New millennium: The conquest of allergy
(Supported by a grant from Novartis Pharmaceutical Corp., East Hanover, NJ)
Series editors: Donald Y. M. Leung, MD, PhD, Stanley J. Szefler, MD, and Harold S. Nelson, MD
The role of viral infections in the natural
history of asthma
James E. Gern, MD,a and William W. Busse, MDb Madison, Wis
Viral infections have been related to the inception of recurrent
wheezing illnesses and asthma in infants and are probably the
most frequent cause of exacerbations of established disease in
older children and adults. The well-recognized clinical effects
of viral infections are mainly caused by virus-induced immune
responses. Clinical studies of natural and experimentally
induced viral infections have led to the identification of mecha-
nisms of inflammation that could be involved in producing air-
way obstruction and lower airway symptoms. In addition, host
factors that are associated with more vigorous viral replication
or severe clinical illness are beginning to be identified.
Advances in molecular virology and our understanding of
immune responses to viral infections may lead to the develop-
ment of new strategies for the prevention and treatment of
virus-induced respiratory disorders. (J Allergy Clin Immunol
2000;106:201-12.)
Key words: Asthma, virus, respiratory syncytial virus, rhinovirus
Asthma is a disease characterized by bronchial inflam-
mation, and as such, the natural history of asthma can be
strongly influenced by allergens, irritants, or infections
that promote inflammation of the small airways. These
distinct stimuli induce or exacerbate inflammation
through unique pathways and have the potential either to
affect the initiation of asthma or trigger acute airway
obstruction in affected individuals. Infections with respi-
ratory viruses, particularly respiratory syncytial virus
(RSV) and parainfluenza virus, are the principal causes
of wheezing illnesses in infants and in some children her-
ald the onset of asthma. In fact, it has been proposed that
certain childhood infections provide a sufficient immune
response to influence the eventual development of the
immune system and modify the risk of subsequent aller-
gy and asthma. The influence of viral infections on asth-
ma continues later in life, and in children and adults with
From the Departments of aPediatrics and bMedicine, University of Wisconsin
Medical School, Madison.
Support by grants AI40685 and AI34891 from the National Institutes of
Health.
Received for publication Mar 28, 2000; revised May 12, 2000; accepted for
publication May 13, 2000.
Reprint requests: James E. Gern, MD, H4/438 University of Wisconsin Hos-
pital, Madison, WI 53792-4108.
Copyright © 2000 by Mosby, Inc.
0091-6749/2000 $12.00 + 0 1/1/108604
doi:10.1067/mai.2000.108604
Abbreviations used
ECP: Eosinophil cationic protein
ICAM: Intercellular adhesion molecule
IL1-ra: IL-1 receptor antagonist
NO: Nitric oxide
RSV: Respiratory syncytial virus
RV: Rhinovirus
established asthma, viral respiratory infections frequently
trigger lower respiratory tract symptoms and exacerba-
tions of asthma.
This review will discuss the epidemiologic associa-
tions between viral infections and asthma, unique fea-
tures of virus-induced inflammation and their relation-
ship to reduced airway function, and interactions with the
pathogenic processes of allergy and asthma. Finally,
prospects for the development of specific therapies for
virus-induced wheezing illnesses will be explored.
DO VIRAL INFECTIONS IN INFANCY ALTER
THE RISK OF ALLERGY OR ASTHMA?
RSV and bronchiolitis
It has long been recognized that infants with wheezing
illnesses, typically RSV bronchiolitis, are at increased
risk for additional episodes of wheezing in infancy and
asthma in childhood. Prospective evaluation of these
children, including the measurement of lung function
before the onset of illness, has identified risk factors for
persistent wheezing and asthma (Table I).1,2 Lung func-
tions of infants with persistent wheeze are initially nor-
mal but are reduced by the age of 6 years. These findings
suggest an interaction between virus-induced wheezing
and either atopy or allergen-induced inflammation to
favor the development of asthma.
Because nearly all children contract RSV infections in
the first 3 years of life, it is likely that the severity of the
infection, and not the infection per se, is related to the
subsequent risk of asthma. Several hypotheses have been
proposed to explain a link between severe RSV infec-
tions and increased asthma. First, RSV infections could
promote immune responses that promote allergic inflam-
mation in susceptible individuals. Supporting this
201
202 Gern and Busse
TABLE I. Risk factors for persistent wheezing
Eczema
Rhinitis apart from colds
Male sex
Elevated total serum IgE (age 9 mo)
Maternal smoking
Maternal asthma
TABLE II. Predictive value of immune responses during
bronchiolitis
Observation Outcome
• ↑RSV-specific IgE11 ↑Risk of recurrent
• ↑ECP (serum or nasal secretions)12,13 wheezing in infancy
• ↑IFN-γ secretion (PBMC, ex vivo)14
• Eosinophilia or lack of eosinopenia15 Persistent wheezing
• Transient ↑IgE15 age 6 y
hypothesis are studies to demonstrate that a particular
RSV protein (protein G) can induce a TH2-like immune
response,3,4 that viral activation of the antiviral protein
kinase in B cells can induce isotype switching to IgE in
vitro,5 and that viral infections can sometimes promote
allergen sensitization in animals.6 However, studies to
determine whether RSV infections enhance allergy in
humans have yielded conflicting results.7-10
Second, it could be that RSV and other severe lower res-
piratory tract infections promote asthma because of their
anatomic location. The severe lower airway inflammation
produced by these infections could affect lung develop-
ment, initiate airway remodeling, or somehow target aller-
gic inflammation to the lower airway in atopic individuals.
Third, it is possible that children with severe RSV
infections have an underlying immune system defect that
has two consequences: (1) promotion of allergen sensiti-
zation and (2) relatively ineffective antiviral responses,
leading to increased viral replication and more severe
lower respiratory involvement during an RSV infection.
Although there are no studies to prospectively evaluate
immune responses before RSV infection and compare
them with the severity of subsequent disease, there is evi-
dence that immune responses during bronchiolitis are dis-
tinct in those infants who go on to have recurrent wheez-
ing or asthma (Table II).11-15 These observations raise the
question of whether these abnormal immune responses,
which have also been associated with atopy, were pre-
existing or were caused by the acute viral infection.
Influence of other infections on the
development of asthma
A consistent finding that has been noted in multiple
epidemiologic surveys is that the risk of allergen sensiti-
zation is inversely related to the number of older siblings
in the family,16-19 and these findings have also been
extended to include asthma. Because large family size,
and having multiple older siblings in particular, presum-
J ALLERGY CLIN IMMUNOL
AUGUST 2000
ably increases the exposure to infectious diseases in early
childhood, studies have been conducted to test the
hypothesis that exposure to certain infectious diseases in
early childhood can reduce the risk of allergy and asth-
ma, perhaps by promoting the development of a protec-
tive TH1-like immune response (Fig 1).17
One of the first of these studies found that Japanese
schoolchildren with a strong positive tuberculin skin test
response after BCG vaccination, possibly signifying
exposure to tuberculosis, also have reduced rates of allergy
and asthma.20 In addition, long-term follow-up of sur-
vivors of a measles epidemic in an African village indi-
cated that measles infection in early childhood was asso-
ciated with reduced risk of allergen sensitization,21
although this finding has not been reproduced in two
studies of measles infections in western societies.22,23
Finally, serologic evidence of hepatitis A in Italian mili-
tary recruits was associated with a reduced rate of allergy
and asthma.24
Attendance in day care, which clearly increases expo-
sure to infectious diseases, may have complex effects on
wheezing illnesses in childhood. Initially, it is clear that
day care attendance increases the risk of recurrent
wheezing episodes in infants and young children.25,26
However, long-term followup of children who attended
day care before the age of 6 months suggests that the risk
of asthma in later childhood may actually be reduced.27
If confirmed, these findings would suggest that the
effects of day care on wheezing illnesses may depend on
both the age of exposure and the age at follow-up.
Together, these epidemiologic studies suggest that
potential effects of viral infections on the developing
immune system could depend on several factors, includ-
ing type of viral infection, infection of the respiratory
tract, age, and factors related to the host immune
response. To determine the true relationships between
viral infections, antiviral immune responses, and the
development of asthma will require prospective evalua-
tion of these factors in a controlled study and the devel-
opment of new antiviral interventions to enable the asso-
ciations identified in epidemiologic studies to be tested.
VIRAL INFECTIONS AS TRIGGERS FOR
ESTABLISHED ASTHMA
Epidemiology
In children, adults, or both with existing asthma, the
association between viral infections and acute wheezing
was first demonstrated more than 25 years ago by detect-
ing viruses by using either serology or culture during
wheezing episodes.28 However, many respiratory virus-
es, particularly rhinovirus (RV), are difficult to detect by
using standard virologic methods, and thus these initial
studies likely underestimated the effect of respiratory
viral infections on wheezing. In more recent studies the
use of extremely sensitive RT-PCR assays29,30 has estab-
lished the dominating importance of respiratory infec-
tions, particularly RV, in causing exacerbations of asthma.
By using RT-PCR in addition to standard techniques to
J ALLERGY CLIN IMMUNOL Gern and Busse 203
VOLUME 106, NUMBER 2

FIG 1. The hygiene hypothesis.17 According to this theory, immune responses to viruses and perhaps other
organisms that generate TH1-like cytokines, such as IL-12 and IFN-γ, suppress TH2 responses that are pre-
dominant in the neonatal immune system. When many siblings are present, repeated infections, through
the activities of TH1-like cytokines, would help T-cell immune responses to mature into a TH1-like pheno-
type that would be less likely to favor allergen sensitization.

identify respiratory viruses, viruses have been detected in
up to 85% of wheezing episodes in children and in
approximately half of exacerbations in adult asthmatic
subjects; the virus most commonly detected was RV.31-34
Virus-induced exacerbations of asthma may be severe;
indeed, seasonal patterns of upper respiratory virus
prevalence correlate closely with hospital admissions for
asthma, especially in children.35,36
Additional epidemiologic studies conducted in acute
care settings indicate that viral infections and markers of
atopy have independent and synergistic effects on the
risk for wheezing illnesses in childhood. In studies eval-
uating wheezing infants and children in a hospital emer-
gency department, wheezing children older than 2 years
of age were more likely to have evidence of atopy (posi-
tive RAST test, nasal eosinophilia, or elevated eosinophil
cationic protein [ECP] in nasal secretions) or evidence of
an RV infection (nasal secretions tested positive by using
RT-PCR) when compared with children without wheez-
ing.34,37 Moreover, the strongest odds for wheezing were
in children with both risk factors, suggesting that there
are synergistic interactions either between allergy or
eosinophilic inflammation and viral infection in the
pathogenesis of wheezing with respiratory illnesses.
Clinical effects of viral infections in asthma
The upper respiratory manifestations of common cold
viruses are quite similar, regardless of the presence of
asthma, and usually begin with a sore throat, followed by
rhinorrhea and nasal congestion, sneezing, and cough.
Lower airway symptoms and reduced peak flow in asth-
matic subjects begin soon after the onset of the cold and
last an average of 14 days.31 There is evidence that
changes in lower airway physiology caused by viral
infections may have some unique features compared with
the effects of poor asthma disease control. Reddel et al38
measured peak flow and calculated diurnal variability on
43 patients whose asthma was poorly controlled on entry
into the study. These subjects were treated with inhaled
budesonide for 18 months, and the effects of the therapy
and of asthma exacerbations on peak flow measurements
were analyzed. Forty exacerbations were noted in 26
subjects, and although viral cultures were not performed,
all but two exacerbations were preceded by symptoms of
an upper respiratory infection.
Patterns of peak flow readings were distinct during the
run-in period, when the asthma was poorly controlled,
and during exacerbations of asthma (Fig 2). Poor asthma
control caused decreased lung function and increased
peak flow variability (21.3%), and the authors point out
that increased diurnal variability has also been observed
when inhaled corticosteroid therapy has been withdrawn
and after allergen exposure. In contrast, diurnal variabil-
ity was not increased during exacerbations of asthma
(7.7% vs 5.3% during stable asthma), although both
morning and evening peak flow readings were lower.
Furthermore, β-agonist responsiveness was demonstrat-
ed during poorly controlled asthma, but the bronchodila-
tor response to β-agonist was diminished during the
exacerbations.
Assuming that most of the exacerbations were in fact
caused by viral infections, these findings indicate that
viral infections induce distinct perturbations of lower air-
way physiology that include reduced peak flow, normal
variability, and impaired response to β-agonist. The
mechanisms of these effects were not determined but
could include pronounced induction of airway edema or
mucus production or interference with β-adrenergic
receptor function. Regardless of the mechanism, the
observed unresponsiveness to β-agonist therapy under-
204 Gern and Busse
FIG 2. Distinct peak expiratory flow (PEF) trends in poorly controlled asthma compared with asthma exac-
erbation associated with upper respiratory tract infection (URI). ICS, Inhaled corticosteroid therapy. Adapt-
ed from Reddel et al.38
scores the need to develop specific therapies for virus-
induced exacerbations of asthma.
Lessons from experimental infection with RV
Experimental infection with RV and other respiratory
viruses has provided a convenient means to study the
pathogenesis of wheezing with viral respiratory infec-
tions while controlling for confounding factors, such as
the time and dose of inoculation and the type of virus
producing the illness. There are, however, important dif-
ferences between natural and experimental infections
with RV. For example, natural infections produce a
broader range of illness severity, and it is likely that some
or all of the viruses used to inoculate volunteers are
attenuated and produce relatively mild clinical illnesses.
Perhaps, as a result of this, it is unusual for subjects with
asthma to experience clinically significant exacerbations
of asthma or changes in FEV1,39 although aerosol inocu-
lation with RV has been shown to increase peak flow
variability.40 Despite these limitations, experimental
inoculation with viruses, such as RV16, have enabled the
analysis of viral effects on upper and lower airway phys-
iology, as well as a system to evaluate potential interac-
tions between allergen exposure and viral infection.
Do viruses that trigger asthma infect the lower airway?
There is little doubt that some respiratory viruses (ie,
influenza, RSV, and parainfluenza virus) infect lower air-
way tissues and cause tissue inflammation and lower air-
way obstruction. Several lines of evidence suggest that
RV infections can also extend into the lower airway and
that effects on asthma are initiated by ensuing lower air-
way inflammation. For example, case reports and epi-
demiologic studies have linked RV to lower airway syn-
dromes, such as bronchitis, bronchiolitis, and
pneumonia.41-46 In addition, experimental RV inocula-
tion increases lower airway inflammation, as indicated
by increased submucosal lymphocytes and epithelial
eosinophils in bronchial biopsy specimens,47 and
increases in the number of neutrophils in bronchial
J ALLERGY CLIN IMMUNOL
AUGUST 2000
lavage fluid.48 Furthermore, RV can replicate in cultured
bronchial epithelial cells and at temperatures approxi-
mating those found in the lower airway.49 Finally,
although RV is difficult to culture from lower airway
secretions obtained through bronchoalveolar lavage,50
RV RNA was detected in bronchoalveolar lavage cells
from volunteers after experimental inoculation with
RV16.51 Interpretation of these findings is limited, how-
ever, by the necessity of passing the bronchoscope
through the upper airway to get lower airway samples.
Nevertheless, these data suggest that, at least under some
conditions, RV viral infections extend into the lower air-
way and induce bronchial inflammation that could con-
tribute to virus-induced exacerbations of asthma.
Viral effects on airway responsiveness. One of the cardi-
nal features of asthma is airway hyperresponsiveness,
which is defined as the increased sensitivity of the airways
to bronchoconstriction to irritants or allergen. It is therefore
of interest that several types of viral infections, including
experimental infection with certain strains of RV (RV16
but not RV39 or RV Hanks), influenza, and RSV, can cause
changes in airway responsiveness to histamine, metha-
choline, or allergen.52 For example, Cheung et al53 inocu-
lated 14 subjects with mild asthma either with RV16 (type
16 rhinovirus) or placebo and found that airway respon-
siveness transiently increased during the acute infection
and returned to baseline levels by 1 week after the inocula-
tion. In addition to increasing the sensitivity of the airway,
RV16 infection also increased the maximal response to
inhaled methacholine for up to 15 days after the acute
infection. Furthermore, there is evidence that experimental
infection with RV16 induces greater changes in airway
responsiveness in volunteers with respiratory allergy54,55 or
mild allergic asthma,47 suggesting a potential mechanism
for the greater severity of the lower airway effects of natu-
rally acquired RV infections in patients with asthma.
Interactions between viral infections and allergic
inflammation. Several studies have been conducted to
test the hypothesis that there are specific interactions
J ALLERGY CLIN IMMUNOL Gern and Busse 205
VOLUME 106, NUMBER 2

FIG 3. RVs approaching ICAM-1 receptors on the surface of an airway epithelial cell. This figure shows the
molecular surface structure of RV14, as solved by x-ray crystallography, approaching an artist’s rendition
of an epithelial cell (gray) with several ICAM-1 molecules (gold) on the surface. The dark grooves that radi-
ate out from the 5-fold axis of symmetry depict canyons that contain the ICAM-1–binding sites. The com-
puter graphic representations of RV14 and ICAM-1 were provided by Dr Jean Yves Sgro (Institute of Mo-
lecular Virology, University of Wisconsin-Madison), with artwork by Robert J. Gordon (Department of
Pediatrics, University of Wisconsin-Madison).

between allergen- and virus-induced inflammation. In
one set of studies, lower airway responses to allergen in
subjects with allergic rhinitis were evaluated before, dur-
ing, and after experimental inoculation with RV.54,56-59
RV infections increased airway responsiveness to hista-
mine, methacholine, and allergen and increased the prob-
ability of development of a late-phase allergic response
after whole lung antigen inhalation.59
In additional studies with bronchoscopy, RV infection
caused an increased release of histamine into the lower
airways after segmental allergen challenge and augmented
the recruitment of both total leukocytes and eosinophils
into the airway 48 hours after allergen challenge.57 These
effects were noted only in allergic individuals, indicating
that RV infection specifically enhanced allergen-induced
responses in the airway.
The possibility that exposure to allergen might
enhance the severity of viral illness has also been evalu-
ated in two separate studies.60,61 Neither nasal challenge
with allergen nor natural exposure to ragweed during the
peak of the season accentuated the severity of experi-
mentally induced infections with RV16 and influenza,
respectively. In fact, nasal allergen challenge delayed the
onset and shortened the duration of RV16-induced colds.
Although the mechanism for this effect is uncertain, it is
conceivable that a component of the allergen-induced
immune response has antiviral activity, and in support of
this theory, it has been demonstrated that eosinophil-
derived neurotoxin, a granular protein released on
eosinophil activation, has RNase activity and can inhibit
replication of RSV.62 Alternately, it is possible that the
preceding allergen-induced inflammation led in turn to
the activation of anti-inflammatory mechanisms (eg,
secretion of IL-10) and that the presence of these factors
at the time of inoculation caused attenuation of the viral
illness. Whatever the mechanism, the findings of this
study do not suggest that allergic inflammation leads to
more severe respiratory viral infections or that this mech-
anism contributes to the pathogenesis of virus-induced
exacerbations of asthma.
Host factors that contribute to the severity of respira-
tory viral infections. Interestingly, despite the use of stan-
dardized lots of viral inoculum, inoculation techniques,
and the enrollment of subjects with no evidence of prior
206 Gern and Busse
FIG 4. Effects of respiratory virus infection on airway tissues (see text). AHR, Airway hyperresponsiveness.
infection with the serotype used, there has been consid-
erable individual variability in the severity of respiratory
symptoms63-65 and in the amount of virus detected in
nasal secretions after experimental inoculation.54,56,59
This variability suggests that there are host factors,
other than the quantity of virus-specific antibody, that
contribute to the outcomes of viral respiratory infections.
Because T-cell responses have been linked to the severity
of viral infections in the response of viruses in animal
models,66 it seems likely that variability in T-cell responses
could be influential in human subjects as well. To test for
relationships between virus-induced lymphocyte responses
and the outcomes of viral infections, PBMCs from
seronegative volunteers were tested for virus-specific pro-
liferation and IFN-γ secretion in tissue culture.67 After the
blood test, the volunteers were inoculated with RV16, and
quantitative viral cultures were performed on samples of
nasal lavage fluid obtained during the acute cold. The
results of this study showed that vigorous RV-specific
lymphocyte responses before the cold (either proliferation
or IFN-γ secretion) were associated with reduced viral
shedding after inoculation. These findings suggest that
variations in virus-induced T-cell responses contribute to
the individual variability in viral shedding during experi-
mentally induced and perhaps naturally acquired RV
infections in subjects with respiratory allergy or asthma.
Additional studies are under way to determine whether T-
cell responses and IFN-γ secretion to viral infection are
different in patients with asthma and whether this could
help to explain the increased lower airway sequela of RV
infections in asthma.
J ALLERGY CLIN IMMUNOL
AUGUST 2000
Virus-induced inflammation
Although the precise mechanisms by which respiratory
viruses, such as RV, cause symptoms are unknown, there
is evidence to suggest that the immune response to the
virus plays a major role in symptom pathogenesis. For
example, RV infections do not cause extensive epithelial
cell destruction, even when severe cold symptoms are
present.68 Second, the severity of respiratory symptoms
correlates closely with the influx of inflammatory cells
and increases in cytokines and mediators in nasal secre-
tions.48,69-72 Whether these factors are participating in
symptom pathogenesis or are markers of severe disease
has not yet been established. Third, studies in rodents
have demonstrated that morbidity of viral infections can
be amplified by the passive transfer of certain T-cell sub-
sets or clones.66,73-75
Although the immune responses to viruses are com-
plex and involve multiple airway cells, cytokines, and
mediators, there are a few cells and mediators that are
likely to play key roles in this process. For example, the
airway epithelial cell is the principal host cell for most
respiratory viruses. Interestingly, RV can also infect air-
way smooth muscle cells and submucosal gland cells in
tissue culture.76,77 If these findings are confirmed in
vivo, it would raise the possibility that viral infection
could directly affect muscle cell responsiveness and air-
way mucus secretion.
Unlike RSV and influenza, which can destroy large
numbers of epithelial cells in vivo or in vitro, only a
small subset of epithelial cells becomes infected with
J ALLERGY CLIN IMMUNOL Gern and Busse 207
VOLUME 106, NUMBER 2

Image available in print only.

FIG 5. Two mechanisms for virus-induced lymphocyte activation. Respiratory viruses, such as RV, can bind to antigen-
presenting cells, such as macrophages, B cells, or dendritic cells, through specific receptors (eg, ICAM-1 and the low-
density lipoprotein receptor [LDLr]). Innate responses can be activated through the secretion of soluble factors, such as
IFN-α, IL-12, and/or IL-18, leading to increased CD69 expression and IFN-γ secretion by T cells and natural killer cells. In
addition, antigen presentation can activate a smaller subset of antigen-specific T cells. (Adapted from Gern JE, Vrtis R,
Kelly EAB, Dick EC, Busse WW. Rhinovirus produces nonspecific activation of lymphocytes through a monocyte-depen-
dent mechanism. J Immunol 1996;157:1605-12. Copyright 1996. Used with permission.)

RV.78,79 By using in situ hybidization and RV-specific
probes, it has been demonstrated that specialized noncil-
iated cells that overlie lymphoid follicles in adenoidal tis-
sue express large amounts of intercellular adhesion mol-
ecule (ICAM) 1, the receptor used by over 90% of RV
serotypes (Fig 3), and are especially susceptible to RV
infection.80 Determining whether the level of ICAM-1
expression or some other factor conveys susceptibility to
these cells has yet to be determined.
Viral replication within epithelial cells is a central
event in the initiation of airway immune responses and
inflammatory processes (Fig 4). Viral replication in the
epithelial cell triggers intracellular signaling pathways,
including proteolysis of IκB and activation of NFκB,81-83
leading to increases in the secretion of multiple
cytokines, chemokines, and adhesion molecules. This is
one area where virus- and allergen-induced inflammation
overlap in that cytokines (TNF-α, G-CSF, and IFN-γ)
and chemokines (IL-8, macrophage inflammatory pro-
tein 1α, and RANTES) that are increased in airway
secretions during viral infections48,72,84-86 can recruit and
activate inflammatory cells (neutrophils, eosinophils, and
activated T cells)87,88 that have been linked to asthma.
There is evidence that endothelial cells are also acti-
vated early during the course of upper respiratory tract
infections and could contribute to airway dysfunction
during respiratory illnesses through several pathways.
First, upregulation of adhesion molecules by cytokines,
such as TNF-α, is an important factor in the recruitment
of inflammatory cells. Perhaps of equal or greater impor-
tance is the transudation of plasma proteins from the vas-
cular tissue of the nasal mucosa, leading to increased
nasal secretions and congestion.89 Peak levels of plasma
proteins, such as albumin and IgG, coincide with the time
of maximal cold symptoms89 and increases in bronchial
responsiveness,53 suggesting that similar processes occur
in the lower airway. Activation of kinins has been
advanced as a possible mechanism for cold-induced
increased endothelial permeability69,90; however, a
bradykinin antagonist NPC 567 did not improve cold
symptoms in a clinical trial.91 Finally, vasodilation is
likely to contribute to edema of the nasal mucosa and
possibly the lower airway during viral respiratory infec-
tions. Leukotrienes are increased in nasal secretions dur-
ing viral infections,86 and studies are under way to deter-
mine whether leukotriene receptor blockers can relieve
cold-related nasal congestion.
Immediately after the transudation of fluids into the
airway, products of goblet cells and mucin glands are
increased.89,92 Mechanisms of mucin gene upregulation
and goblet cell degranulation are now being elucidated,
and potent stimuli include cytokines (TNF-α, and IL-9)
and bacterial cell wall components.93,94 Activation of the
epithelial growth factor receptor has been identified as a
key mechanism for the differentiation and degranulation
of goblet cells and may be activated by a number of dif-
ferent stimuli.95 Because secreted mucus is a major con-
tributor to upper and lower airway obstruction during
viral respiratory infections, developing specific
inhibitors of this process could be an important advance
in the therapy of exacerbations of asthma and other dis-
orders characterized by overproduction of mucus.
As a result of epithelial-derived chemokines and
increased expression of endothelial adhesion molecules,
leukocytes are recruited into airway secretions during the
acute stages of viral infections. Neutrophils are the main
cells found in nasal and lower airway secretions during
acute viral infections,68,96 and increases in blood and
nasal neutrophils correlate with cold and asthma symp-
tom scores and cold-induced changes in airway hyperre-
sponsiveness.72 Once recruited to the airway, respiratory
viruses can activate neutrophil inflammatory functions,
208 Gern and Busse
as indicated by enhancement of superoxide responses,
chemotaxis, and adhesion.97 In addition, proteases
released by activated neutrophils are potent secreta-
gogues for airway submucosal glands.98
Although the neutrophil is the predominant cell in nasal
secretions during acute viral infections, eosinophil granular
proteins have also been detected in the nasal secretions of
children with wheezing illnesses caused by RV or
RSV.84,99,100 In addition, increases in sputum ECP during
the acute phase of experimentally induced RV infection
correlated with increased airway responsiveness in a group
of adult asthmatic subjects after experimental inoculation
with RV16.101 Experiments conducted in vitro indicate that
RV does not activate eosinophils directly,102 and therefore
it is likely that eosinophil activation is secondary to the
activity of virus-induced mediators or cytokines secreted
by T cells, epithelial cells, or other airway cells.103
Mononuclear cells are also recruited to the upper and
lower airway during acute viral infections.47,104
Macrophages, which predominate in lower airway secre-
tions, can bind RV in vitro and secrete cytokines that
have antiviral (IFN-α) effects, proinflammatory (IL-1
and TNF-α) effects, or both.105,106 Virus-activated
macrophages and lymphocytes are likely to help clear
viruses and virus-infected cells from the airway.
Lymphocyte responses may be of particular impor-
tance because of their central role in orchestrating both
allergic inflammation107 and antiviral responses. Viruses
can activate T cells either through innate or antigen-spe-
cific pathways (Fig 5). Innate immune responses to virus
can occur rapidly (within 24-48 hours) after exposure to
virus and may be caused by soluble mediators, such as
IFN-α, secreted by antigen-presenting cells.103,108,109
Virus-specific T-cell responses are generally not
detectable in the airway or blood until 7 to 10 days after
inoculation with virus; however, T-cell responses to either
influenza or RV can be cross-reactive among different
viral serotypes.110-112 Because different serotypes either
of RV or influenza virus can cause many infections in the
same host over a lifetime, T-cell reactivity to a particular
strain of virus can be detected in some seronegative indi-
viduals.67 As discussed previously, these mechanisms to
rapidly activate T cells and natural killer cells may serve
to enhance antiviral responses and limit viral replication.
Finally, perhaps of equal importance to proinflammato-
ry mechanisms are the pathways to downregulate virus-
induced immune response to promote healing of the air-
way and lung tissue. Nitric oxide (NO), which is increased
both in patients with asthma and patients with upper respi-
ratory tract infections, could have complex effects on air-
way physiology. On the one hand, NO is a potent vasodila-
tor and could increase airway wall edema and thereby
increase airway obstruction in asthma. Effects of NO that
could be beneficial include inhibition of viral (including
RV) replication113 and bronchodilation through relaxation
of airway smooth muscle. The overall effect of NO may be
beneficial because greater NO production during experi-
mentally induced RV infections correlated with a smaller
increase in airway responsiveness.114
J ALLERGY CLIN IMMUNOL
AUGUST 2000
In addition, virus-induced secretion of cytokines with
antiviral properties has been investigated. Respiratory
viruses can stimulate IL-10 secretion, which can in turn
downregulate antigen presentation by monocytes.115 In
addition, IL-10 secretion from PBMCs was impaired in
allergic individuals after experimentally induced infec-
tion with influenza.116 This suggests that allergic indi-
viduals may have reduced capacity to suppress virus-
induced inflammation after the acute phase of infection.
Finally, IL-1 receptor antagonist (IL-1ra) has been
detected in the nasal secretions of volunteers infected
with RV.117 IL-1ra binds to IL-1 receptors without caus-
ing activation and thereby blocks the proinflammatory
effects of active forms of IL-1. Interestingly, RV infec-
tion induces secretion of a brief and modest peak of IL-
1β 2 days after inoculation, whereas IL-1ra is secreted in
much greater amounts for up to 3 days after inoculation.
These findings suggest that IL-1ra may be an important
regulator of inflammatory effects mediated by the IL-1
receptor during common cold infections.
Effects of viral infections on neural regulation of the
airway. Although neural mechanisms of virus-induced
bronchoconstriction and airway obstruction are of great
interest, they are particularly difficult to study in human
subjects because definitive experiments often require the
disruption of neural tissue. Consequently, much of our
understanding has been gained through the use of animal
models infected with respiratory viruses other than RV.
Viral infections could potentially cause bronchoconstric-
tion and increased airway responsiveness by enhancing
parasympathetic bronchoconstrictive responses, by stim-
ulating reflex bronchospasm or neuropeptide release
from sensory C fibers, or by interfering with the function
of nonadrenergic noncholinergic neurons, which produce
the potent bronchodilator nitric oxide. Each of these
mechanisms has been explored and is the subject of
recent reviews.52,118,119 Further advances in the under-
standing of virus effects on neural control of the airways
await the development of new specific antagonists of
neural pathways or the development of new experimental
techniques.
SUMMARY AND THERAPEUTIC
IMPLICATIONS
Viral respiratory infections exert considerable influ-
ence on airway function and asthma in all age groups.
In infancy respiratory viruses, such as RSV, cause
episodes of wheezing that may be recurrent but are
largely transient. In addition, there are indications that
early viral infections may be able to affect the devel-
opment of the immune system and modify the subse-
quent risk of allergy and asthma. Finally, in children
and adults with established asthma, common cold
viruses, such as RV, frequently trigger acute symptoms
of asthma.
This model suggests that specific antiviral therapies
could have a major effect on reducing the morbidity of
wheezing illnesses in infancy and of asthma in older
J ALLERGY CLIN IMMUNOL
VOLUME 106, NUMBER 2
children and adults. Moreover, strategies to prevent
severe respiratory illnesses in infancy, either through
vaccination or antiviral medications, could potentially
reduce the incidence of asthma in childhood. Vaccina-
tion against influenza is widely recommended for
patients with asthma, and vaccines for RSV are under
development. Administration of a monoclonal neutraliz-
ing antibody to RSV (palivizumab) has proved to be an
effective strategy to prevent RSV infection in premature
and high-risk infants, but this therapy is too expensive
for general use.120 Greater understanding of the role of
RSV infection in the initiation of asthma and risk factors
for severe RSV infection is needed to design more com-
prehensive and cost-effective programs to prevent RSV-
related morbidity.
Unfortunately, because there are more than 100 RV
serotypes, standard vaccination is not an option for pro-
phylaxis of RV-induced exacerbations of asthma.
In the absence of an RV vaccine, antiviral agents have
the potential to either treat or prevent virus-induced exac-
erbations of asthma, although there are still a few barri-
ers to overcome. Experience with antiviral medications,
such as the influenza neuraminidase inhibitors, has
demonstrated that treatment needs to be started early in
the disease course to produce clinical benefit, and similar
restraints apply to new medications, such as soluble
ICAM-1, that prevent RV binding or uncoating.121
Another potential barrier is cost. Although prophylac-
tic treatment with anti-RV medications during the fall
and spring cold seasons may not be practical for normal
individuals because of the anticipated high cost of the
new medications, this approach could be cost-effective
for children and adults at increased risk for RV-related
morbidity because of asthma or chronic obstructive pul-
monary disease. Whether the new antiviral agents that
interfere with viral attachment or enzymes (3C protease
inhibitors)122 can prevent exacerbations of asthma if used
preventively or, better yet, if started at the first sign of a
cold, remains to be determined.
Another critical challenge is to determine why indi-
viduals with allergy and lower airway inflammation are
so susceptible to the effects of respiratory viruses, such
as RV, that cause mild disease in normal individuals.
Data in infants infected with RSV suggest that immune
responses to this virus are distinct in children who go on
to have recurrent wheezing and asthma, and host factors
that are associated with greater viral replication in adults
are beginning to be identified. Key challenges include
establishing whether antiviral immune responses are
determined solely by genetics or whether environmental
factors play a significant role in their development and to
ascertain which elements of the antiviral, or perhaps anti-
inflammatory, immune responses are impaired in patients
with recurrent wheezing. Are immune abnormalities
associated with asthma only in response to allergens, or
is there also a fundamental defect in the immune
response to respiratory viruses? The answers to these
questions may provide new therapeutic targets for asth-
ma and respiratory viral illnesses.
Gern and Busse 209
REFERENCES
1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Mor-
gan WJ, et al. Asthma and wheezing in the first six years of life. N Engl
J Med 1995;332:133-8.
2. Martinez F. Maturation of immune responses at the beginning of asth-
ma. J Allergy Clin Immunol 1999;103:355-61.
3. Jackson M, Scott R. Different patterns of cytokine induction in cultures
of respiratory syncytial (RS) virus-specific human T-H cell lines fol-
lowing stimulation with RS virus and RS virus proteins. J Med Virol
1996;49:161-9.
4. Alwan WH, Record FM, Openshaw PJM. Phenotypic and functional
characterization of T cell lines specific for individual respiratory syncy-
tial virus proteins. J Immunol 1993;150:5211-8.
5. Rager KJ, Langland JO, Jacobs BL, Proud D, Marsh DG, Imani F. Acti-
vation of antiviral protein kinase leads to immunoglobulin E class
switching in human B cells. J Virol 1998;72:1171-6.
6. Suzuki S, Suzuki Y, Yamamoto N, Matsumoto Y, Shirai A, Okubo T.
Influenza A virus infection increases IgE production and airway respon-
siveness in aerosolized antigen-exposed mice. J Allergy Clin Immunol
1998;102:732-40.
7. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B.
Asthma and immunoglobulin E antibodies after respiratory syncytial
virus bronchiolitis: a prospective cohort study with matched controls.
Pediatrics 1995;95:500-5.
8. Cogswell JJ, Halliday DF, Alexander JR. Respiratory infections in the
first year of life in children at risk of developing atopy. BMJ
1982;284:1011-3.
9. Welliver RC. RSV and chronic asthma. Lancet 1995;346:789-90.
10. Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction 10
years after infection with respiratory syncytial virus in infancy. BMJ
1982;284:1665-9.
11. Welliver RC, Wong DT, Rijnaldo D, Ogra PL. Predictive value of respi-
ratory syncytial virus-specific IgE responses for recurrent wheezing fol-
lowing bronchiolitis. J Pediatr 1986;109:776-80.
12. Koller DY, Wojnarowski C, Herkner KR, Weinlander G, Raderer M, Eich-
ler I, et al. High levels of eosinophilic cationic protein in wheezing infants
predict the development of asthma. J Allergy Clin Immunol 1997;99:752-6.
13. Reijonen TM, Korppi M, Kleemola M, Savolainen K, Kuikka L,
Mononen I, et al. Nasopharyngel eosinophil cationic protein in bronchi-
olitis—relation to viral findings and subsequent wheezing. Pediatr Pul-
monol 1997;24:35-41.
14. Renzi PM, Turgeon JP, Yang JP, Drblik SP, Marcotte JE, Pedneault L, et
al. Cellular immunity is activated and a TH-2 response is associated
with early wheezing in infants after bronchiolitis. J Pediatr
1997;130:584-93.
15. Martinez FD, Stern DA, Wright AL, Taussig LM, Halonen M. Differen-
tial immune responses to acute lower respiratory illnesses in early life
and subsequent development of persistent wheezing and asthma. J
Allergy Clin Immunol 1998;102:915-20.
16. von Mutius E, Martinez FD, Fritzsch C, Nicolai T, Reitmeir P, Thiemann
HH. Skin test reactivity and number of siblings. BMJ 1994;308:692-5.
17. Strachan DP. Hay fever, hygiene, and household size. BMJ
1989;299:1259-60.
18. Strachan DP, Harkins LS, Johnston IDA, Anderson HR. Childhood
antecedents of allergic sensitization in young British adults. J Allergy
Clin Immunol 1997;99:6-12.
19. von Mutius E. The environmental predictors of allergic disease. J Aller-
gy Clin Immunol 2000;105:9-19.
20. Shirakawa T, Enomoto T, Shimazu S-I, Hopkin JM. The inverse associ-
ation between tuberculin responses and atopic disorder. Science
1997;275:77-9.
21. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell AW, et al.
Measles and atopy in Guinea-Bissau. Lancet 1996;347:1792-6.
22. Paunio M, Heinonen OP, Virtanen M, Leinikki P, Patja A, Peltola H.
Measles history and atopic diseases: a population based cross-sectional
study. JAMA 2000;283:343-6.
23. Farooqi IS, Hopkin JM. Early childhood infection and atopic disorder.
Thorax 1998;53:927-32.
24. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta M, Chionne
P, et al. Cross sectional retrospective study of prevalence of atopy
among Italian military students with antibodies against hepatitis A virus.
BMJ 1997;314:999-1003.
210 Gern and Busse
25. Nafstad P, Hagen JA, Oie L, Magnus P, Jaakkola JJK. Day care centers
and respiratory health. Pediatrics 1999;103:753-8.
26. Marbury MC, Maldonado G, Waller L. Lower respiratory illness, recur-
rent wheezing, and day care attendance. Am J Respir Crit Care Med
1997;155:156-61.
27. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD,
Wright AL. Exposure to siblings and day care during infancy and the
subsequent development of asthma and frequent wheeze [abstract]. Am
J Respir Crit Care Med 2000;161:A704.
28. Minor TE, Dick EC, DeMeo AN, Ouellette JJ, Cohen M, Reed CE. Virus-
es as precipitants of asthmatic attacks in children. JAMA 1974;227:292-8.
29. Gama RE, Horsnell PR, Hughes PJ, North C, Bruce CB, al-Nakib W, et
al. Amplification of rhinovirus specific nucleic acids from clinical sam-
ples using the polymerase chain reaction. J Med Virol 1989;28:73-7.
30. Johnston SL, Xie P, Johnson W. Comparison of standard virology and
PCR in diagnosis of rhinovirus and respiratory syncytial virus infections
in nasal aspirates from children hospitalized with wheezing illness and
bronchiolitis [abstract]. Am J Respir Crit Care Med 1996;153:A503.
31. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs
L, et al. Community study of role of viral infections in exacerbations of
asthma in 9-11 year old children. BMJ 1995;310:1225-9.
32. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerba-
tions of asthma in adults. BMJ 1993;307:982-6.
33. Atmar RL, Guy E, Guntupalli KK, Zimmerman JL, Bandi VD, Baxter
BD, et al. Respiratory tract viral infections in inner-city asthmatic
adults. Arch Intern Med 1998;158:2453-9.
34. Rakes GP, Arruda E, Ingram JM, Hoover GE, Zambrano JC, Hayden
FG, et al. Rhinovirus and respiratory syncytial virus in wheezing chil-
dren requiring emergency care. IgE and eosinophil analyses. Am J
Respir Crit Care Med 1999;159:785-90.
35. Johnston SL, Pattemore PK, Sanderson G, Smith S, Campbell MJ,
Josephs LK, et al. The relationship between upper respiratory infections
and hospital admissions for asthma: a time trend analysis. Am J Respir
Crit Care Med 1996;154:654-60.
36. Dales RE, Schweitzer I, Toogood JH, Drouin M, Yang W, Dolovich J, et
al. Respiratory infections and the autumn increase in asthma morbidity.
Eur Respir J 1996;9:72-7.
37. Duff AL, Pomeranz ES, Gelber LE, Price HW, Farris H, Hayden FG, et
al. Risk factors for acute wheezing in infants in infants and children:
viruses, passive smoke, and IgE antibodies to inhalant allergens. Pedi-
atrics 1993;92:535-40.
38. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differ-
ences between asthma exacerbations and poor asthma control. Lancet
1999;353:364-9.
39. Fleming HE, Little FF, Schnurr D, Avila PC, Wong H, Liu J, et al. Rhi-
novirus-16 colds in healthy and in asthmatic subjects: similar changes in
upper and lower airways. Am J Respir Crit Care Med 1999;160:100-8.
40. Grünberg K, Timmers MC, De Klerk EPA, Dick EC, Sterk PJ. Experi-
mental rhinovirus 16 infections causes variable airway obstruction in sub-
jects with atopic asthma. Am J Respir Crit Care Med 1999;160:1375-80.
41. Kellner G, Popow-Kraupp T, Kundi M, Binder C, Kunz C. Clinical
manifestations of respiratory tract infections due to respiratory syncytial
virus and rhinoviruses in hospitalized children. Acta Paediatr Scand
1989;78:390-4.
42. Horn MEC, Brain E, Gregg I, Yealland SJ, Inglis JM. Respiratory viral
infection in childhood. A survey in general practice, Roehampton 1967-
1972. J Hyg (Camb) 1975;74:157-68.
43. Monto AS, Cavallaro JJ. The Tecumseh study of respiratory illness II.
Patterns of occurrence of infection with respiratory pathogens. Am J
Epidemiol 1971;94:280-9.
44. Nicholson KG, Kent J, Hammersley V, Cancio E. Risk factors for lower
respiratory complications of rhinovirus infections in elderly people liv-
ing in the community: prospective cohort study. BMJ 1996;313:1119-23.
45. Henderson FW, Clyde WA Jr, Collier AM, Denny FW, Senior RJ, Sheaf-
fer CI, et al. The etiologic and epidemiologic spectrum of bronchiolitis
in pediatric practice. J Pediatr 1979;95:183-90.
46. Las Heras J, Swanson VL. Sudden death of an infant with rhinovirus
infection complicating bronchial asthma: case report. Pediatr Pathol
1983;1:319-23.
47. Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate
ST. Lower airway inflammation during rhinovirus colds in normal and
in asthmatic subjects. Am J Respir Crit Care Med 1995;151:879-86.
J ALLERGY CLIN IMMUNOL
AUGUST 2000
48. Jarjour NN, Gern JE, Kelly EAB, Swenson CA, Dick CR, Busse WW.
The effect of an experimental rhinovirus 16 infection on bronchial
lavage neutrophils. J Allergy Clin Immunol 2000;105:1169-77.
49. Schroth MK, Grimm E, Frindt P, Galagan DM, Love R, Gern JE. Rhi-
novirus replication causes RANTES production in primary bronchial
epithelial cells. Am J Respir Cell Mol Biol 1999;20:1220-8.
50. Halperin SA, Eggleston PA, Hendley JO, Suratt PM, Gröschel DH,
Gwaltney JM Jr. Pathogenesis of lower respiratory tract symptoms in
experimental rhinovirus infection. Am Rev Respir Dis 1983;128:806-10.
51. 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;155:1159-61.
52. 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;157:1708-20.
53. Cheung D, Dick EC, Timmers MC, De Klerk EPA, Spaan WJM, Sterk
PJ. Rhinovirus inhalation causes long-lasting excessive airway narrow-
ing in response to methacholine in asthmatic subjects in vivo. Am J
Respir Crit Care Med 1995;152:1490-6.
54. Gern JE, Calhoun WJ, Swenson C, Shen G, Busse WW. Rhinovirus
infection preferentially increases lower airway responsiveness in aller-
gic subjects. Am J Respir Crit Care Med 1997;155:1872-6.
55. Bardin PG, Sanderson G, Robinson BS, Holgate ST, Tyrrell DAJ.
Experimental rhinovirus infection in volunteers. Eur Respir J
1996;9:2250-5.
56. Calhoun WJ, Swenson CA, Dick EC, Schwartz LB, Lemanske RF Jr,
Busse WW. Experimental rhinovirus 16 infection potentiates histamine
release after antigen bronchoprovocation in allergic subjects. Am Rev
Respir Dis 1991;144:1267-73.
57. Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold virus,
rhinovirus 16, potentiates airway inflammation after segmental antigen
bronchoprovocation in allergic subjects. J Clin Invest 1994;94:2200-8.
58. Gern JE, Busse WW. The effects of rhinovirus infections on allergic air-
way responses. Am J Respir Crit Care Med 1995;152:S40-5.
59. Lemanske RF Jr, Dick EC, Swenson CA, Vrtis RF, Busse WW. Rhi-
novirus upper respiratory infection increases airway hyperreactivity and
late asthmatic reactions. J Clin Invest 1989;83:1-10.
60. Avila PC, Abisheganaden JA, Wong H, Liu J, Yagi S, Schnurr D, et al.
Delayed onset of rhinovirus (RV)-16 common cold in allergic rhinitic
subjects primed with nasal allergen challenges. J Allergy Clin Immunol
1999;103:S117.
61. Exelbert RL, Skoner DP, Gentile DA, Doyle WJ, Seroky J, Angelini BL,
et al. Upper airway response in ragweed-primed and unprimed adult
subjects during experimental infection with influenza A (FLU) virus. J
Allergy Clin Immunol 2000;105:S198.
62. Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF. Recombi-
nant human eosinophil-derived neurotoxin/RNase 2 functions as an
effective antiviral agent against respiratory syncytial virus. J Infect Dis
1998;177:1458-64.
63. Doyle WJ, Skoner DP, Fireman P, Seroky JT, Green I, Ruben F, et al.
Rhinovirus 39 infection in allergic and nonallergic subjects. J Allergy
Clin Immunol 1992;89:968-78.
64. Eggleston PA, Hendley JO, Gwaltney JM Jr. Mediators of immediate
hypersensitivity in nasal secretions during natural colds and rhinovirus
infection. Acta Otolaryngol (Stockh) 1984;413:25-35.
65. Turner RB, Weingand KW, Yeh CH, Leedy DW. Association between
interleukin-8 concentration in nasal secretions and severity of symptoms
of experimental rhinovirus colds. Clin Infect Dis 1998;26:840-6.
66. Alwan WH, Kozlowska WJ, Openshaw PJ. Distinct types of lung dis-
ease caused by functional subsets of antiviral T cells. J Exp Med
1994;179:81-9.
67. 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;105:692-8.
68. Winther B, Farr B, Thoner RB, Hendley JO, Mygrind N, Gwaltney JM.
Histopathologic examination and enumeration of polymorphonuclear
leukocytes in the nasal mucosa during experimental rhinovirus colds.
Acta Otolaryngol (Stockh) 1984;413(Suppl):19-24.
69. Naclerio RM, Proud D, Lichtenstein LM, Kagey-Sobotka A, Hendley
JO, Sorrentino J, et al. Kinins are generated during experimental rhi-
novirus colds. J Infect Dis 1988;157:133-42.
J ALLERGY CLIN IMMUNOL
VOLUME 106, NUMBER 2
70. Einarsson O, Geba GP, Zhu Z, Landry M, Elias JA. Interleukin-11: stim-
ulation in vivo and in vitro by respiratory viruses and induction of air-
ways hyperresponsiveness. J Clin Invest 1996;97:915-24.
71. Proud D, Gwaltney JM Jr, Hendley JO, Dinarello CA, Gillis S,
Schleimer RP. Increased levels of interleukin-1 are detected in nasal
secretions of volunteers during experimental rhinovirus colds. J Infect
Dis 1994;169:1007-13.
72. Grünberg K, Timmers MC, Smits HH, De Klerk EPA, Dick EC, Spaan
WJM, et al. Effect of experimental rhinovirus 16 colds on airway hyper-
responsiveness to histamine and interleukin-8 in nasal lavage in asth-
matic subjects in vivo. Clin Exp Allergy 1997;27:36-45.
73. Folkerts G, Verheyen A, Janssen M, Nijkamp FP. Virus-induced airway
hyperresponsiveness in the guinea pig can be transferred by bron-
choalveolar cells. J Allergy Clin Immunol 1992;90:364-72.
74. Cannon MJ, Openshaw PJM, Askonas BA. Cytotoxic T cells clear virus
but augment lung pathology in mice infected with respiratory syncytial
virus. J Exp Med 1988;168:1163-8.
75. Alwan WH, Record FM, Openshaw PJM. CD4+ T-cells clear virus but
augment disease in mice infected with respiratory syncytial virus—
comparison with the effects of CD8+ T-cells. Clin Exp Immunol
1992;88:527-36.
76. Hakonarson H, Maskeri N, Carter C, Hodinka RL, Campbell D, Grun-
stein MM. Mechanism of rhinovirus-induced changes in airway smooth
muscle responsiveness. J Clin Invest 1998;102:1732-41.
77. Yamaya M, Sekizawa K, Suzuki T, Yamada N, Furukawa M, Ishizuka S,
et al. Infection of human respiratory submucosal glands with rhinovirus:
effects on cytokine and ICAM-1 production. Am J Physiol
1999;277:L362-71.
78. Arruda E, Mifflia TE, Gwaltney JM Jr, Winther B, Hayden FG. Local-
ization of rhinovirus replication in vitro with in situ hybridization. J
Med Virol 1991;54:634-8.
79. Bardin PG, Johnston SL, Sanderson G, Robinson BS, Pickett MA,
Fraenkel DJ, et al. Detection of rhinovirus infection of the nasal mucosa
by oligonucleotide in situ hybridization. Am J Respir Cell Mol Biol
1994;10:207-13.
80. Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney JM, Hayden FG.
Localization of human rhinovirus replication in the upper respiratory
tract by in situ hybridization. J Infect Dis 1995;171:1329-33.
81. Zhu Z, Tang W, Wu Y, Einarsson O, Landry ML, Gwaltney JM Jr, et al.
Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence
for nuclear factor kappa B-dependent transcriptional activation. J Clin
Invest 1996;97:421-30.
82. Zhu Z, Tang W, Gwaltney JMJ, Wu Y, Elias JA. Rhinovirus stimulation
of interleukin-8 in vivo and in vitro: role of NF-κB. Am J Physiol
1997;273:L814-24.
83. Jamaluddin M, Casola A, Garofalo RP, Han Y, Elliott T, Ogra PL et al.
The major component of IkappaBalpha proteolysis occurs independent-
ly of the proteasome pathway in respiratory syncytial virus-infected pul-
monary epithelial cells. J Virol 1998;72:4849-57.
84. Teran LM, Seminario MC, Shute JK, Papi A, Compton SJ, Low JL, et
al. RANTES, macrophage-inhibitory protein 1α, and the eosinophil
product major basic protein are released into upper respiratory secre-
tions during virus-induced asthma exacerbations in children. J Infect
Dis 1999;179:677-81.
85. Noah TL, Henderson FW, Wortman IA, Devlin RB, Handy J, Koren HS,
et al. Nasal cytokine production in viral acute upper respiratory infec-
tion of childhood. J Infect Dis 1995;171:584-92.
86. van Schaik SM, Tristram DA, Nagpal IS, Hintz KM, Welliver RC, Welliv-
er RC. Increased production of IFN-gamma and cysteinyl leukotrienes in
virus-induced wheezing. J Allergy Clin Immunol 1999;103:630-6.
87. Kameyoshi Y, Dorschner A, Mallet AI, Christophers E, Schroder JM.
Cytokine RANTES released by thrombin-stimulated platelets is a potent
attractant for human eosinophils. J Exp Med 1992;176:587-92.
88. Zhang L, Redington AE, Holgate ST. RANTES: a novel mediator of
allergic inflammation? Clin Exp Allergy 1994;24:899-904.
89. Igarashi Y, Skoner DP, Doyle WJ, White MV, Fireman P, Kaliner MA.
Analysis of nasal secretions during experimental rhinovirus upper res-
piratory infections. J Allergy Clin Immunol 1993;92:722-31.
90. Proud D, Naclerio RM, Gwaltney JM, Hendley JO. Kinins are generat-
ed in nasal secretions during natural rhinovirus colds. J Infect Dis
1990;161:120-3.
91. Higgins PG, Barrow GI, Tyrrell DA. A study of the efficacy of the
Gern and Busse 211
bradykinin antagonist, NPC 567, in rhinovirus infections in human vol-
unteers. Antiviral Res 1990;14:339-44.
92. Yuta A, Doyle WJ, Gaumond E, Ali M, Tamarkin L, Baraniuk JN, et al.
Rhinovirus infection induces mucus hypersecretion. Am J Physiol Lung
Cell Mol Physiol 1998;274:L1017-23.
93. Longphre M, Li D, Gallup M, Drori E, Ordonez CL, Redman T, et al.
Allergen-induced IL-9 directly stimulates mucin transcription in respi-
ratory epithelial cells. J Clin Invest 1999;104:1375-82.
94. Basbaum C, Lemjabbar H, Longphre M, Li D, Gensch E, McNamara N.
Control of mucin transcription by diverse injury-induced signaling path-
ways. Am J Respir Crit Care Med 1999;160:S44-8.
95. Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, et al.
Epidermal growth factor system regulates mucin production in airways.
Proc Natl Acad Sci 1999;96:3081-6.
96. Everard ML, Swarbrick A, Wrightham M, Mcintyre J, Dunkley C, James
PD, et al. Analysis of cells obtained by bronchial lavage of infants with
respiratory syncytial virus infection. Arch Dis Child 1994;71:428-32.
97. Busse WW, Vrtis RF, Steiner R, Dick EC. In vitro incubation with
influenza virus primes human polymorphonuclear leukocyte generation
of superoxide. Am J Respir Cell Mol Biol 1991;4:347-54.
98. Schuster A, Fahy JV, Ueki I, Nadel JA. Cystic fibrosis sputum induces
a secretory response from airway gland serous cells that can be pre-
vented by neutrophil protease inhibitors. Eur Respir J 1995;8:10-4.
99. Heymann PW, Rakes GP, Hogan AD, Ingram JM, Hoover GE, Platts-
Mills TA. Assessment of eosinophils, viruses and IgE antibody in wheez-
ing infants and children. Int Arch Allergy Immunol 1995;107:380-2.
100. Garofalo R, Kimpen JLL, Welliver RC, Ogra PL. Eosinophil degranula-
tion in the respiratory tract during naturally acquired respiratory syncy-
tial virus infection. J Pediatr 1992;120:28-32.
101. Grünberg K, Smits HH, Timmers MC, de KE, Dolhain RJ, Dick EC, et
al. Experimental rhinovirus 16 infection. Effects on cell differentials
and soluble markers in sputum in asthmatic subjects. Am J Respir Crit
Care Med 1997;156:609-16.
102. Handzel ZT, Busse WW, Sedgwick JB, Vrtis R, Lee WM, Kelly EAB,
et al. Eosinophils bind rhinovirus and activate virus-specific T cells. J
Immunol 1998;160:1279-84.
103. Gern JE, Vrtis R, Kelly EAB, Dick EC, Busse WW. Rhinovirus pro-
duces nonspecific activation of lymphocytes through a monocyte-
dependent mechanism. J Immunol 1996;157:1605-12.
104. Levandowski RA, Weaver CW, Jackson GG. Nasal secretion leukocyte
populations determined by flow cytometry during acute rhinovirus
infection. J Med Virol 1988;25:423-32.
105. Gern JE, Dick EC, Lee WM, Murray S, Meyer K, Handzel ZT, et al.
Rhinovirus enters but does not replicate inside monocytes and airway
macrophages. J Immunol 1996;156:621-7.
106. Hayden FG, Albrecht JK, Kaiser DL, Gwaltney JM Jr. Prevention of
natural colds by contact prophylaxis with intranasal alpha 2-interferon.
N Engl J Med 1986;314:71-5.
107. Romagnani S. The role of lymphocytes in allergic disease. J Allergy
Clin Immunol 2000;105:399-408.
108. Tough DF, Borrow P, Sprent J. Induction of bystander T cell prolifera-
tion by viruses and type I interferon in vivo. Science 1996;272:1947-50.
109. Sareneva T, Matikainen S, Kurimoto M, Julkunen I. Influenza A virus-
induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma
gene expression in human T cells. J Immunol 1998;160:6032-8.
110. Rimmelzwaan GF, Osterhaus ADME. Cytotoxic T lymphocyte memo-
ry: role in cross-protective immunity against influenza? Vaccine
1995;13:703-5.
111. Gern JE, Dick EC, Kelly EAB, Vrtis R, Klein B. Rhinovirus-specific T
cells recognize both shared and serotype-restricted viral epitopes. J
Infect Dis 1997;175:1108-14.
112. Wimalasundera SS, Katz DR, Chain BM. Characterization of the T cell
response to human rhinovirus in children: implications for understanding
the immunopathology of the common cold. J Infect Dis 1997;176:755-9.
113. Sanders SP, Siekierski ES, Porter JD, Richards SM, Proud D. Nitric
oxide inhibits rhinovirus-induced cytokine production and viral replica-
tion in a human respiratory epithelial cell line. J Virol 1998;72:934-42.
114. de Gouw HWFM, Grünberg K, Schot R, Kroes ACM, Dick EC, Sterk
PJ. Relationship between exhaled nitric oxide and airway hyperrespon-
siveness following experimental rhinovirus infection in asthmatic sub-
jects. Eur Respir J 1998;11:126-32.
115. Stockl J, Vetr H, Majdic O, Zlabinger G, Kuechler E, Knapp W. Human
212 Gern and Busse
major group rhinoviruses downmodulate the accessory function of
monocytes by inducing IL-10. J Clin Invest 1999;104:957-65.
116. Gentile DA, Patel A, Ollila C, Fireman P, Zeevi A, Doyle WJ, et al.
Diminished IL-10 production in subjects with allergy after infection
with influenza A virus. J Allergy Clin Immunol 1999;103:1045-8.
117. Yoon HJ, Zhu Z, Gwaltney JM Jr, Elias JA. Rhinovirus regulation of IL-
1 receptor antagonist in vivo and in vitro: a potential mechanism of
symptom resolution. J Immunol 1999;162:7461-9.
118. Fryer AD, Costello RW, Jacoby DB. Muscarinic receptor dysfunction in
asthma. Allergy Clin Immunol Int 2000;12:63-7.
119. Folkerts G, Nijkamp FP. Virus-induced airway hyperresponsiveness:
J ALLERGY CLIN IMMUNOL
AUGUST 2000
role of inflammatory cells and mediators. Am J Respir Crit Care Med
1995;151:1666-74.
120. Storch GA. Humanized monoclonal antibody for prevention of respira-
tory syncytial virus infection. Pediatrics 1998;102:648-51.
121. Turner RB, Wecker MT, Pohl G, Witek TJ, Mcnally E, St George R, et
al. Efficacy of tremacamra, a soluble intercellular adhesion molecule 1,
for experimental rhinovirus infection - A randomized clinical trial.
JAMA 1999;281:1797-804.
122. Patick AK, Binford SL, Brothers MA, Jackson RL, Ford CE, Diem MD,
et al. In vitro antiviral activity of AG7088, a potent inhibitor of human rhi-
novirus 3C protease. Antimicrob Agents Chemother 1999;43:2444-50.