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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the influence of atopy on virus-induced airway inflammation by comparing the nasal response to naturally acquired upper respiratory tract infection in atopic and nonatopic subjects by measurement of cytokine, chemokine, and mediator levels in nasal lavage from 44 adults (23 atopic) taken during the acute and
the convalescent phases of the common cold. Nasal aspirates were
examined for the presence of upper respiratory viruses by RT-PCR.
In atopic and nonatopic subjects there were increased levels of IL-1
,
IL-6, IL-8, TNF-
, RANTES, sICAM-1, MPO, ECP, IL-10, and IFN-
in nasal lavage during the acute compared with the convalescent phase
(p < 0.001). During the acute phase histamine levels were significantly higher in the atopic than in the nonatopic subjects (p < 0.05),
whereas IL-10 levels were significantly greater in the nonatopic
than in the atopic subjects (p < 0.05). At convalescence levels of
IL-1, IL-6, sICAM-1, ECP, RANTES and albumin were significantly higher in the atopic group (p < 0.05). An upper respiratory tract virus was found in 27 volunteers (61%) during the acute stage and in
two volunteers (4%) at convalescence. We conclude that virus-induced inflammatory changes within the nose are more prolonged in atopic than in nonatopic subjects and that this is associated with reduced IL-10 levels in atopic compared with nonatopic subjects during the acute phase of upper respiratory tract infection.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Upper respiratory tract (URT) viral infection is an important cause of exacerbations of asthma. Cohort studies have shown that URT viral infection, predominantly rhinovirus, is associated with 80 to 85% of exacerbations of asthma in children (1) and 44% of asthma exacerbations in adults (2). Experimental and naturally occurring URT infection has been shown to lead to increases in nonspecific bronchial reactivity (BHR) in asthmatic volunteers (3). This suggests that URT viruses have widespread effects on the inflammatory response throughout the airway (4), which is borne out by studies showing virus-induced changes in the immediate and late phase response to allergen challenge (5).
Experimental rhinovirus infection has been shown to lead to an influx of eosinophils and CD4+ and CD8+ lymphocytes into the bronchial mucosa in both asthmatic and nonasthmatic volunteers (6), and it has been shown to lead to a more prolonged airway eosinophilia in asthmatic than in nonasthmatic volunteers. These cellular changes are likely to be driven by changes in airway cytokine production since URT viruses are known to have potent effects on cytokine production from a number of cell sources (4). However, to date, no studies have been carried out to investigate differences between atopic/asthmatic subjects and nonatopic subjects in terms of their cytokine response to respiratory viral infection.
The nose is an accessible part of the respiratory tract that enables the study of inflammatory changes within the airway associated with URT viral infection. Nasal lavage was thus used to investigate the recovery of cytokines, chemokines, and markers of cell activation in airway lining fluid in association with naturally acquired "wild" URT infections. The responses of normal nonatopic subjects were compared with those in otherwise healthy atopic subjects.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Design
Subjects were recruited to the study by a poster campaign that asked for individuals who felt that they had just started to develop a cold. Subjects with symptoms consistent with an URT infection of acute onset were investigated by nasal lavage (for mediator measurements) and nasal aspirate (for virus detection) within 48 h of the onset of their symptoms and again at 28 d. All subjects were assessed at their initial visit with regard to their atopic status by skin prick testing, and symptom severity was assessed by questionnaire. No subject was receiving nasal therapy (topical or systemic). The study took place between the months of October and January, which was well outside the UK pollen season. All subjects gave informed written consent, and the study was approved by the Southampton University and Hospital Joint Ethics Committee. Each subject attended on presentation (Day 0) and on Day 28.
Symptom Determination
All subjects completed a questionnaire on Days 0 and 28 asking them to grade the following symptoms as absent, mild, moderate, or severe (scored 0, 1, 2, or 3, respectively); cough, hoarse voice, sore throat, blocked nose, sneezing, increased tissue use, stuffy nose, sinus pain, phlegm, chills, runny eyes, headache, and malaise (1). These were then summed to give a total symptom score.
Skin Prick Testing
Epicutaneous skin prick testing was performed against the house dust mite Dermatophagoides Pteronyssinus, cat hair, and mixed grass pollens. Subjects were considered atopic if they developed a wheal with a diameter 3 mm greater than that of the negative saline control to any one or more of the allergens tested.
Nasal Lavage and Supernatant Measurements
Nasal lavage was performed on Days 0 and 28. Subjects were seated
with their head tipped backwards and asked to undertake a valsalva
maneuver; 2.5 ml of warm 0.9% saline was instilled into each nostril
and held for 10 s. Subjects then flexed their neck to allow collection of
lavage into a universal container. The process was repeated, and the
collected samples were pooled and sieved. The sample was centrifuged at 4° C for 8 min at 400 × g, aliquoted into 1-ml aliquots, and
immediately stored at 
20° C. Samples were later analyzed by ELISA
for interleukin (IL)-1, IL-1, IL-4, IL-6, IL-10, tumour necrosis factor- (TNF-), interferon- (IFN-), soluble intercellular adhesion
molecule-1 (sICAM-1), RANTES, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using commercially available kits
(R&D Systems, Oxford, UK). IL-8 was quantified by ELISA using
IL-8 Mabs (supplied by Dr. I Lindley, Sandoz, Vienna, Austria). The
mediators, eosinophilic cationic protein (ECP), myeloperoxidase (MPO),
and histamine, respectively, considered primarily to be markers of
eosinophil, neutrophil, and mast cell activation, were measured by radioimmunoassay using commercially available kits (Pharmacia, Milton Keynes, UK, for ECP and MPO; Serotec, Oxford, UK for histamine). The detection limits of these assays were IL-1, 0.5 pg/ml; IL-1,
1 pg/ml; IL-4, 0.13 pg/ml; IL-6, 0.7 pg/ml; IL-10, 0.5 pg/ml; TNF-, 0.18 pg/ml; IFN-, 3 pg/ml; sICAM-1, 0.35 pg/ml; RANTES, 5 pg/ml; GM-CSF, 3 pg/ml; IL-8, 1 pg/ml; ECP, 2 µg/ml; MPO, 3 µg/ml; histamine, 1 nM.
Total protein concentrations were measured in 0.25-ml replicates of nasal lavage fluid by the method of Bradford (7) using Coomassie Blue G-250 reagent (Pierce Chemicals, Rockford, IL) as indicator. Absorbance was read at 595 nm and compared with a standard curve constructed with bovine serum albumin. Albumin levels were measured by rocket immunoelectrophoresis (8). Three-microliter aliquots of nasal lavage fluid were introduced into wells cut in agarose gel and subjected to electrophoresis (4 V/cm) for 29 h into a window of agarose containing 1.8 µl/ml of rabbit antihuman albumin antibody (Nordic, Tilburg, The Netherlands). Immunoprecipitates were stained with Coomassie Brilliant Blue, and albumin levels were quantified by comparison with standard curves constructed using human albumin (Sigma Chemical, Poole, UK). Detection limits of these assays were 5 µg/ml for protein assay and 3 µg/ml for the albumin assay.
Nasal Aspiration and RNA Extraction
Nasal aspiration was performed as previously described (1). Briefly, a
suction catheter with a mucus trap (Vygon UK Ltd, Gloucester, UK)
was attached to a foot pump, and the subject was asked to place the
tip of the catheter just inside their nostril. The subject then blew his or
her nose while gentle suction was applied by means of the foot pump,
and the mucus aspirated was caught in the trap. This was repeated
with the catheter placed in the other nostril. The mucus was then diluted in 10 ml of virus transport medium, aliquoted, and stored immediately at 80° C.
A common extraction was used for all RNA viruses. Sixty microliters of sample were combined with 240 µl of ultra high quality water
(UHQ) and 300 µl of Trizol (Gibco BRL, Paisley, Scotland) were
added. Extraction and precipitation were then carried out according
to manufacturer's instructions. The resulting RNA pellets were vacuum-dried for 5 min and resuspended in 30 µl of warm UHQ, and 1 µl
of RNA guard (Pharmacia Biotech, St. Albans, UK) was added to
each tube. The redisolved pellet was divided into six equal aliquots
and stored at 80° C.
RT-PCR
RT-PCR was performed for rhinovirus, coronavirus, parainfluenza, influenza A and B, RSV Chlamydia pneumoniae and Mycoplasma pneumonia using previously described and validated techniques (1, 9- 12). Reverse transcription was performed using primers specific for each virus, and PCR was performed using pairs of specific primers. For rhinovirus, parainfluenza, and mycoplasma, RT-PCR was followed by internal probe hybridization. Nested PCRs were performed for coronavirus, influenza A and B, and RSV.
Data Analysis
Data were analyzed using Wilcoxon's signed rank test for paired data and the Mann-Whitney test for unpaired data. Mediator levels were expressed as raw data. Correlations were determined using Spearman's rank correlation.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Forty-four subjects entered the study. Twenty-three (11 M/12 F) were atopic and 21 (9 M/12 F) were nonatopic. There were nine smokers of whom five were atopic and four nonatopic.
Symptoms
Median symptom scores were 11.2 at Day 0 (range, 4 to 21) and 2.1 (range, 0 to 9) on Day 28 (p < 0.0001). There were no significant differences in total symptom scores between atopic and nonatopic subjects on entry to the study: 11 (7 to 18) versus 11 (4 to 21).
Nasal Lavage Measurements
Mediator cytokine and chemokine measurements were made in 38 subjects (19 atopic) as six subjects were unable to tolerate nasal lavage. There was no difference in the volume of nasal lavage recovered during the acute and the convalescent phases, with 70% recovered for each phase. Similarly, the presence or absence of atopy did not influence the recovery of nasal lavage fluid. The results of mediator measurements and statistical analysis for the nasal lavage are shown in Table 1 and Figure 1A-D.
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Acute versus Convalescent Nasal Lavage Measurements
For the group as a whole the concentrations were all significantly higher in the acute phase (Day 0) than in the convalescent phase (Day 28) for IL-1, IL-8, IL-10, sICAM-1, RANTES,
TNF-, IFN-, ECP, MPO, and albumin. There were no significant differences in measured levels of histamine or IL-4
between the two time points. Levels of IL-1 (not graphically
represented) did not differ significantly between the two time
points (acute-phase median, 9.92 pg/ml [range, 2.1 to 68.9];
convalescent-phase median, 8.89 pg/ml [range, 0 to 45.4]).
Acute-phase Measurements, Atopic versus Nonatopic
During the acute phase, histamine levels in recovered lavage were significantly higher in the atopic group than in the nonatopic group (p < 0.05). Conversely, the levels of IL-10 recovered in nasal lavage were significantly higher in the nonatopic group than in the atopic group (p < 0.05) (Figure 2). There were no significant differences between the two groups in the concentrations of the other cytokines or mediators measured during the acute phase.
|
Convalescent-phase Measurements, Atopic versus Nonatopic
In the convalescent phase the concentrations of IL-1, IL-6,
sICAM-1, ECP, RANTES, and albumin in recovered nasal lavage were significantly higher in the atopic than in the nonatopic group (Figure 3). There were no significant differences
in IL-10 levels during the convalescent phase (Figure 2) and
no other significant differences in mediator measurements at
this time point. There were no detectable levels of GM-CSF in
nasal lavage at any time point.
|
The concentration of IL-10 recovered during the acute phase
correlated positively with the decrease in levels of TNF-, IL-6, IL-8, IFN-, and IL-1 that occurred in the nasal lavage between the acute phase and Day 28 (p < 0.05 for each correlation).
RT-PCR
Upper respiratory tract viruses were detected in 27 volunteers during the acute phase (15 rhinovirus, nine coronavirus, one RSV, eight influenza B, one chlamydia, including seven dual infections). There was no difference in the rate of virus detection between the atopic and the nonatopic volunteers (14 of 23 and 13 of 21 volunteers, respectively). Upper respiratory tract viruses were detected from three volunteers (all atopic) during the convalescent phase. In two of these volunteers the virus (coronavirus and rhinovirus) was also detected in the acute phase, in the other the infective agent (mycoplasma) was detected only in the convalescent phase.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Upper respiratory tract viruses are potent stimulators of cytokine and chemokine production, and the induced changes in the nasal airways are likely to underlie some of the demonstrated proinflammatory effects of URT infection. Previous in vitro
work has shown that URT viruses potentiate release of IL-1,
IL-1, IL-6, IL-8 (13), IFN- (14), GM-CSF (15), RANTES
(16), and sICAM-1 (17) as well as histamine (18). To our knowledge this is the first study to investigate the in vivo production of
all these mediators after naturally acquired URT viral infection and also the first to compare differences in cytokine, chemokine, and mediator recovery between atopic and nonatopic subjects in both the acute and the convalescent phases.
We confirmed previous findings of increased levels of IL-1
(19), IL-6 (20), IL-8 (21), TNF- (22), IFN- (23), histamine
(24), and albumin (22) during the acute phase of naturally acquired colds and have also demonstrated, for the first time in
vivo, significantly increased levels of sICAM-1, ECP, and
RANTES. The secretion of these mediators may contribute to the mechanisms by which URT viruses induce inflammatory
cell recruitment and activation. IL-1 activates B cells, monocytes,
and T cells, IL-6 is a T-cell activator, IL-8 a neutrophil chemoattractant, TNF- is chemotactic for monocytes and increases
eosinophil cytotoxicity, and RANTES is a potent chemoattractant for eosinophils, T lymphocytes, and monocytes/macrophages. IFN-, as well as playing a crucial role in host defense,
will promote inflammation by acting as an eosinophil chemoattractant (25) and possibly increasing basophil/mast cell histamine releasibility (26).
The finding of raised levels of MPO and ECP during the acute phase will most likely reflect neutrophil and eosinophil recruitment and subsequent activation. Neutrophil recruitment is well documented after experimental rhinovirus infection, and mucosal accumulation of eosinophils is evident in bronchial biopsies taken after the onset of experimental rhinovirus infection (6). Eosinophil activation has been linked to epithelial damage, and the increased recovery of sICAM-1 could be indicative of enhanced cleavage of this epithelially expressed adhesion molecule. Such cleavage may also reflect enhanced proteinase activity associated with leukocyte recruitment. Alternatively, it could represent increased generation of ICAM-1, as has previously been shown in vitro with rhinovirus infection of bronchial epithelial cells (27).
An important difference during the acute phase between the two groups was the significantly higher recovery of histamine in the nasal lavage of the atopic subjects. An enhanced susceptibility to histamine release in response to allergen challenge during URT infection has previously been described, suggestive of enhanced mast cell degranulation (28), and increased levels of histamine have been found in nasal lavage from atopic subjects after experimental rhinovirus infection (29).
We have shown, for the first time, important differences in
mediator profile between the atopic and the nonatopic groups
in the convalescent phase of URT infection. Levels of the proinflammatory cytokines IL-1, IL-6, RANTES, and sICAM-1
were significantly higher in the atopic group than in the nonatopic group during convalescence, suggesting that in the
atopic person URT viral infection leads to a more prolonged
upregulation of cytokine production than in the nonatopic
person. The identification of significantly higher nasal lavage
levels of ECP in atopic volunteers, as compared with nonatopic volunteers, at this convalescent time point is consistent
with previous work showing prolonged airway eosinophilia in
atopic volunteers after URT infection (6). Furthermore our study extends these findings by demonstrating that the cytokine changes are associated with persistent eosinophil activation. This prolonged inflammatory response in the atopic group
is of interest in the context of the findings relating to IL-10 during the acute phase of infection. The IL-10 concentrations in
nasal lavage fluid from the atopic subjects were significantly
lower than those in the nonatopic group at this time. Interleukin-10 is an anti-inflammatory cytokine that acts to reduce cytokine production by both Th1 and Th2 lymphocytes (30) as
well as by mononuclear phagocytes (31) and natural killer
cells (32). In particular, IL-10 has been shown to inhibit the
synthesis of IL-1, IL-6, IL-8, TNF-, and IFN- (30, 31), all
cytokines upregulated in response to URT infection, as well as
having the ability to inhibit IL-4 and IL-5 synthesis. In addition IL-10 has been shown to decrease eosinophil survival. An
increase in IL-10 during the acute phase of an URT infection
would therefore down regulate and limit the virus-induced inflammatory response. The failure to mount an equivalent IL-10
response in the atopic subjects may thus represent an important deficiency that promotes the development of a prolonged
inflammatory response after URT infection. The finding of a
significant correlation between IL-10 levels during the acute
phase and the decrease in levels of TNF-, IL-6, IL-8, IFN-,
and IL-1 that occurred between the acute phase and Day 28 adds further support to this hypothesis.
We chose to examine subjects after naturally acquired as opposed to experimentally induced viral infection. Although this meant true baseline levels could not be obtained, since subjects were recruited on the development of symptoms, it was thought important since previous work has suggested differences between experimentally induced and naturally acquired URT infections, with experimentally induced URT infections producing fewer symptoms (6). Results from the questionnaire showed that all volunteers had symptoms compatible with an URT infection that either disappeared or lessened considerably during follow up. RT-PCR confirmed URT viral infection in 61% of cases, which is similar to other studies using RT-PCR to detect rhinoviruses during symptomatic colds in adults (33). The rate of dual infection was slightly higher, but it is consistent with studies that have used RT-PCR for the detection of all URT viruses (34). There was no difference in the clinical characteristics or acute phase response between those subjects from which URT viruses were identified and those in whom it was not. It is likely that the presently employed PCR techniques fail to detect all the URT viruses and that undetected viruses were responsible for symptoms in the other subjects. The conduct of nasal lavage before nasal aspiration also may have reduced viral recovery and the chance of detection. Certainly the acute symptoms of the nature described were unlikely to be due to allergic rhinitis as the major allergen in most patients was grass pollen and the study was conducted well outside the UK pollen season.
In summary, we have demonstrated differences in cytokine
profile between atopic and nonatopic subjects in the acute and
convalescent stages of the common cold. Specifically we have
shown significantly higher levels of IL-10 in the nasal lavage of
nonatopic compared with atopic subjects during the acute
phase of the cold and significantly higher levels of histamine in
atopic subjects. During the convalescent phase we have shown
significantly higher levels of IL-1, IL-6, sICAM-1, RANTES,
and ECP in the atopic subjects. Taken together these results
suggest that the difference between URT virus-induced inflammation between atopic and nonatopic subjects may lie in the duration of the inflammatory response rather than in its
initial characteristics, with perhaps an important limiting role
for the anti-inflammatory cytokine IL-10, the production of
which is defective in allergic disease.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Jonathan Corne, Department of Respiratory Medicine, Level D, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK.
(Received in original form February 1999 and in revised form May 31, 2000).
Acknowledgments: The writers would like to thank Jennie Hunter and Gwen Sanderson for their help with the PCR. JC was involved in the design of the study, was responsible for the virological analysis, and data analysis, and contributed to the writing of this report. LL performed the measurement of nasal cytokines and mediators. SS and RD were responsible for the recruitment of volunteers and sample collection and helped with data analysis. SJ was involved in the virological analysis and data analysis and contributed to the writing of the report. PH initiated the study and was involved in the design of the study and data analysis, in addition to contributing to the writing of the report.
Supported by grants from the Medical Research Council (UK) and from the University of Southampton.
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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N. G. Papadopoulos, M. Moustaki, M. Tsolia, A. Bossios, E. Astra, A. Prezerakou, D. Gourgiotis, and D. Kafetzis Association of Rhinovirus Infection with Increased Disease Severity in Acute Bronchiolitis Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1285 - 1289. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 598 - 618. [Full Text] [PDF]
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