Rhinovirus Respiratory Infections and Asthma
James E. Gern, MD
Viral infections, particularly respiratory illnesses
caused by rhinovirus, are the most common cause of
asthma exacerbations in children and contribute in
large part to asthma morbidity in adults. Epidemio-
logic studies and increasingly sophisticated viral de-
tection methodologies have helped to define the role
of rhinovirus as a potential causative agent in asthma
exacerbations. Rhinovirus-induced lung disease is
multifaceted and can be characterized in terms of a
variety of physiologic, immunologic, and viral pro-
cesses. The precise direct and indirect mechanisms
of viral contribution to exacerbations must still be
elucidated. Understanding them will have an impact
on the design of future treatment modalities. Am J
Med. 2002;112(6A):19S–27S. © 2002 by Excerpta Med-
ica, Inc.
From the Department of Pediatrics, University of Wisconsin–Madison,
Madison, Wisconsin, USA.
Requests for reprints should be addressed to James E. Gern, MD,
Department of Pediatrics, University of Wisconsin–Madison, K4/918
CSC, 600 Highland Avenue, Madison, Wisconsin 53792-9988.
© 2002 by Excerpta Medica, Inc.
All rights reserved.
R
hinoviruses are the most frequent cause of viral
respiratory infections (VRIs), or the common
cold, and have been shown to be responsible for
more than 50% of colds during the peak fall season.1–3 Of
even greater clinical significance, however, is the growing
body of evidence implicating rhinovirus-induced respi-
ratory infections as a cause of asthma exacerbations
in children and adults.3–5 Rhinovirus infections of the
upper and lower respiratory tracts in individuals with
asthma have important implications for the epidemiol-
ogy, associated risk factors, pathogenesis, and therapeutic
management of this disease.
Epidemiology of Asthma and Rhinovirus
Infections
Use of Reverse Transciption Polymerase
Chain Reaction to Identify Presence of Viruses
Early studies attempting to establish the connection be-
tween respiratory pathogens and wheezing or related
breathing disorders were limited by the use of relatively
insensitive standard cell culture techniques or methods to
detect increasing titers of virus-specific antibody. The de-
velopment of reverse transcription polymerase chain re-
action (RT-PCR) assays has helped to clarify the role of
viruses, and rhinovirus in particular, in asthma exacerba-
tions.3–5 Although RT-PCR detection is more sensitive
and rapid than culture, currently this method is primarily
a research tool for identification of rhinoviruses.
Rhinovirus Isolation in Epidemiologic Studies
in Children and Adults with Asthma
Using PCR and standard viral diagnostic tests, Johnston
et al3 reported that viral infection was associated with
80% to 85% of asthma exacerbations (as defined by re-
ported symptomatology and reduced peak expiratory
flow rates) in school-aged children aged 9 to 11 years who
had a history of asthma. In this study, viruses were de-
tected in 226 of 292 reported episodes of respiratory ill-
ness or reduced peak expiratory flow: picornaviruses
(which include the subgroups rhinoviruses and enterovi-
ruses) accounted for about 66% (147 of 226) of detected
viruses.
Nicholson et al5 found that among 138 adults who had
asthma, colds were reported in 80% (223 of 280) of epi-
sodes with symptoms of wheeze, chest tightness, or
breathlessness, and 89% (223 of 250) of colds were asso-
ciated with asthma symptoms. Viruses were identified in
57% of subjects with symptomatic colds and asthma ex-
acerbations, with exacerbations defined as decreased pul-
monary function (ie, greater than 50 L/min reduction in
0002-9343/02/$20.00 19S
PII S0002-9343(01)01060-9
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern
Table 1. Risk Factors for More Severe Rhinovirus Infections
● Low neutralizing antibody titers
● Asthma
—Allergy
—IgE
—Cytokine production
IFN-␥
IL-5
● Chronic lung diseases
● Extremes in age
IFN ⫽ interferon; Ig ⫽ immunoglobulin; IL ⫽ interleukin.
Adapted from Clin Microbiol Rev.4
mean peak expiratory flow rate). Again, rhinovirus was
the most frequent virus identified by PCR in these epi-
sodes, isolated from 76 (33%) of the 229 nose and throat
swabs from patients with symptoms of asthma or colds,
or both. Together, these results demonstrate that a large
majority of emergent wheezing illnesses in both children
and adults can be linked to infection with common cold
viruses such as rhinovirus.
Rhinovirus Seasonality
Further evidence for rhinovirus involvement with
asthma is based on the seasonality of exacerbations. Rhi-
novirus infections occur year round with peaks in fall and
spring.1–3 Johnston et al6 conducted a time-trend analysis
comparing the seasonal patterns of respiratory infections
and hospital admissions for asthma among adults and
children. Strong correlations were found between the
seasonal patterns of upper respiratory infections (URIs)
and 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). URIs and admissions for asthma were
more frequent in the fall and spring when children went
back to school after vacations (P ⬍0.001). Rhinoviruses
were the major pathogens implicated in these infections.
The authors speculated that school attendance and
crowding of children in classrooms facilitate spread of the
virus.
Risk Factors for Rhinovirus-induced
Exacerbations of Asthma
A number of factors might place asthma patients at in-
creased risk for more severe rhinovirus infections result-
ing in lower respiratory manifestations (Table 1).4
Because bronchospasm during asthma results from
airway inflammation and hyperresponsiveness, the ef-
fects of infection on these conditions are of special inter-
est. The finding that rhinovirus infections frequently
exacerbate asthma suggests specific interactions between
viral infections and respiratory allergies or the disease
itself on airway biology and immunology.
20S April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A)
IgE and Atopy
Researchers at the University of Virginia conducted a
study to evaluate potential interactions between rhinovi-
rus infections and age, atopic status, and eosinophil
markers. In a cross-sectional emergency department
study of 70 children with wheezing and 59 control sub-
jects,7 respiratory viruses were detected in more than
80% of wheezing children 2 months to 16 years of age.
Rhinoviruses were the predominant pathogens in wheez-
ing children older than 2 years of age and accounted for
71% of respiratory illnesses. After 2 years of age, the
strongest odds for wheezing were observed among those
who had a positive PCR test for rhinovirus plus positive
radioallergosorbent tests, nasal eosinophilia, or elevated
nasal eosinophil cationic protein (odds ratios ⫽ 17, 21,
and 25, respectively). These findings suggest that there
may be synergistic interactions between rhinovirus infec-
tions and allergic airway inflammation to increase the
risk of wheezing illnesses.
Cytokine Production
The pattern of cytokine production in patients with
asthma may also confer risk of an exacerbation in the
presence of rhinovirus infection. Recent experimental in-
oculation studies with the rhinovirus RV16 have related
cytokine production to clinical symptoms and to the de-
gree of viral replication.8,9
To test the hypothesis that rhinovirus-induced im-
mune responses influence the outcome of rhinovirus in-
fections, 22 seronegative subjects who had either asthma
or allergic rhinitis were experimentally infected with
RV16.8 Before the cold, the peripheral blood mononu-
clear cell response to inoculation was assessed by mea-
surement of levels of rhinovirus-induced IFN-␥ from the
culture supernatants. Peak rhinovirus shedding mea-
sured during the most symptomatic part of the illness was
inversely related to IFN-␥ production. That is, subjects
who produced adequate levels of IFN-␥ tended to shed
less virus during their cold.
During the acute illness, mRNA for both IFN-␥ and in-
terleukin-5 (IL-5) was measured in the sputum to deter-
mine the relationship between virus-induced Th1 and Th2
cytokine production and effects of viral infection.9 The ratio
of IFN-␥ to IL-5 mRNA from sputum was also evaluated
(Figure 1) as an immune-response indicator. Th1-like cyto-
kines such as IFN-␥ are frequently produced in response to
viral infection, whereas Th2 cytokines such as IL-5 may pro-
mote allergic inflammation. Therefore, a high IFN-␥–IL-5
mRNA ratio may represent a strong antiviral response. In
this study, there was an inverse relationship between this
ratio and peak symptom scores. That is, individuals who
tended to have a more Th1-like response (ie, patients with
high IFN-␥ and low IL-5) tended to have fewer symptoms
during the peak of the cold.9
The duration of viral shedding was also assessed. The
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern

Figure 1. Sputum interferon-␥/interleukin-5 (IFN-␥/IL-5) ratio and respiratory symptoms. A strong Th1-like cytokine response
(high IFN-␥ and low IL-5) in the airway may play an important role in limiting the amount of viral replication and respiratory
symptoms in colds caused by rhinovirus. In this study, there was an inverse relation between this ratio and peak symptom scores. That
is, individuals who tended to have a more Th1-like response tended to have fewer symptoms during the peak of the cold. mRNA ⫽
messenger RNA. (Reprinted with permission from Am J Respir Crit Care Med.12)

IFN-␥ –IL-5 ratio was compared with the presence of
rhinovirus in nasal secretions and sputum at 7 and 14
days. At 14 days, rhinovirus RNA was found in the spu-
tum of approximately 50% of individuals. In those who
had cleared the virus at 14 days, there was a significantly
higher IFN-␥–IL-5 mRNA ratio compared with those
who had not cleared the virus.9 When considered to-
gether, these findings suggest that a predominant Th1
response (ie, high IFN-␥–IL-5 ratio) is associated with a
more powerful antiviral response, more rapid clearing of
the virus, and shorter duration of illness. Additional stud-
ies are needed to determine whether reduced interferon
response to viral infection contributes to more severe
lower respiratory manifestations in patients with asthma.
Finally, because cytokine dysregulation has also been as-
sociated with allergic sensitization, it will be of interest to
determine whether these risk factors for more severe
manifestations of rhinovirus infection are concordant
and associated or instead have independent effects.
Pathogenesis of Viral Infection and
Asthma
The studies discussed suggest that there may be certain
pathologic mechanisms, particularly in asthma but also
in allergic disease in general, that may promote more se-
vere VRIs in individuals with allergy or asthma. The un-
resolved question is how viral infections, particularly
with rhinoviruses, provoke asthma.
Direct and/or Remote Effects of Viral Infection
Direct and/or remote effects of viral infection may have a
role in provoking asthma.4 First, it is possible that the
VRI, which clearly involves the upper airway, also in-
volves lower airway epithelium and that viral replication
in the lower airway causes inflammation and provokes
bronchospasm, airway obstruction, and wheezing. It is
also possible that the virus is largely confined to the upper
airway and that remote, indirect mechanisms provoke
asthma. These remote effects might be neural reflexes or a
virus-induced systemic immune stimulation that affects
the lung if there is pre-existing inflammation. A variety of
immune factors are associated with lower airway symp-
toms in individuals with asthma.
The Association Between Circulating
Neutrophils and Symptoms
Studies have noted that rhinovirus infections, like other
viral infections, cause a transient increase in the number
of circulating neutrophils that correspond with the peak
symptoms. Peak symptom scores and the magnitude of
the change in neutrophils also are related.10,11 Our group
reported on possible action of rhinovirus on certain local
factors that could, in turn, act on the bone marrow to
increase peripheral blood neutrophils.9,10 Seronegative
individuals with allergic rhinitis or asthma were inocu-
lated with RV16. On days 1 and 2 after the inoculation, we
performed nasal lavage for viral cultures and cell counts

April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A) 21S
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern
and obtained blood specimens for interleukin-8 (IL-8)
and granulocyte colony-stimulating factor (G-CSF). IL-8
is known to be an important chemoattractant for neutro-
phils, and IL-8 levels generally correlate with neutrophil
increases in the nose. G-CSF is known to stimulate the
production of neutrophils in the bone marrow.
G-CSF and IL-8 increased significantly in the nasal se-
cretions during the acute phase of the cold, correlating
with peak symptoms after experimental inoculation. Fur-
thermore, the amount of G-CSF in the nose correlated
with serum G-CSF (correlation coefficient 0.95). Serum
G-CSF also significantly correlated with changes in the
number of blood neutrophils, suggesting that there is a
systemic immune response to the viral infection and that
increased mediators in the serum in turn act on the bone
marrow.
There was also a positive correlation between serum
G-CSF and symptoms (r ⫽ 0.72, P ⬍0.05) and between
serum neutrophils and symptom scores (r ⫽ 0.86, P
⬍0.005). These findings suggest that rhinovirus infects
the respiratory epithelium locally, and the generation of
G-CSF in the nose also increases levels in the serum (Fig-
ure 2). Then, serum G-CSF affects the bone marrow, re-
sulting in an increase in neutrophil synthesis and release.
G-CSF may also affect neutrophil attraction and recruit-
ment into the airway by means of mechanisms that have
not yet been defined.
The true nature of the relationship between rhinovirus
infection, increased neutrophil numbers, and the gener-
ation of respiratory symptoms remains to be determined.
Are the increased neutrophil numbers merely a reflection
of more severe infections, or do they participate in the
pathogenesis of respiratory symptoms and in asthma air-
way obstruction? The answer to this question awaits the
development of specific inhibitors of neutrophil recruit-
ment (eg, IL-8 antagonist) or activation.
Rhinovirus Infections and Lower Airway
Physiology
One of the cardinal features of asthma is airway hyperre-
sponsiveness, which is defined as an increased propensity
to bronchoconstriction in response to such irritants as
histamine, tobacco smoke, or allergens. It has long been
recognized that VRIs can transiently increase airway re-
sponsiveness, and several studies have been conducted to
determine the mechanisms for this effect.12
One such study, by Grunberg et al,13 examined the
effect of RV16 infection on airway hypersensitivity to his-
tamine and on IL-8 in nasal lavage. This placebo-con-
trolled, parallel study involved 27 nonsmoking, atopic
subjects with mild asthma who were given a dose of RV16
or placebo administered nasally.13 Symptom scores were
measured throughout, and histamine challenges were
performed at entry and on days 4 and 11 after inoculation
to assess changes in airway responsiveness. Airway hyper-
22S April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A)
responsiveness, as measured by PC20 (the concentration
of histamine that causes a 20% reduction in lung func-
tion), is an indicator of lower airway sensitivity to non-
specific irritants, which is a consistent feature of asthma.
In the RV16-treated patients there was an increased
sensitivity to histamine at day 4, which was most pro-
nounced in those with a severe cold (P ⫽ 0.01). In addi-
tion, IL-8 levels increased in the RV16 group at days 2 and
9 (P ⬍0.001), and the increase in nasal IL-8 at day 2 cor-
related significantly with the change in PC20 at day 4 (r ⫽
⫺0.48, P ⫽ 0.04). These results suggest that more severe
colds may be required to disturb lower airway physiology
and, by extension, to cause exacerbations of asthma. Fur-
thermore, this study was able to relate changes in an up-
per airway inflammatory response (increased IL-8) to an
increase in lower airway sensitivity to histamine. Whether
this occurred by means of systemic immune stimulation
or was an indicator of concurrent increases in lower air-
way IL-8 could not be determined by this study design.
Does rhinovirus infection of the lower airway cause
exacerbations of asthma? Studies to determine the
mechanisms by which viruses cause lower airway disease
are hampered by difficulty in sampling lower airways, and
efforts to culture rhinovirus from the lower airway after
experimental inoculation have met with limited success.4
However, studies using advanced technologies to detect
virus, such as RT-PCR and in situ hybridization, have
detected rhinovirus in the lower airway.14,15
Gern et al14 reported that the use of RT-PCR with
bronchoscopy consistently identified virus in patients af-
ter inoculation. Furthermore, Papadopoulos et al15 used
in situ hybridization for RV16 on bronchial biopsy sam-
ples taken before infection (baseline), during the peak of
the infection, and 6 to 8 weeks after infection to obtain
definitive evidence that rhinovirus infection occurs in the
human lung. These researchers showed that virus, at least
under some conditions, can actively replicate in the lower
airway.
Effect of temperature on viral replication. Most rhino-
viruses preferentially grow at temperatures cooler than
37⬚ C (98.6⬚ F), and this has been cited as a potential
barrier to growth in the lower airway. Direct thermal
mapping of the airways has revealed, however, that tem-
peratures in the lower airways are conducive to the
growth of rhinoviruses.
For example, McFadden et al16 found that during quiet
breathing at rest, at room temperature, the carina had a
temperature of 32⬚ C inspiratory and 33⬚ C expiratory,
which is perfect for rhinovirus replication (Figure 3). It
was not until the temperature probe reached peripheral
airways that recorded temperatures were high enough to
inhibit rhinovirus replication. Additional studies have
demonstrated that rhinoviruses can grow in bronchial
epithelial cells.17 Therefore, it appears that the environ-
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern

Figure 2. Rhinovirus (RV)-induced recruitment of polymorphonuclear leukocytes (PMN). The RV infects the respiratory epithe-
lium locally, causing an increase of granulocyte colony-stimulating factor (G-CSF) first in the nasal secretions and then in the blood.
Increased G-CSF affects the bone marrow, resulting in an increase in neutrophil synthesis and release. Interleukin-8 (IL-8), and
possibly G-CSF, then increase neutrophil recruitment into the airway.

Figure 3. Thermal mapping of the airways. In the large airways of the lung, inspiratory and expiratory temperatures are sufficiently
low to allow rhinovirus replication to occur. (Adapted from J Appl Physiol.16)

ment is appropriate, at least in the large airways, for rep-
lication of rhinovirus.
Although the presence of rhinovirus in the lower air-
ways has been confirmed, the quantity present is unclear.
It is uncertain whether levels of rhinovirus are sufficiently
high to cause local inflammation resulting in the effects of
asthma.
Cellular Mechanisms Contributing to
Rhinovirus-induced Asthma
The potential cellular mechanisms that contribute to rhi-
novirus-induced asthma are illustrated in Figure 4.4 Vi-
rus-infected epithelium releases a host of cytokines and
mediators that regulate airway inflammation. In particu-
lar, such factors as IL-8 (regulated upon activation, nor-
mal T-cell expressed and secreted) and G-CSF are se-
creted during acute colds. These cytokines increase the
synthesis of leukocytes, recruit them into the airway, and
help to activate the inflammatory functions of neutro-
phils, macrophages, and lymphocytes. Plasma leakage oc-
curs very early during the cold, which contributes to
edema and secretions in the airway that can cause ob-
struction.18 After the plasma leakage, there is mucus hy-

April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A) 23S
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern

Figure 4. Cellular mechanisms contributing to rhinovirus-induced asthma. Virus-infected epithelium releases cytokines and
mediators that can recruit additional cells to the airway. Plasma leakage occurs, which contributes to edema and secretions in the
airway that can cause obstruction. Then mucus hypersecretion causes thick, viscous secretions that could occlude the airway. Other
effects that may contribute to airway hyperresponsiveness and bronchospasm include neural stimulation by virus that could promote
bronchospasm and cough during these episodes. (Reprinted with permission from Clin Microbiol Rev.4)

persecretion, thick, viscous secretions that could occlude
the airway. Other effects also may contribute to airway
hyperresponsiveness and bronchospasm. For example,
neural stimulation and neurogenic inflammatory re-
sponses to virus could result in bronchospasm and cough
during these episodes.
The neutrophil is the primary cell recruited to the up-
per airway during VRIs, and recent studies indicate that
this also occurs in lower airways. In a study by Jarjour et
al10 to assess changes in lower airways, 8 subjects who had
a history of allergic asthma were experimentally inocu-
lated with RV16, and lower airway secretions were evalu-
ated using bronchoscopy and lavage. Before the cold,
bronchoscopy itself was associated with small increases in
lavage neutrophils (pre-cold BL1 vs BL2; Figure 5). How-
ever, during the acute cold there was a significant increase
in bronchial lavage neutrophils 96 hours after inocula-
tion (acute cold BL2 vs BL1). Typically, this is the time
when changes in airway responsiveness are observed.13
Studies, such as this one, using experimental rhinovi-
rus inoculation have begun to establish the sequence of
neutrophilic inflammation in different body compart-
ments. For example, the greatest changes in blood neu-
trophils have been found 1 day after inoculation. Upper
airway symptoms and inflammatory responses tend to
peak 2 to 3 days after experimental inoculation. Inflam-
mation in the lower airway and changes in airway respon-
siveness occur 4 to 7 days after inoculation. This suggests
that infection may progress from the upper airway to the
lower airway and lead to asthma exacerbations.
Implications for Therapy
The immune response to VRIs contributes to airway ob-
struction and respiratory symptoms by inducing produc-

24S April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A)
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern

Figure 5. The effect of rhinovirus 16 (RV16) infection on bronchial lavage (BL) neutrophils (n ⫽ 8). Bronchoscopy and BL were
conducted twice before inoculation and twice after inoculation with RV16. Before inoculation, few neutrophils were found in BL
fluid. During the acute cold, there were few neutrophils 2 days after inoculation (acute cold BL1). However, 4 days after inoculation
(acute cold BL2), there was a significant increase in BL neutrophils from the initial values (acute cold BL1) and from both pre-cold
values (pre-cold BL1 and BL2). *P ⬍0.05 vs BL values (pre-cold and cold); †P ⬍0.05 vs BL2 pre-cold. (Reprinted with permission
from J Allergy Clin Immunol.11)

tion of proinflammatory cytokines and mediators. The
inflammatory cascade, along with direct effects of the vi-
rus, activates neural mechanisms to trigger airway hyper-
responsiveness and promote airway obstruction. It is
likely that the immune response to the viral infection can
enhance the pre-existing airway inflammation in asthma,
leading to clinical exacerbations. This model suggests op-
portunities for the design of therapeutic interventions
(Figure 6).4
Vaccination is not a viable therapeutic option, because
there are more than 100 serotypes of human rhinovirus.
However, several antiviral medications are in various
stages of development. Rhinoviruses bind to specific re-
ceptors (90% of rhinovirus serotypes bind to intercellular
adhesion molecule–1) on the epithelial cell in order to
replicate; the multiple generations of rhinovirus in the
cell trigger secretion of cytokines and chemokines. Sev-
eral antiviral agents have been developed to inhibit spe-
cific steps in the virus replication cycle.
Interferon-␣ (IFN-␣) was the first antirhinovirus
agent to be tested in clinical trials. One such study com-
pared intranasal ␣-2 IFN with placebo begun within 48
hours of the onset of illness to prevent respiratory illness
in healthy contacts of ill family members. Respiratory ill-
ness developed in 52 of 222 persons in the placebo group,
compared with 32 of 226 in the interferon group (P ⫽
0.02). In the 2-week period during and after spraying,
rhinovirus colds developed in 1.3% of the treated group
and in 15.1% of the placebo group.19
The clinical utility of IFN-␣ is limited, however, in that
it causes local nasal irritation, and it is generally ineffec-
tive if administration is delayed until after the onset of
symptoms. In addition, IFN-␣ administered to patients
with chronic respiratory disease (including asthma) after
close contact with people who have upper respiratory
symptoms does not prevent cold-related lower respira-
tory symptoms.20
Several new antiviral agents have been developed for
the treatment of rhinovirus infection, including soluble
intercellular adhesion molecule–1 and capsid-binding
agents, which either hinder rhinovirus binding to cellular
receptors or inhibit uncoating of the virus and release of
RNA inside the cell.21,22 In addition, inhibitors of rhino-
virus 3C protease inhibit rhinovirus replication in vitro.23
Some of these compounds have been tested in clinical
trials and have demonstrable antiviral activity.24 Whether
these agents can be used at the first sign of a cold to pre-
vent asthma exacerbations or are better used prophylac-
tically during peak rhinovirus seasons has yet to be deter-
mined.
Once viral replication occurs, epithelial cells and leu-
kocytes in the airway produce pro-inflammatory cyto-
kines, which are likely to contribute to common cold
symptoms and perhaps airway obstruction in asthma. In-

April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A) 25S
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern
Figure 6. Potential therapeutic interventions include specific antiviral medications targeted to the rhinovirus, mechanisms that
interfere with signaling pathways for cellular activation, and agonists and antagonists that moderate the host inflammatory response.
(Reprinted with permission from Clin Microbiol Rev.4)
vestigators are now defining intracellular mechanisms by
which viruses activate cytokine genes.4 Methods to block
the signaling pathways for cellular activation are potential
therapeutic targets to reduce virus-induced inflamma-
tion and symptoms. Short bursts of oral corticosteroids
early during the course of a VRI in patients with asthma
have been effective in reducing the severity and duration
of asthma exacerbations.25 However, although effective
in reducing lower airway symptoms, they do not lessen
the cold symptoms.26 Furthermore, systemic steroids
have undesirable side effects. Therefore, corticosteroids
may not be the optimal therapeutic approach. Because
many of the involved inflammatory cells, cytokines, and
mediators have overlapping effects, therapeutic ap-
proaches may need to inhibit multiple inflammatory
pathways in order to reverse the effects of rhinovirus on
airway function.
Conclusions
Rhinovirus infection can trigger severe episodes of
asthma exacerbations. The immune response to VRIs,
which is crucial to clearing the virus, may also contribute
to airway obstruction and respiratory symptoms. Al-
though the mechanisms for these effects are not fully elu-
cidated, they appear to be associated with the ability of
respiratory viruses to induce the production of proin-
flammatory cytokines and mediators. In the context of
asthma, the immune response to rhinoviruses is likely to
enhance pre-existing inflammation in the lower airway,
leading to clinical exacerbations.
26S April 22, 2002 THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A)
Virus-induced exacerbations of asthma tend to be re-
sistant to treatment with bronchodilators and inhaled
corticosteroids.27 Oral corticosteroids, although partially
effective, can be associated with significant side effects.
These findings suggest that development of antirhinovi-
rus medications or specific inhibitors of rhinovirus-in-
duced inflammation could have a major impact on re-
duction of the severity, and perhaps frequency, of asthma
exacerbations.
REFERENCES
1. Arruda E, Pitkäranta A, Witek TJ, Doyle CA, Hayden FG.
Frequency and natural history of rhinovirus infections in
adults during autumn. J Clin Microbiol. 1997;35:2864 –
2868.
2. Gwaltney JM Jr, Hendley JO, Simon G, Jordan WS Jr.
Rhinovirus infections in an industrial population. I. The oc-
currence of illness. N Engl J Med. 1966;275:1261–1268.
3. Johnston SL, Pattemore PK, Sanderson G, et al. Commu-
nity study of role of viral infections in exacerbations of
asthma in 9 –11 year old children. BMJ. 1995;310:1225–
1229.
4. Gern JE, Busse WW. Association of rhinovirus infections
with asthma. Clin Microbiol Rev. 1999;12:9 –18.
5. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and
exacerbations of asthma in adults. BMJ. 1993;307:982–
986.
6. Johnston SL, Pattemore PK, Sanderson G, et al. The rela-
tionship between upper respiratory infections and hospital
admissions for asthma: a time-trend analysis. Am J Respir
Crit Care Med. 1996;154:654 – 660.
7. Rakes GP, Arruda E, Ingram JM, et al. Rhinovirus and
respiratory syncytial virus in wheezing children requiring
 A Symposium: Rhinovirus Respiratory Infections and Asthma/Gern
emergency care. IgE and eosinophil analyses. Am J Respir
Crit Care Med. 1999;159:785–790.
8. Parry DE, Busse WW, Sukow KA, Dick CR, Swenson CA,
Gern JE. Rhinovirus-induced peripheral blood mononuclear
cell responses and outcome of experimental infection in
allergic subjects. J Allergy Clin Immunol. 2000;105:692–
698.
9. Gern JE, Vrtis R, Grindle KA, Swenson C, Busse WW.
Relationship of upper and lower airway cytokines to out-
come of experimental rhinovirus infection. Am J Respir Crit
Care Med. 2000;162:2226 –2231.
10. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR,
Busse WW. The effect of an experimental rhinovirus 16
infection on bronchial lavage neutrophils. J Allergy Clin
Immunol. 2000;105:1169 –1177.
11. Levandowski RA, Weaver CW, Jackson GG. Nasal secre-
tion leukocyte populations determined by flow cytometry
during acute rhinovirus infection. J Med Virol. 1988;25:423–
432.
12. Folkerts G, Busse WW, Nijkamp FP, Sorkness R, Gern JE.
State of the art: virus-induced airway hyperresponsiveness
and asthma. Am J Respir Crit Care Med. 1998;157:1708 –
1720.
13. Grunberg K, Timmers MC, Smits HH, et al. Effect of exper-
imental rhinovirus 16 colds on airway hyperresponsiveness
to histamine and interleukin-8 in nasal lavage in asthmatic
subjects in vivo. Clin Exp Allergy. 1997;27:36 – 45.
14. Gern JE, Galagan DM, Jarjour NN, Dick EC, Busse WW.
Detection of rhinovirus RNA in lower airway cells during
experimentally induced infection. Am J Respir Crit Care
Med. 1997;155:1159 –1161.
15. Papadopoulos NG, Bates PJ, Bardin PG, et al. Rhinovi-
ruses infect the lower airways. J Infect Dis. 2000;181:1875–
1884.
16. McFadden ER Jr, Pichurko BM, Bowman HF, et al. Thermal
mapping of the airways in humans. J Appl Physiol. 1985;
58:564 –570.
April 22, 2002
17. Schroth MK, Grimm E, Frindt P, et al. Rhinovirus replication
causes RANTES production in primary bronchial epithelial
cells. Am J Respir Cell Mol Biol. 1999;20:1220 –1228.
18. Igarashi Y, Skoner DP, Doyle WJ, White MV, Fireman P,
Kaliner MA. Analysis of nasal secretions during experimen-
tal rhinovirus upper respiratory infections. J Allergy Clin
Immunol. 1993;92:722–731.
19. Hayden FG, Albrecht JK, Kaiser DL, Gwaltney JM Jr. Pre-
vention of cold by contact prophylaxis with intranasal alpha
2-interferon. N Engl J Med. 1986;314:71–75.
20. Wiselka MJ, Nicholson KG, Kent J, Cookson JB, Tyrrell
DAJ. Prophylactic intranasal alpha2 interferon and viral ex-
acerbations of chronic respiratory disease. Thorax. 1991;
46:706 –711.
21. Rotbart HA. Pleconaril treatment of enterovirus and rhino-
virus infections. Infect Med. 2000;17:488 – 494.
22. Huguenel ED, Cohn D, Dockum DP, et al. Prevention of
rhinovirus infection in chimpanzees by soluble intercellular
adhesion molecule-1. Am J Respir Crit Care Med. 1997;
155:1206 –1210.
23. Dragovich PS, Prins TJ, Zhou R, et al. Structure-based
design, synthesis, and biological evaluation of irreversible
human rhinovirus 3C protease inhibitors. 3. Structure-ac-
tivity studies of ketomethylene-containing peptidomimet-
ics. J Med Chem. 1999;42:1203–1212.
24. Turner RB. The treatment of rhinovirus infections: progress
and potential. Antiviral Res. 2001;49:1–14.
25. Brunette MG, Lands L, Thibodeau LP. Childhood asthma
prevention of attacks with short-term corticosteroid treat-
ment of upper respiratory tract infection. Pediatrics. 1988;
81:624 – 629.
26. Gustafson LM, Proud D, Hendley JO, Hayden FG, Gwaltney
JM. Oral prednisone therapy in experimental rhinovirus in-
fections. J Allergy Clin Immunol. 1996;97:1009 –1014.
27. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Wool-
cock A. Differences between asthma exacerbations and
poor asthma control. Lancet. 1999; 353:364 –369.
THE AMERICAN JOURNAL OF MEDICINE威 Volume 112 (6A) 27S