Viral infections, asthma, and ... substance P

[Guest guest]

This article on Medscape is about viral infections leading to asthma.

May be interesting for anyone out there with this problem (like me!).

Interestingly enough, somewhere down in the medical lingo that old demon

comes up again - substance P!

Barbara in Fla

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Expert Column

Respiratory Viral Infections and Asthma: Is There a Link?

Erwin W. Gelfand, MD

[Medscape Pulmonary Medicine 4(4), 2000. © 2000 Medscape, Inc.]

Introduction

Viral respiratory infections have been estimated to account for more than

80% of acute exacerbations of asthma in children and at least 30% to 40%

of exacerbations in adults with asthma. The most significant

asthma-associated viruses include respiratory syncytial virus (RSV),

rhinovirus, and parainfluenza.[1] This article will review the

association of respiratory viral infections and asthma, bronchial

inflammation and airway hyperresponsiveness associated with viral

infections, viral-induced effectors of the inflammatory response, the

role of noninflammatory mechanisms in virus-induced wheezing, the

persistence of infection, the interactions between viral respiratory

tract infection (RTI) and allergic sensitization, and current

developments in vaccines for viral infections.

Association of Respiratory Viral Infection and Asthma

The association between lower RTIs, acute exacerbations of asthma, and

the initial onset of asthma in infants has been documented in numerous

epidemiologic studies.[2-7] This association has been noted particularly

with occurrences of RSV infections. Whether symptomatic infections in

early life induce or identify asthma in genetically susceptible

individuals has not yet been documented. The current prevailing view is

that infections in early life do not induce atopic asthma. Specifically,

RSV infection is not generally viewed as a key event in the induction of

asthma.[8]

Bronchial Inflammation and Airway Hyperresponsiveness

The interactions between virus and host are very complicated. Although

the relationship between respiratory viral infections and the onset of

asthma has not been entirely defined, a link between exacerbations of

bronchial inflammation and enhancement of allergic airway responses is

much more clear. Acute infection can intensify airway narrowing and

airway hyperresponsiveness (AHR). Viral-induced alterations of epithelial

cell structure and function, increased inflammatory cell accumulation in

the tissue and around airways, edema of airway walls, and exposure of

airway nerve endings in sites of epithelial cell sloughing contribute to

altered airway function.[1] These alterations in airway function may

contribute to asthma exacerbation.

Viral-Induced Effectors of the Inflammatory Response

Adhesion Molecules

The complexity of the effects of respiratory infection on airway function

are underscored by the many cell-mediated immune responses to viruses

(Figure). Increased expression of a number of important adhesion

molecules can be detected in response to infection. These proteins

regulate inflammatory cell migration, enhancing airway inflammatory

responses. One example is intercellular adhesion molecule 1 (ICAM-1), a

molecule in which expression is increased during and following viral

infection. ICAM-1 is expressed on a wide variety of cells, including

epithelial cells, endothelial cells, fibroblasts, lymphocytes, and

monocytes. Expression of ICAM-1 is increased by the pro-inflammatory

mediators (cytokines) interferon-gamma, interleukin (IL)-1, and tumor

necrosis factor (TNF).

ICAM-1 is the major human rhinovirus receptor. Upregulation of ICAM-1 has

been detected following experimental rhinovirus infection. Binding of the

virus to ICAM-1 on different cell types triggers the release of a number

of cytokines and further increases in ICAM-1 expression on adjacent

cells, thereby enhancing adhesion and spread of the virus. With increased

expression of ICAM-1, eosinophil and neutrophil migration, adhesion and

attraction are augmented; this leads to enhanced inflammation, which

increases AHR. Support for this pathway in the pathogenesis of disease is

provided by studies in different animal models where blockade of ICAM-1

reduces inflammatory cell accumulation.

Figure Host-virus interactions.

Chemokines and Cytokines

Many of the respiratory viruses, but especially RSV, can affect the

respiratory epithelium, triggering the release of both eosinophil

chemoattractants (eg, Rantes) and IL-6, IL-8, GM-CSF, and macrophage

inflammatory protein (MIP-1alpha). In a recent study of RSV-stimulated

neutrophils, the release of IL-8 and MIP-1beta and neutrophil

degranulation were demonstrated.[9] Rantes is a potent chemoattractant

for eosinophils, while GM-CSF is important for eosinophilopoiesis. IL-8

will lead to the influx of neutrophils, which, in turn, can further

contribute to inflammation by the release of their stored/de novo

synthesized chemokines and granular enzymes.

MIP-1alpha stimulates eosinophil and basophil chemotaxis and

degranulation, which leads to further recruitment of these cells and the

subsequent release of eosinophil cationic proteins (ECP) and histamine

into the airways.

MIP-1beta is a member of the c-c chemokine family. Its function is not

fully defined, but it appears capable of stimulating antigen-specific Th2

lymphocyte proliferation and upregulating the costimulatory molecule CD80

on antigen-presenting cells. Of note, ECP, eosinophil neurotoxin, and

histamine have been identified in the respiratory secretions of

bronchoalveolar lavage fluid of infants with RSV bronchiolitis.

Neutrophils, IL-8, and neutrophil myeloperoxidase have also been found in

the respiratory secretions of children with viral-induced asthma.

Another inflammatory mechanism possibly involved in the development of

asthmatic symptoms may be the increase in production of IL-11 by

epithelial cells following viral infection. In children with viral upper

RTI and in those with wheezing, IL-11 levels are elevated in nasal

secretions. Administration of recombinant IL-11 into the lungs of mice

results in increased airway responsiveness to methacholine. The role

IL-11 plays in virus-induced lung disease remains to be determined.

Eosinophils and M2 Receptor Dysfunction

The inflammatory response elicited by viral RTI and particularly the

accumulation of eosinophils most likely play essential roles in the

development of wheezing during acute infection. The study authors have

recently reported in a murine model[10,11] that the eosinophilic

component of the inflammatory response to acute RSV infection and the

associated development of AHR to methacholine provocation are dependent

on the presence of IL-5. Blockade of the eosinophil adhesion molecule

VLA-4 prevented both eosinophil migration into the airways and the

associated development of AHR. These data extend some of the clinical

observations that development of RSV-induced AHR is associated with the

presence of eosinophils and may be dependent on this eosinophilic

response.

Dependence of virus-induced AHR on IL-5 has also been reported in a

guinea pig model of parainfluenza infection. Studies in guinea pigs

revealed a mechanism by which eosinophils could influence airway tone and

reactivity. Cationic proteins released by eosinophils are capable of

binding to presynaptic M2 muscarinic receptors on postganglionic

parasympathic airway nerves. The resulting blockade interrupts an

inhibitory feedback mechanism, resulting in increased release of

acetylcholine and in increased airway muscle tone and reactivity. This

mechanism has been demonstrated both in models of allergic sensitization

and following acute viral infection. Parainfluenza neuraminidase can also

bind to M2 muscarinic receptors directly and may be responsible for

effects described in the absence of eosinophilic inflammation. In

addition, viral infection and interferon-gamma downregulate M2 receptor

gene expression.

Noninflammatory Mechanisms in Virus-Induced Wheezing

Additional noninflammatory mechanisms may contribute to the development

of wheezing following viral RTI. Viral infection of respiratory

epithelium results in reduced nitric oxide production associated with AHR

in guinea pigs. Nitric oxide is the putative bronchodilator agonist of

the nonadrenergic, noncholinergic inhibitory (NANCi) system. This system

can be defective during and after respiratory viral infection resulting

in AHR, as demonstrated in a study of RSV infection of cotton rats.[12]

A reduced barrier function of the respiratory epithelium may expose

sensory C fibers to enhanced stimulation. This results in the release of

neuropeptides, such as substance P and neurokinin A, both agonists of the

nonadrenergic, noncholinergic activating system; further, it induces a

brainstem reflex leading to bronchoconstriction. Neuropeptides can also

contribute to airway obstruction by causing increased leukotriene

synthesis, release of mast cell mediators, and increased mucus secretion.

In addition, infected epithelial cells produce smaller amounts of neutral

endopeptidase, an enzyme that degrades neuropeptides. The role of sensory

C fibers in virus-induced asthma exacerbations in humans remains

controversial. Bradykinin provocation following experimental rhinovirus

infection in mild asthmatics does not result in increased bronchial

hyperresponsiveness. Bradykinin is a strong stimulator of sensory C

fibers and may be expected to cause increased bronchial

hyperresponsiveness if this system plays a major part in virus-induced

asthma.

Persistence of Infection

At present, the mechanisms by which acute respiratory tract virus

infection can affect the development of asthma long after the infection

has resolved are unclear. Some of the pathologic changes may simply

persist for long periods after the acute infection. A defect in NANCi

function has been demonstrated to last for up to 24 weeks following RSV

infection in ferrets. Persistence of infection, resulting in chronic

alterations of epithelial cell function and chronic inflammation, is

supported by findings in guinea pigs and calves where RSV antigen can be

detected in the lung 6 and 12 weeks after the infection. In guinea pigs,

this persistence is associated with persistent AHR.

Interactions Between Viral RTI and Allergic Sensitization

To define potential mechanisms of interaction between viral RTI and

allergic sensitization to inhaled allergens, a number of rodent models

have been developed. The majority of these models showed increased

allergic sensitization following respiratory virus infection, resulting

in eosinophilic airway inflammation and AHR. In some of these models,

animals were first exposed to allergen during the acute infection phase

followed by subsequent allergen challenges, resulting in increased

allergic sensitization with elevated serum levels of allergen-specific

IgE.

In these experimental approaches, enhanced allergic sensitization was

potentially due to increased allergen uptake across inflamed mucous

membranes. Indeed, in both a guinea pig and a mouse model, exposure to

ovalbumin aerosol caused increased levels of serum ovalbumin if

administered during acute virus infection.

Schwarze and colleagues[10] reported on a murine model of RSV infection

and subsequent sensitization to aerosolized ovalbumin. In this model,

exposure to allergen over 10 days was begun only after the resolution of

the acute (RSV) infection. This resulted in enhanced responses to

allergen and, as a consequence, airway inflammation with the influx of

neutrophils and eosinophils. This was associated with altered airway

responsiveness to inhaled methacholine.

In contrast to many of the models discussed above, allergen-specific IgE

serum levels were not higher in the group that was infected with RSV

prior to allergic sensitization. This may indicate that mechanisms other

than increased allergen uptake are likely responsible for the effects of

RSV infection on the subsequent exposure to allergen. As demonstrated,

sensitization following acute RSV infection triggers eosinophilic

inflammation and associated AHR. Anti-IL-5 treatment during the allergen

exposure phase prevents lung eosinophilia and the development of AHR.

Prospects for Prevention and Treatment: Vaccines

A number of new approaches toward developing an RSV vaccine have shown

promise despite many earlier failures.[6] Two major problems have slowed

the development of effective RSV vaccines. The first issue is that prior

immunity can enhance the severity of naturally occurring disease. Second,

natural infection does not result in specific protection against

reinfection.

The new vaccines include a purified fusion protein vaccine, a reverse

engineered live attenuated vaccine, and naked DNA vaccination. A

humanized monoclonal antibody to RSV has been shown to be effective in

preventing lower RTI in high-risk children with bronchopulmonary

dysplasia.[13]

Conclusion

The importance of viral RTIs in asthma exacerbations has been documented

in numerous epidemiologic studies. It is much less clear that viral

infection, including RSV infection, induces atopic asthma. The immune

inflammatory response to virus infection is complex, dependent on the

peculiarities of individual host-virus interactions, and, with many

target cells, is capable of releasing numerous potent mediators of

inflammatory cell accumulation and end-organ toxicity.

The concordant or sequential interactions between viral infection and

allergen exposure in enhancing atopic asthma responses are equally

complex. Defining key elements in the pathways linking viral infection

and asthma exacerbations will provide better treatment options for our

patients.

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