The document discusses virus-induced asthma attacks. It notes that viruses are a common cause of asthma attacks, with rhinoviruses being the most frequent trigger. Viruses can induce airway inflammation through epithelial cell production of inflammatory mediators. They may also impair inactivation of tachykinins and histamine, potentiate allergic responses, and alter neural control of the airways. Treatment of virus-induced asthma attacks should include anticholinergic bronchodilators, steroids, and prevention of viral infections through vaccination and antiviral medications when available.

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‫الرحيم‬ ‫الرحمن‬ ‫ا‬ ‫بسم‬

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Virus-Induced Asthma Attacks
Moustapha Mounib,FCCP
Consultant of Chest Diseases
Military Medical Academy

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Introduction
Asthma is a disease of attacks and
remissions. The cause of an attack can
often be identified by carefully taking a
history. Common causes of asthma attacks
include inhaled irritants, inhaled allergens,
and viral infections of the respiratory tract.

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Numerous studies have demonstrated viral
infections at the time of acute asthma
attacks. Methods used include serologic
testing, viral culture, and, most recently,
reverse transcription-polymerase chain
reaction to detect viral RNA; the viruses
associated with asthma attacks are RNA
viruses. In children and adults, the most
common viruses in this setting are
rhinoviruses (a picornavirus that is the usual
cause of the common cold), followed by
influenza, parainfluenza, respiratory
synvytial virus (RSV), and coronaviruses.

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Figure1. Viruses Detected During Respiratory
S ymptom And Peak Respiratory Flow Episodes
0
10
20
30
40
50
60PicornavirusCoronavirus
InfluenzaParainfluenza
RSV
Other
No
Virus
Episodes
%

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• In contrast, the role of bacterial infections in
acute asthma is far from established.
Evidence linking acute infection with common
respiratory bacteria is weak, and although
such bacteria may be found in the airway with
increased frequency in patients with airway
disease, an increase during acute
exacerbations of asthma has been difficult to
demonstrate.

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Possible exceptions to this rule are mycoplasma
and chlamydia. These infections have been
implicated in some studies of both acute and
chronic asthma, and treatment of chlamydia has
been associated with improvement in some
series. However, controlled trials have not yet
been conducted, and the possibility that these
organisms are important contributors to acute
asthma, although provocative, cannot yet be
viewed as established.

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Mechanisms Of Virus-Induced
Asthma Attacks

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Virus-Induced Airway Inflammation
Airway epithelial cells produce a
variety of inflammatory mediators in
response to viral infection (Table)

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Inflammatory Mediators Produced By E pithelial C ells in R esponse to Viral
Infection
Inflammatory Mediators Produced By E pithelial C ells in R esponse to Viral
Infection
E ffect of VirusVirus
E pithelial
Product
Inflammatory
Mediators
IncreasedR VInterleukin 1
IncreasedR VT NF-a
Increased
R V,Influenza,R
S VInterleukin 6
Increased
R V,Influenza,R
S VInterleukin 8
UnknownInterleukin 10
IncreasedR S VInterleukin 11
IncreasedR S VInterleukin 12
UnknownInterleukin 16
Increased or
UnchangedR S VMC P-1
UnchangedR S VMC P-3
IncreasedR S VMC P-1a
UnchangedR S VMC P-1ß
Increased
R S V,R V.Influen
zaR ANT E S
IncreasedR V,R S VG M-C S F
IncreasedR VG -C S F
UnknownR VC S F -1
UnknownM-C S F
E ffect of
Virus
VirusE pithelial Produc t
Growth F actors
IncreasedR S VE ndothelin
IncreasedR S VVE G F
IncreasedR VG R O-a
UnknownG R O-ß
Immune F actors
Increased
Parainfluenz
a
Interferon a and Interferon ß
Increased
Parainfluenz
a
MHC class I
molecules
Increased
Parainfluenz
a
MHC class II
molecules
UnknownDefensins
Adhes ion molecules
IncreasedR VIC AM-1
IncreasedR VVC AM
Others
IncreasedInfluenzaOxygen radicals
IncreasedR S V,R VAntioxidant enzymes
IncreasedR S V,R V
Inducible nitric oxide
S ynthase
IncreasedR S V5- Lipoxygenase

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Viruses can also enter macrophages
and replicate in them, which may
result in the production of a wide
range of inflammatory mediators,
overlaping many of those produced
by the epithelium.

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Viral infections also potentiate the response to
subsequent inhaled allergens in terms of
inflammatory response and bronchoconstriction.
Similarly, allergic responses in dust mite-
sensitized mice are potentiated by repeated
RSV infections. IgE production can be
potentiated by viral infection, which may also
contribute to maintaining asthmatic airway
inflammation and potentiating the response to
allergens.

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Virus-Induced Impairement in Inactivation
of Tachykinins and Histamine
The effects of a variety of mediators in the
airways are increased during viral
infections. Included among these
mediators are tachykinins, a group of
peptide transmitters produced in sensory
nerves. They cause bronchoconstriction,
increase vascular permeability that leads
to airway edema, stimulate gland
secretion, and cause migration of
leukocytes into the airways.

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During viral infection these effects are
potentiated because of loss of activity
of neural endopeptidase, an enzyme in
the airways that degrades and
inactivates tachykinins. Changes in
tachykinin expression and neurokinin
receptors (which mediate the response
to tachykinins) in the airways may also
contribute.

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The airway response to histamine is
also potentiated. Although this
response is largely due to increased
reflex bronchoconstriction, viral
infections also decrease the activity of
the enzyme histamine N-
methyltransferase, which normally
inactivate histamine.

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Nitric Oxide Production
Because of the multiple effects of nitric oxide, the
net effect of virus-induced changes in nitric oxide
production is difficult to predict . Some studies
suggest that nitric oxide contributes to tissue
damage in the virus-infected lung, whereas others
suggest that defective production of nitric oxide
contributes to bronchoconstriction. Nitric oxide
suppresses rhinovirus replication and the
production of proinflammatory cytokines in airway
epithelial cells.

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Virus-induced Changes in Neural Control
of the Airways
Viral infections increase vagally mediated
reflex bronchoconstriction. They may also
potentiate responses to tachykinins and
cause defective airway relaxation.

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In the airways, the dominant neural
control is provided by cholinergic fibers
in the vagus nerves. Increased
cholinergic reflex bronchoconstriction
has been demonstrated in humans with
naturally ocurring viral infections.
Animal studies clearly demonstrate
increases in the efferent part of the
reflex.

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Release of acetylcholine from vagal nerve
endings is limited by M2 muscarinic
receptors on the airway nerves.
Acetylcholine released from
parasympathetic fibers stimulates smooth
muscle contraction and
bronchoconstriction by binding to M3
receptors on the smooth muscle. However,
at the same time, released acetylcholine
feeds back onto inhibitory M2 receptors
on the nerve endings themselves. Binding
of acetylcholine to these inhibitory
autoreceptors provides negative feedback,
decreasing further release of acetylcholine.

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Viruses and interferons produced in
response to viral infection downregulate the
expression of the M2 receptors gene.
Animal studies demonstrate that the
inhibitory M2 receptors lose function during
viral infections, which eliminates the normal
negative feedback inhibition of acetylcholine
release and increases vagally mediated
bronchoconstriction. This loss of function
can be reversed by corticosteroids, which
increase M2 receptor gene expression and
function.

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M2 receptor dysfunction may also occur via
eosinophil-dependent mechanisms. In
patients who have died from severe
asthma, eosinophils are found clustered
along the airway nerves. These eosinophils
release major basic protein, which binds to
M2 receptors, blocking their function.

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Studies in experimental animals
demonstrate that viral infection can activate
eosinophils to cause M2 receptor
dysfuntion and bronchoconstriction via this
mechanism. The mechanism by which
viruses activate eosinophils is not well
understood, but experimental studies
suggest that CD8 T lymphocytes are
involved.

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Airway parasympathetic neurons express
eotaxin, which attract eosinophils. These
neurons also express intercellular
adhesion molecule 1 (ICAM-1) and
vascular cell adhesion molecule.
Expression of ICAM-1 is inhibited by
dexamethasone, which also prevents the
influx of eosinophils into the airway nerves
and dysfuntion of the M2 receptor.

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The eosinophil may also be beneficial in virus-
infected airways, exerting a substantial antiviral
effect. Preliminary studies suggest that the antiviral
effects of eosinophils are mediated via the
production of hypobromous acid. It has also been
suggested that production of ribonucleases by
eosinophils may participate in the antiviral effect by
degrading viral RNA. Thus, both TH1-type cytokines
(interferon γ) and TH2 -type cytokines (leading to
eosinophilia) can participate in virus-induced M2
receptor dysfunction.

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Studies suggest that sensitization to a nonviral
antigen or possibly a background of atopy, as is
present in many patients with asthma, may
predispose patients to the latter pathway in
which eosinophils are activated by viral
infections. In contrast, in the absence of an
atopic background, viruses lead to production of
interferons that can downregulate M2 receptor
expression and function. Because levels of
interferon γ are increased in the airways of
patients with atopic asthma, this mechanism
may also apply in these patients.

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Implications For Treatment

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Anticholinergic Bronchodilators
Anticholinergic therapy offers modest benefits in stable
asthma, but acute exacerbations of asthma appear to
respond more favorably when anticholinergics are added
to b-agonists than when b-agonists are used alone. Thus,
a National Institutes of Health Expert Panel Report
recommends anticholinergics in addition to β-agonists for
the initial treatment of severe asthma attacks and for
patients admitted to the hospital with acute asthma.
Controlled studies show that emergency treatment of
acute asthma attacks with anticholinergics in addition to β-
agonists decreases the hospitalization rate in adults and
children. The benefit of anticholinergic treatment is
greatest in those with more severe attacks.

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Steroids
Treatment with steroids is a standard
therapy for asthma attacks. Although
many mechanisms are likely to
contribute to the beneficial effects of
steroids, it is likely to be significant that
steroids can reverse the effects viruses
and interferons on M2 receptor gene
expression and that they can increase
M2 receptor expression and function.

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Treatment and Prevention of
Viral Infections
Because viruses may precipitate asthma
attacks, prevention or treatment of viral
infections is advisable in patients with
asthma. Unfortunately, among the the
viruses commonly implicated in asthma
attacks, effective vaccination is available
only for influenza.

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Influenza
Patients with asthma should receive flu shots,
although an overall decrease in asthma
attacks in patients receiving flu shots has
been difficult to demonstrate, probably
because less than 10% of asthma attacks are
caused by influenza. Treatment and
prevention of influenza infection with
neuraminidase inhibitors may also be
advisable, although again a reduction in
asthma attacks has yet to be demonstrated.

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Respiratory Syncytial Virus
The association of RSV infection with asthma attacks in older
children and adults suggests that treatment and prevention of
RSV infections might also be beneficial in patients with
asthma. However, neither a vaccine nor an effective
treatment is available for this virus. Treatment with
humanized monoclonal antibodies(palivizumab) is costly and
has not been evaluated in older patients or in those with
asthma. The antiviral medication ribavirin has been used to
treat these infections in infants and children, but a beneficial
effect has been difficult to demonstrate.

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Parainfluenza and Coronavirus
Parainfluenza virus and coronaviruses
are common causes of upper
respiratory tract infections. In patients
with asthma, they may precipitate
attacks. Neither treatments nor vaccines
are available.

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Rhinovirus
Rhinovirus infections are the predominant
cause of the common cold and of virus-induced
asthma attacks. Unfortunately, it has not yet
been possible to develop a vaccine. There are
more than 100 serotypes of rhinovirus.
Immunity follows infection with each one;
however, because they are all immunologiclly
distinct, antibodies to a very wide range of
antigens would be required to confer immunity
to all rhinoviruses. Both a soluble form of ICAM-
1 and the compound pleconaril can interfere
with rhinovirus binding and may hold promise
for treating infection.

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Antibiotics
Conventional bacteria are probably not
major causes of asthma attacks. For this
reason, antibacterial treatment cannot be
viewed as standard care during asthma
attacks unless there is definite evidence of
a bacterial infection. The role of treatment
for mycoplasmal and chlamydial infections
in acute and chronic asthma awaits
controlled clinical trials.

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CONCLUSIONS

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According to the data reviewed here, the following
can be recommended:
1-The management of acute asthma should include
anticholinergic bronchodilators in addition to β-
agonists and steroids.
2-Routine use of antibiotics is probably not justified.
3- Prevention of viral infections by using vaccination
as well as antiviral medications as they become
available is likely to be advisable in patients with
asthma.

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4-As neurokinin receptor antagonists are
develoloped, they may be particularly
effective in this group of patients because
tachykinin-mediated responses are
potentiated.
5- The long list of known virus-induced
proinflammatory mediators may suggest new
therapeutic directions as antagonists of thes
mediators become available.

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Thank you.