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Asthma exacerbations are frequently linked to rhinovirus infections. However, the associated inflammatory pathways are poorly understood, and treatment of exacerbations is often unsatisfactory. In the present study we investigated whether antiinflammatory treatment with inhaled corticosteroids prevents any rhinovirus-induced worsening of lower airway inflammation. To that end, we selected 25 atopic patients with mild asthma who underwent experimental rhinovirus 16 (RV16) infection, while receiving double-blind, placebo-controlled treatment with the inhaled corticosteroid budesonide (800 µg twice a day) throughout the study period, starting 2 wk before infection. We assessed inflammatory cell numbers in the bronchial mucosa as obtained by bronchial biopsies 2 d before and 6 d after RV16 infection, and analyzed those in relation to cold symptoms, changes in blood leukocyte counts, airway obstruction, and airway hyperresponsiveness. RV16 colds induced an increase in CD3+ cells in the lamina propria (p = 0.03) and tended to decrease the numbers of epithelial eosinophils (p = 0.06) in both groups analyzed as a whole. The T cell accumulation was positively associated with cold symptoms. Budesonide pretreatment improved airway hyperresponsiveness (p = 0.02) and eosinophilic airways inflammation (p = 0.04). Yet it did not significantly affect the RV16-associated changes in the numbers of any of the inflammatory cell types. We conclude that RV16 infection by itself induces only subtle worsening of airway inflammation in asthma, which is not improved (or worsened) by inhaled corticosteroids. The latter finding is in keeping with the limited protection of inhaled corticosteroids against acute asthma exacerbations.
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Keywords: asthma; inflammation; rhinoviruses; corticosteroids
Patients with asthma frequently suffer from transient worsening of their disease during respiratory virus infections. Rhinoviruses are most commonly associated with such exacerbations (1, 2). Indeed, experimental rhinovirus infection in patients with asthma worsens asthma symptoms (3, 4), variable airway obstruction (5), and airway hyperresponsiveness to various bronchoconstrictor stimuli (3, 4, 6). This suggests that rhinovirus infection is able to promote airway inflammation in preexisting asthma.
Indeed, there is evidence that rhinovirus infections enhance airway inflammation in asthma, as reflected by an increase in local production of inflammatory mediators such as
interleukin (IL)-1
, IL-8, IL-6, and ECP, detectable in nasal
lavage (4, 7) and/or in induced sputum (8). In addition, rhinovirus 16 (RV16) infections enhance ICAM-1 expression in
the bronchial epithelial layer (9), and promote the infiltration
of T cells into the bronchial lamina propria, and of eosinophils
into the bronchial epithelium during the acute phase of infection in a sample that combined normal subjects and subjects
with asthma (10). The relevance of these observations for development of rhinovirus-induced exacerbations of asthma is,
however, still unclear.
Inhaled or oral glucocorticosteroids are the most commonly used antiinflammatory drugs for regular asthma therapy (11). In vitro, glucocorticoids appear to be effective against rhinovirus replication, cytokine release, and ICAM-1 upregulation in cell cultures (12, 13). On the other hand, there is some evidence that glucocorticoids, by suppressing the immune response (14), may hamper viral clearance (15), thereby potentially worsening or protracting the disease. Evidence on the effectiveness of glucocorticoids during proven rhinovirus infections is lacking. Clinical studies in children show little or no benefit of inhaled glucocorticoids in preventing (16) or treating (17) acute exacerbations of asthma. In view of the potential role of inhaled glucocorticoids in patient self-management of acute exacerbations, the effectiveness of inhaled glucocorticoids for rhinovirus-associated exacerbations of asthma needs to be investigated.
In the present study we hypothesized that RV16 colds in subjects with asthma induce worsening of the underlying inflammation of the lower airways, which can be prevented (in part) by pretreatment with inhaled glucocorticoids. We conducted a trial in atopic patients with asthma who all underwent experimental RV16 infection, and received double blind, placebo-controlled treatment with inhaled budesonide throughout the study period, starting 2 wk before infection. The primary outcome parameters of the study were the numbers of inflammatory cells in bronchial lamina propria and epithelium before and after RV16 infection, as obtained from bronchial biopsy specimens. The observed changes in these outcome parameters were analyzed in relation to cold score, changes in peripheral blood leukocyte counts (as an indicator of severity of colds), airway obstruction, and airway hyperresponsiveness (as indicators of asthma severity).
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Twenty-five nonsmoking atopic steroid-naive adults with asthma with
low rhinovirus 16-neutralizing serum titers were recruited (Table 1).
The study was approved by the Medical Ethics Committee of the
Leiden University Medical Center and all subjects gave their written
informed consent. The subjects only used inhaled short-acting 2-agonists on demand. All participants underwent RV16 inoculation on
Days 0 and 1. Inhaled budesonide (Turbohaler, 800 µg, twice a day)
(BUD) was administered in a randomized, double blind, placebo-controlled (PLAC) fashion for 4 wk, starting 16 d before RV16 inoculation (Day 
16). Blood samples were drawn at Days 17, 2, 3, 6, and
28. FEV1 and the provocative concentration of histamine causing a
20% fall in FEV1 (PC20) were recorded at Days 17, 4, 4, and finally
at Day 13. Bronchial biopsies were taken at Days 2 and 6.
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RV16 inoculation took place according to a previously described protocol (3, 4, 20, 21). The total RV16 dose was 0.6-2.1 × 104 50% tissue culture infective dose (TCID50). Infection was confirmed by at least a 4-fold increase in RV16-neutralizing serum antibody titer and/or by recovery of RV16 from nasal washes (4). Finally, the subjects scored their cold symptoms three times daily (4).
Venous blood leukocyte counts (cells × 109/L) were made by automated blood count analysis (Technicon H1, Technicon, Tarrytown, NY). After assessment of baseline FEV1, PC20 was determined by standardized 2 min tidal breathing challenge tests (4, 22) using doubling concentrations of histamine (0.03-8 mg/ml). A standardized fiberoptic bronchoscopy procedure under local anesthesia (lignocaine 10% and 2% [wt/vol]) (23) was carried out after 6 h of fasting. Premedication consisted of 0.5 mg atropine subcutaneously, 20 mg codeine orally, and 400 µg inhaled salbutamol. The bronchoscope (Pentax Optical Co., Japan, outer diameter 6 mm) was introduced through the mouth. Bronchial biopsies were taken at the (sub) segmental level, using cup forceps (Olympus FB-20C, Tokyo, Japan). Alternate biopsy sites (right or left lung) were randomized over the two visits.
Immunohistochemical staining was performed on 4-µm sections of the formalin-fixed paraffin-embedded biopsies (Table 2). The primary antibodies to CD3, CD4, CD8, EG2, elastase, and AA1 were visualized using the streptavidin-biotin complex (SABC). Biotinylated rabbit anti-mouse antibodies (or swine anti-rabbit antibodies for CD3) were used. Automated cell counting (24) was performed in a blinded fashion on digitized (25) images from a three-chip color camera (KS-400 system, Kontron/Zeiss, The Netherlands). First, the basement membrane was manually delineated. Lamina propria area, defined by the widest possible 125-µm deep zone beneath the basement membrane of at least 86,000 µm2 (excluding BALT, cartilage, and smooth muscle) was automatically determined. The epithelial area above the basement membrane of at least 25,000 µm2 was then determined. Damaged epithelium was not excluded, to avoid bias due to possible virus-induced epithelial damage. The automated cell counting consisted of the following steps: level off background staining, normalize staining intensity, delete noise, fuse stained fragments, delineate stained clusters, and determine the cell count by an algorithm. Cell counts were expressed as cells/0.1 mm2.
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Statistical analysis was performed on log-transformed cell counts, after addition of 1 to allow for transformation of zero values (25). The results were expressed as geometric mean ± SEM in doubling cell number (DC), which is the SEM of the logged data, divided by log[2]. Likewise, changes in cell numbers were expressed as doubling cell numbers, being the difference in logged data pairs, divided by log[2]. Paired and unpaired Student's t tests were used where applicable. Relationships between various outcome parameters were investigated using Pearson's correlation test. p Values < 0.05 were considered to be significant.
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All 25 patients completed the study. One patient (3) did not
undergo the bronchoscopies due to strong subjective discomfort. RV16 infection was confirmed in all RV16-inoculated
subjects, except subjects 2, 8, 17, and 23, who were excluded
from the statistical analysis of the effect of RV16. All RV16-treated subjects had an anti-RV16 titer serum 
1:1 before entering the study. However, reassessment just before inoculation of RV16 revealed slightly elevated titers in subjects 7, 8, and 23, coinciding with symptoms of a common cold in subjects 8 and 23, which was confirmed in subject 8 by rhinovirus-positive (RV16-negative) culture of the nasal lavage. Since
low levels of neutralizing antibodies per se have not been
shown to preclude a symptomatic common cold (4), subject 7 was not excluded from the analysis.
Peripheral Blood Leukocyte Counts
The effects of treatment and RV16 on peripheral blood leukocyte counts are depicted in Figure 1A. In the placebo group the cold score (Table 1) correlated significantly with the increase in the numbers of neutrophils between Days 3 and 6 (r = 0.82, p = 0.003).
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0.75, between groups: p = 0.27). Eosinophil numbers decreased in both groups (p Lung Function and Airways Hyperresponsiveness
Before commencement of treatment FEV1 (% predicted) (26) was not significantly different between the groups (mean ± SEM BUD: 84.6 ± 2.4, PLAC: 89.2 ± 2.5, p = 0.21). During the pretreatment period FEV1 tended to increase in the budesonide group (p = 0.07), however, this increase was not significantly different between the groups (p = 0.63). RV16 infection had no significant effect on FEV1 (p = 0.41), and changes were not significantly different between the groups (p = 0.09).
In the budesonide group the PC20 to histamine showed an
increase during the pretreatment period (p = 0.005) that was
different from placebo (p = 0.02). As a result, there was a
(borderline) significant between-group difference in PC20 at
Day 4 (p = 0.05). Subsequently, there was no significant effect of RV16 infection on PC20 within either treatment group
(PLAC: p = 0.18, BUD: p = 0.65), nor was the effect significantly different between the groups (p = 0.20). PC20 was still
higher in the budesonide group as compared with placebo at
Day 4 after infection (p = 0.02), but no longer so at Day 13 (p = 0.18) (Figure 1B).
Biopsies: Lamina Propria
The average area of lamina propria per patient that was examined for all stainings and all visits was 266,000 ± 11,000 µm2 (SEM). The descriptive and statistical analyses are presented in Table 3. In both groups there was a similar trend toward an increase in the numbers of CD3+ cells. This increase was significant in the analysis of the pooled data of the two groups (p = 0.03). The increase can be attributed in part to a significant increase in CD8+ cells in the placebo group (p = 0.04). We observed a trend toward a decrease in the number of eosinophils (p = 0.06) only in the placebo group.
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In the placebo group cold scores tended to correlate significantly with the increase in the number of CD3+ cells (r = 0.59, p = 0.07) (Figure 2A). In the placebo group, we found
that the larger the decrease in the number of lamina propria
EG2+ cells, the larger the early phase increase in the number
of peripheral blood eosinophils (Day 3: r = 0.74, p = 0.04),
and the smaller the worsening of PC20 to histamine was (Day
4: r = 0.70, p = 0.02).
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Biopsies: Epithelium
The average area of epithelium per patient that was examined for all stainings and all visits was 90,000 ± 5,000 µm2 (SEM). The descriptive and statistical analyses are presented in Table 4. First, the data show a significantly lower number of EG2+ cells in the budesonide group as compared with placebo after 2 wk treatment (p = 0.04). After RV16 infection, there was a significant increase in the number of CD3+ cells in the budesonide group (p = 0.04), which was not significantly different from the effect in the placebo group (p = 0.41).
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Similar to the relationship in lamina propria, the higher the
cold score, the larger the epithelial accumulation of CD3+
cells in the placebo group (r = 0.77, p = 0.02) (Figure 2B). This may not be surprising, as the accumulation of CD3+cells
in the epithelium and lamina propria was significantly correlated (r = 0.66, p = 0.04). Moreover, accumulation of CD8+
cells (in the placebo group) or CD4+ cells (in the budesonide
group) was associated with decreased worsening of PC20 during the RV16 cold (PLAC: r = 0.71, p = 0.02, BUD: r = 0.67, p = 0.047) (Figures 3A and 3B). Finally, the rise in numbers of
circulating monocytes (a CD4+ cell) in the early phase of the
cold (Day 3) was significantly, but inversely related to accumulation of epithelial CD4+ cells (r = 0.74, p = 0.03) in the
placebo group.
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In this study we demonstrated that an experimental RV16 infection in subjects with asthma is associated with subtle inflammatory changes within the bronchial wall. Six days after RV16 infection we observed an accumulation of T cells, particularly cytotoxic T cells, accompanied by a trend toward lowering of eosinophil numbers in lamina propria and epithelium. Two weeks treatment with inhaled budesonide improved airway hyperresponsiveness and lowered the numbers of eosinophils in biopsies, and this improvement was maintained after subsequent RV16 infection. There were no significant effects of budesonide on the RV16-associated accumulation of any of the inflammatory cell types. Our results suggest the rhinovirus infection alone may not be sufficient to provoke the physiological and inflammatory events observed during "spontaneous" exacerbation of asthma. This precludes definite conclusions as to the effectiveness of inhaled corticosteroids against rhinovirus-induced exacerbations of asthma.
This is the first study to describe the effects of placebo-controlled (pre)treatment with inhaled glucocorticoids on lower airways inflammation, as induced by experimental RV16 colds in subjects with asthma. The observed RV16-associated infiltration by T cells into the lamina propria confirms the results of a previous study on RV16-induced airways inflammation by Fraenkel and coworkers (10). The absence of an increase in numbers of activated eosinophils is in keeping with findings in normal and atopic subjects after natural colds (27), but is in apparent contrast to the observed increase in EG2+ cells in the epithelium in the previously mentioned study (10). Methodological differences such as patient selection (atopic subjects with asthma only versus a mixed sample of normal subjects and subjects with asthma) and study design (biopsies taken 6 d versus 4 d after inoculation) may have contributed in part to the different outcomes in these two studies.
The lack of significant effects of budesonide on airway obstruction, airway hyperresponsiveness, or cellular infiltration into the bronchial mucosa after the rhinovirus infection seems to be in keeping with clinical studies, showing a lack of effectiveness to protect against or treat acute exacerbations of asthma in children (16). However, in view of the mildness of the current responses to RV16 infection, it remains to be determined whether this also holds true for more severe virus-associated exacerbations of asthma. Reassuringly, neither did we observe any detrimental effects of inhaled steroids on any of the parameters, in terms of severity of response and recovery time, which a priori could not be excluded, based on potentially impaired viral clearance (14, 15).
The results of this study were obtained after carefully considering study design and subjects selection, while using validated methods for administering RV16 (3, 20) and recording lung function and airway responsiveness (22). By using an automated system to perform biopsy cell counting we were able to analyze relatively large amounts of tissue for each staining (25), in a standardized and highly reproducible way (24). We included only steroid-naive patients who had mild persistent asthma, who were eligible for regular treatment with inhaled steroids, according to treatment guidelines (11). However, the dosage used (800 µg twice a day) was higher than the recommended dose for mild persistent asthma (11), to ensure the optimal protection that can be achieved in a relatively short pretreatment period (28). The decrease in airway hyperresponsiveness and the reduced eosinophil counts in the bronchial mucosa of the budesonide-treated subjects after the 2 wk pretreatment period fit in with the results of previous studies on the effects of inhaled corticosteroids (29, 30), and indicate that the pretreatment with inhaled corticosteroids was adequate to produce distinct antiinflammatory effects (28). Whether more prolonged pretreatment aimed at reduction of the lymphocytic infiltrate and airway remodeling (23) would be more effective for preventing virus-induced airways inflammation remains to be investigated.
The present data do not seem to be affected by lack of statistical power, as the power allowed detection of a 2-fold difference in eosinophil numbers between the groups after 2 wk budesonide treatment, and also of the rhinovirus-associated within-group changes in cell numbers of similar or smaller magnitude (25). The various correlations between biopsy cell counts and clinical/physiological outcome parameters indicate that even variation resulting in nonsignificant changes may not just be random noise, but can indeed have biological relevance. As the present sample size has previously been shown to allow detection of the effect of placebo-controlled treatment with inhaled steroids on bronchial inflammatory cell counts (29), we speculate that any effects of budesonide treatment on rhinovirus-induced airways inflammation are likely to be smaller than those observed during treatment with inhaled steroids alone.
In the present study, RV16 inoculation resulted in successful infection in 21 of 25 patients. Yet in contrast to previous studies by others (20) and ourselves (4), the RV16 colds in the present study were not associated with a significant increase in airway hyperresponsiveness to histamine. The severity of infection, as reflected by cold scores and rise in numbers of circulating neutrophils, has been shown to be linked to the rhinovirus-associated enhancement of airways hyperresponsiveness (4), such that only the severest colds lead to a significant decrease in PC20. The cold scores tended to be lower than those described in a previous study (4), and we speculate that this might explain the observed lack of increase in airway hyperresponsiveness. Possibly, unidentified virus- or host-associated factors might explain this variation. Yet the present data extend previous findings (4) by showing that the severity of cold symptoms significantly correlated not only with the rise in numbers of circulating neutrophils but also with the accumulation of T cells in the bronchial mucosa. This indicates that mild rhinovirus infections may exacerbate some aspects of airway inflammation, even in the absence of marked clinical worsening of asthma.
We observed RV16-associated accumulation of CD3+ cells in the groups as a whole, and of CD8+ cells in the lamina propria in the placebo group in particular. These findings are in keeping with an MHC class I restricted cytotoxic T cell response. Such an immune response is considered to be most efficient for viral clearance and recovery (31), and adds to previous evidence of rhinoviral infection of the bronchial tissues themselves (34, 35). Indeed, the increase in epithelial CD8+ cell infiltration was associated with improvement rather than worsening of airway hyperresponsiveness in the placebo group. In the budesonide-treated subjects, however, it was the migration of CD4+ cells that appeared to be associated with changes in airway hyperresponsiveness. Based on the observations that the average numbers of CD4+ cells exceed CD3+ cell numbers in the lamina propria, and that accumulation of CD4+ cells correlates significantly with the shift in numbers of circulating monocytes, it seems likely that the CD4+ cell infiltrate represents both T helper cells and monocytes. Therefore, additional studies are required in order to assess the relative contribution of monocytes and T helper cells in an MHC class II restricted response to rhinovirus-induced airway pathology, particularly in relation to ICAM-1 expression and to glucocorticoid therapy.
We did not observe an effect of budesonide treatment on
rhinovirus-induced cellular infiltration of the bronchial mucosa. The interaction of glucocorticoids, rhinovirus infection,
and underlying allergic airways inflammation is likely to be
complex. For example, glucocorticosteroids down-regulate cytokine expression (36). However, some cytokines (IL-4, IFN-
)
counteract the glucocorticoid-induced inhibition of the effects
of IL-1 (37, 38), which is a pivotal cytokine in the rhinovirus-induced immune response (39, 40). Moreover, all three factors
may affect monocyte responsiveness in various ways (38, 41,
42). Based on the present results one could argue that glucocorticoids reduce allergic airway inflammation, possibly even
during a rhinovirus infection, whereas they do not seem to
have a detrimental effect on the antiviral immune response.
In summary, our data demonstrate that rhinovirus colds per se have rather limited effects on bronchial inflammation. Experimental rhinovirus infection seems to promote the accumulation of T cells, particularly cytotoxic T cells, in the bronchial mucosa. Treatment with inhaled steroids improves airway hyperresponsiveness and eosinophilic airway inflammation. However, inhaled corticosteroid treatment does not appear to affect the inflammatory changes associated with rhinovirus infections. The present findings indicate that rhinovirus infection by itself may not be sufficiently deleterious to induce the clinical and inflammatory worsening as are observed during spontaneous exacerbations. This may require the presence of cofactors, such as ongoing allergen exposure. Our data suggest that the merits of prophylaxis with inhaled steroids lie in improvement of the baseline condition of patients with asthma, while their effectiveness for preventing and treating severe rhinovirus-induced exacerbations of asthma remains to be established.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. P. J. Sterk, M.D., Lung Function Laboratory, C2-P, Leiden University Medical Center (LUMC), Albinusdreef 2/P.O. Box 9600, NL-2300 RC Leiden, The Netherlands. E-mail: p.j.sterk{at}lumc.nl
(Received in original form February 27, 2001 and accepted in revised form August 20, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors wish to thank AstraZeneca and the Department of Clinical Pharmacy and Toxicology of the LUMC for providing the study medication, the laboratory for Clinical Hematology for performing the blood analysis, and the pulmonologists and technicians for skillfully performing the bronchoscopies.
Supported by the Netherlands Asthma Foundation (Grant 93.17) and AstraZeneca, The Netherlands.
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