 10. Links

New treatment regimes for virus-induced exacerbations of asthma.

MR, Kebadze T, MW, ston SL.

Department of Respiratory Medicine, Fleming Institute of Infection &

Immunity,

National Heart Lung Institute, Imperial College London, UK.

michael.edwards@...

This review will focus on the role of viruses as causes of asthma exacerbations.

The article

will briefly review the current literature supporting this view, with a special

focus on

human rhinovirus (RV), the main virus associated with exacerbations of asthma.

The

review will then refer to possible strategies for treatment, and will include

discussion on

treatment with specific anti-viral therapy and type I interferon as a treatment

for RV. The

review will also include a discussion on current therapies for asthma, such as

glucocorticosteroid and beta(2) agonist therapy alone and in combination and why

this

may be relevant to virus-induced exacerbations of asthma. Finally, the potential

for future

anti-inflammatory/immunomodulatory therapies with a focus on NF-kappaB

inhibition will

be discussed.

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Abstract 7

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J Exp Med. 2005 Mar 21;201(6):937-47. Links

Asthmatic bronchial epithelial cells have a deficient innate immune response to

infection

with rhinovirus.

Wark PA, ston SL, Bucchieri F, R, Puddicombe S, Laza-Stanca V,

Holgate ST,

Davies DE.

The Laboratories, University of Southampton, Southampton SO16 6YD, UK.

p.wark@...

Rhinoviruses are the major trigger of acute asthma exacerbations and asthmatic

subjects

are more susceptible to these infections. To investigate the underlying

mechanisms of this

increased susceptibility, we examined virus replication and innate responses to

rhinovirus

(RV)-16 infection of primary bronchial epithelial cells from asthmatic and

healthy control

subjects.Viral RNA expression and late virus release into supernatant was

increased 50-

and 7-fold, respectively in asthmatic cells compared with healthy controls.

Virus infection

induced late cell lysis in asthmatic cells but not in normal cells. Examination

of the early

cellular response to infection revealed impairment of virus induced caspase 3/7

activity

and of apoptotic responses in the asthmatic cultures. Inhibition of apoptosis in

normal

cultures resulted in enhanced viral yield, comparable to that seen in infected

asthmatic

cultures. Examination of early innate immune responses revealed profound

impairment of

virus-induced interferon-beta mRNA expression in asthmatic cultures and they

produced

>2.5 times less interferon-beta protein. In infected asthmatic cells, exogenous

interferon-

beta induced apoptosis and reduced virus replication, demonstrating a causal

link between

deficient interferon-beta, impaired apoptosis and increased virus replication.

These data

suggest a novel use for type I interferons in the treatment or prevention of

virus-induced

asthma exacerbations.

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Abstract 8

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Proc Am Thorac Soc. 2005;2(2):150-6. Links

Overview of virus-induced airway disease.

ston SL.

Department of Respiratory Medicine, National Heart & Lung Institute and

Fleming

Institute of Infection & Immunity, Imperial College London, Norfolk Place,

London W2 1PG,

UK. s.johnston@...

Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD)

are the

major cause of morbidity, mortality, and health costs of both diseases.

Currently available

treatments are poorly effective in both acute treatment of and prevention of

acute

exacerbations. New treatments for intervention and prophylaxis are therefore

required; to

facilitate their development, we must understand the causes and mechanisms of

exacerbations. Respiratory viral infections (2/3 rhinoviruses) precipitate 80%

or more of

asthma exacerbations in children, and the majority of exacerbations of asthma

and COPD

in adults, but mechanisms of virus-induced lower airway inflammation and of host

resistance against respiratory viruses are poorly understood. Development of in

vitro

experimental models of virus infection has identified interferon-beta and nitric

oxide as

possible therapeutic targets to augment antiviral immunity, and nuclear

factor-kappaB as

a target for development of anti-inflammatory therapies. In vivo models could

also serve

to identify and validate targets and as an experimental system to test candidate

molecules

as they emerge into clinical studies. Studies in asthma have paved the way for

development of an asthma model; a similar experimental model in COPD would

accelerate

development of new therapies for these common diseases with enormous burdens of

illness.

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Abstract 9

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Pediatr Infect Dis J. 2004 Nov;23(11 Suppl):S235-45. Links

" Hit-and-run " effects of paramyxoviruses as a basis for chronic respiratory

disease.

Holtzman MJ, Shornick LP, Grayson MH, Kim EY, Tyner JW, Patel AC, Agapov E,

Zhang Y.

Division of Pulmonary and Critical Care Medicine, Department of Medicine,

Washington

University School of Medicine, St. Louis, MO, USA.

BACKGROUND: The traditional scheme for asthma pathogenesis depends on increased

T

helper type 2 (Th2) over T helper type 1 (Th1) responses to allergic and

nonallergic stimuli

and consequent airway inflammation, hyperreactivity and hypersecretion. Here we

question whether the innate immune system, including airway epithelial cells,

and the

adaptive one may manifest an aberrant antiviral response as an additional basis

for

chronic inflammatory diseases, including asthma. METHODS: We focused on the

signal

transduction and genetic basis for mucosal immunity, inflammation and

remodeling,

especially in relation to airway diseases. We concentrated on the response to

paramyxoviruses because these agents are closely associated with common acute

and

chronic airway diseases. We used viral, cellular and mouse models, as well as

human

subjects, for study and made comparisons among these systems. Our approach aims

to

answer 2 major questions: (1) what are the factors that control acute

paramyxoviral

infection; and (2) how can these transient infections cause long term airway

disease?

CONCLUSIONS: Our studies show that antiviral defense depends on a special

network of

epithelial immune response genes that signal to the adaptive immune system.

Viruses

ordinarily trigger this network, but it is also permanently activated in asthma,

even in the

absence of viral infection.

==> In addition, we find that, in susceptible genetic backgrounds, respiratory

viruses

cause a " hit-and-run " phenomenon indicated by the development of an asthmatic

phenotype long after the infection has cleared. On the basis of this

information, we

developed a new scheme for asthma pathogenesis that includes epithelial, viral

and

allergic components and allows viral reprogramming of host behavior.

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Abstract 10

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Drug Discov Today. 2004 Oct 1;9(19):831-7. Links

Comment in:

Drug Discov Today. 2005 Nov 15;10(22):1500-2.

Respiratory infections and asthma: current treatment strategies.

Weinberger M.

Pediatric Allergy & Pulmonary Division, College of Medicine, University of Iowa,

Iowa, USA.

miles-weinberger@...

Infections such as lower respiratory illness potentially contribute to the

initiation of

asthma and are major factors in recurring acute exacerbations of the condition.

Although

typical bacterial respiratory pathogens such as Streptococcus pyogenes,

Streptococcus

pneumoniae and Hemophilus influenzae do not initiate asthmatic exacerbations,

data from

a subgroup of adults suggest a potential role for Mycoplasma pneumoniae and

Chlamydia

pneumoniae in the onset of asthma. Common cold viruses, predominantly

respiratory

syncytial virus (RSV) in young children and rhinoviruses in older children and

adults, are

the major causes of acute exacerbations of asthma. These exacerbations are not

prevented with maintenance therapies that are used for chronic asthma, but do

respond to

short courses of systemic corticosteroids. There are continued attempts to

produce a

successful vaccine and antiviral agents for the treatment of RSV that are more

effective and

more practical to use than ribavirin, which is currently the only available

antiviral for RSV.

The prevention and treatment of rhinovirus infections have focused on the major

receptor

for the virus, intercellular adhesion molecule-1 (ICAM-1), which is located on

respiratory

epithelial cells. A multivalent, recombinant, antibody fusion protein identified

as CFY196

has high avidity for ICAM-1 and has the potential to protect against rhinovirus

infection.

Another approach for preventing and treating rhinovirus infection uses a

recombinant,

soluble, truncated form of ICAM-1 in which the transmembrane and intracellular

domains

of the protein have been deleted. An initial clinical study on this agent

demonstrated

clinical efficacy in ameliorating the symptoms of experimental rhinovirus

infection in

volunteers, but did not significantly prevent infection.

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Abstract 11

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Eur J Pharmacol. 2006 Mar 8;533(1-3):145-55. Epub 2006 Feb 7. Links

The broken balance in aspirin hypersensitivity.

Szczeklik A, Sanak M.

Department of Medicine, Jagiellonian University School of Medicine, Skawinska 8,

31-066

Krakow, Poland. mmszczek@...

Aspirin was introduced into medicine over a century ago and has become the most

popular drug in the world. Although the first hypersensitivity reaction was

described soon

after aspirin had been marketed, only recently a phenomenon of cysteinyl

leukotriene

overproduction brought new insights on a balance between pro- and

anti-inflammatory

mediators derived from arachidonic acid. We describe the most common clinical

presentations of aspirin hypersensitivity, i.e. aspirin-induced asthma,

rhinosinusitis and

aspirin-induced urticaria. We also present their biochemical background. Despite

relatively

high incidence of these reactions, aspirin hypersensitivity remains

underdiagnosed

worldwide. Acute reactions of aspirin hypersensitivity are elicited via

cyclooxygenase

inhibition by non-steroid anti-inflammatory drugs. ibs, selective inhibitors

of

cyclooxygenase-2 isoenzyme, do not precipitate symptoms in susceptible patients.

Though hypersensitivity correlates with cyclooxygenase-1 inhibition, diminished

tissue

expression was described only for cyclooxygenase-2. Aspirin-induced asthma and

aspirin-induced urticaria, in a substantial part of the patients, are driven by

a release of

mediators from activated mast cells. These cells in physiological conditions are

under

inhibitory control of prostaglandin E2.

===> The origin of aspirin hypersensitivity remains unknown, but accumulating

data

from genetic studies strongly suggest that environmental factor, possibly a

common viral

infection, can trigger the disease in susceptible subjects.