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ABSTRACT |
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INTRODUCTION
METHODS
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The inflammatory events in the airways at the time of acute respiratory failure from acute severe asthma are poorly understood. To determine the patterns of cellular inflammation in the airways in acute severe asthma, we analyzed tracheal aspirates collected within 12 h of intubation from patients intubated emergently for acute severe asthma (n = 10) and from patients intubated electively for nonpulmonary surgery (n = 14). The number of neutrophils in tracheal aspirates from asthma patients was 10 times higher than normal (4.2 [0.6 to 335.0] [median, range] versus 0.4 [0.009 to 9.4] × 106/ml, p = 0.001), and there was a strong trend for a positive relationship between neutrophil number and duration of intubation (rs = 0.64, p = 0.06). Although eosinophil numbers were also significantly higher than normal (0.5 [0.0 to 23.3] versus 0.0 [0.0 to 0.1] × 106/ml, p = 0.003), the numbers of eosinophils were 8-fold less than neutrophils, and there was no significant correlation between eosinophil number and duration of intubation (rs = 0.4, p = 0.26). Interleukin-8 (IL-8), a chemoattraction for neutrophils, was 19 times higher than normal in tracheal aspirates from asthmatic patients (75.0 [9.0 to 168.0] versus 4.0 [0.08 to 24.0] ng/ml, p < 0.05) and correlated significantly with the neutrophil number (rs = 0.77, p = 0.03). Furthermore, the IL-8 levels correlated positively with the duration of mechanical ventilation (rs = 0.74, p = 0.03). Surprisingly, the number of neutrophils increased significantly during the period of intubation in the asthmatic subjects, possibly because of intravenous corticosteroid treatment. We conclude that neutrophils are the dominant inflammatory leukocyte characterizing airway inflammation in acute severe asthma that requires mechanical ventilation, and that IL-8 is an important mediator of this neutrophilia.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Very few studies have characterized the nature of airway inflammation during acute severe asthma exacerbations, and basic questions remain about the type of cellular inflammation in the airways during these exacerbations. Although airway eosinophilic inflammation is recognized as an important feature of chronic stable asthma (1), recent evidence supports an important role for neutrophils in acute severe asthma (2). Understanding the type of cellular inflammation in acute severe asthma has important implications not only for the treatment of acute severe asthma but also for its prevention.
The objective of this study was to determine the cellular
characteristics of airway secretions in acute severe asthma requiring mechanical ventilation. Specifically, we studied total
and differential cell counts in airway secretions from asthmatic
patients intubated for acute severe asthma by analyzing tracheal aspirates collected through the endotracheal tube. To our
knowledge, there are no previously published reports of the cellular analysis of tracheal aspirates from intubated asthmatic patients. Patients whose tracheal aspirates were collected after
12 h of intubation were excluded in order to limit the confounding effects of corticosteroid treatment on our results. In addition to the cellular analysis, the levels of putative mediators of
acute airway inflammation such as interleukin-8 (IL-8), free
neutrophil elastase, tumor necrosis factor-
(TNF-), eosinophil cationic protein (ECP), and interleukin-6 (IL-6) were also
examined. As controls, tracheal aspirates were collected from
patients intubated for general anesthesia for nonpulmonary surgical procedures.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Protocol Summary
Asthmatic subjects intubated for acute severe asthma and control subjects undergoing nonpulmonary surgery were studied. Patients who had smoked cigarettes in the previous 10 yr were excluded. Also excluded were asthmatic patients with a history of lung disease other than asthma, and control subjects with any history of lung disease. Airway secretions were sampled by tracheal aspirate via the endotracheal tube. Tracheal aspirates were obtained within 12 h of intubation in all the asthmatic patients and additional aspirates were taken at 12 to 14 h intervals until extubation. A single tracheal aspirate was obtained intraoperatively 0 to 4 h postintubation from the control patients.
Subjects
Asthma patients. Patients in whom acute severe asthma was diagnosed by emergency room or intensive care physicians at Moffitt-Long Hospital and San Francisco General Hospital at the University of California, San Francisco (UCSF) and intubated for management of severe asthma were studied. Only those asthmatic patients who had been intubated for less than 12 h were included. After extubation, these patients were asked to sign a consent form approved by the Committee on Human Research at UCSF, and a detailed medical questionnaire was filled out (in one patient who died, his parents signed the consent form and assisted with the questionnaire).
Ten asthmatic patients (six female) with a mean age of 41 yr were studied (Table 1). All had wheeze audible on chest examination and severe airflow obstruction evident from analysis of inspiratory pressure recordings on the mechanical ventilator. Six of the patients had been previously hospitalized for management of severe asthma, three had been previously intubated and mechanically ventilated for management of severe asthma, and three were dependent on oral cortico- steroids for control of asthma.
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Four of the 10 asthmatic patients were intubated within 3 h of the onset of symptoms of acute severe asthma, and the remaining six patients had a history of worsening asthma symptoms for as long as 7 d before presentation. After presentation to the hospital, all asthmatic patients were treated intravenously with corticosteroids (typically 60 mg of methylprednisolone every 6 h), nebulized albuterol, and nebulized ipratropium bromide, and one of the patients was started on intravenous antibiotics. None of the patients had evidence of chest radiograph infiltrates on admission, although one patient had evidence of collapse of the right upper lobe on admission chest radiograph, which resolved within 24 h.
Nine of the 10 asthmatic patients survived and one died. In the nine patients who survived, seven were extubated between 17 and 48 h after intubation, and two were extubated 7 to 9 d after intubation. The patient who died was a 24-yr-old man with a history of asthma since early childhood whose only medication was albuterol. His asthma worsened 12 h prior to presentation to the hospital where he was intubated emergently for severe respiratory acidosis (pH, 6.97; PCO2, 123 mm Hg). His acute bronchospasm largely reversed by hospital Day 3, as evidenced by a reduction in peak inspiratory pressures on the mechanical ventilator, from 60-90 to 20-25 cm H2O. However, his acute asthma attack was complicated by rhabdomyolysis, acute renal failure, and acute ischemic colitis necessitating total colectomy, and new infiltrates on chest radiographs (starting on hospital Day 4). He died on hospital Day 12. Tracheal aspirates were obtained on this patient from hospital Day 1 through Day 3.
Control subjects. Patients undergoing nonpulmonary surgical procedures at Moffitt-Long Hospital, UCSF and intubated for administration of general anesthesia had tracheal aspirates collected 0 to 4 h after intubation. Prior to anesthesia, patients were asked to sign a consent form approved by the Committee on Human Research at UCSF. They then filled out a medical questionnaire. Fourteen patients (seven female) with a mean age of 40 yr satisfied inclusion and exclusion criteria and had tracheal aspirates collected. One of the 14 patients had a history of cigarette smoking, but had not smoked cigarettes for at least 10 yr; for both healthy and asthmatic subjects, current smokers and subjects who smoked in the previous 10 yr were excluded.
Collection of Tracheal Aspirates
The routine clinical care of intubated asthmatic patients requires removal of airway secretions by aspiration of the trachea and large airways. A 30-cm thin plastic catheter (Suction Catheter Kit; Kendall
Health Care Products Company, Mansfield, MA) connected in series to
a clean plastic container and a suction source (
200 mm Hg) was passed
through the endotracheal tube and into the airway. One milliliter of sterile saline was injected into the airway, and airway secretions were aspirated as the catheter was slowly withdrawn from the airway and endotracheal tube.
Processing of Tracheal Aspirates
Tracheal aspirates were processed within 1 h of collection. For the
asthmatic patients the sample volume was determined, an equal volume of phosphate-buffered saline (PBS) was added, and the mixture
was briefly mixed gently by vortex mixer before adding a volume of
0.01% dithiothreitol in saline (10% "Sputolysin"; Behring Diagnostics Inc., Somerville, NJ) equal to the combined volume of sputum
and PBS (= 4-fold total dilution of original sample). For the control
patients, aspirate volume was determined and an equal volume of
0.01% dithiothreitol in saline was added (= 2-fold total dilution of
original sample) and briefly mixed gently by vortex mixer. All samples were then incubated in a shaking water bath at 37° C for 15 min,
with removal for brief gentle mixing using a transfer pipette at 5-min
intervals. An aliquot of diluted homogenized aspirate was used for cell
count and cell differential, as previously described (5). Cell differentials, inclusive and exclusive of squamous cells, were calculated. The remaining homogenized samples were centrifuged at 1,037 g for 5 min
and the supernatant was aspirated and stored at 70° C for later analysis. The median volume of tracheal aspirate processed was 1.6 ml
(range: 0.3 to 4.9 ml) in the asthmatic patients and 0.9 ml (range, 0.3 to
2.3 ml) in the control patients. The appearance of the tracheal aspirates was mucoid or mucopurulent in the asthmatic patients and thin
and clear in the control patients.
Analysis of Tracheal Aspirates
The activity of free neutrophil elastase was determined using a chromogenic substrate specific for human neutrophil elastase, as previously described (6). IL-8, IL-6, and TNF- levels were measured using
specific and sensitive human immunoassays (ELISA, Quantikine;
R&D Systems, Minneapolis, MN). ECP was measured using a specific
and sensitive radioimmunoassay (Pharmacia Diagnostics Inc., Fairfield, NJ). The lower limits of detection for these assays were: neutrophil elastase, 10
7 molar; IL-6, 4 pg/ml; IL-8, 31.2 pg/ml; IL-6, 3.2 pg/
ml; ECP, 2 ng/ml; and TNF-, 15.6 pg/ml.
Statistics
Data are presented as mean ± standard error of the mean (SEM), and the median and range of values are also presented for most data. Undetectable values in the immunoassays were assigned a value of zero. Because most of the data were not normally distributed, the Mann-Whitney U test was used in most instances to compare tracheal aspirates collected at different time points from the asthmatic patients. Spearman's rank order test was used to determine correlations between data.
The tracheal aspirate collected at 72 h from the asthmatic patient who died was considered the "extubation" sample. For correlations between cell counts and cytokines and the length of intubation, this subject was assigned an imputed number of hours of intubation (250 h) that resulted in him having the longest duration of intubation. A probability value of < 0.05, using two-tailed tests, was considered significant.
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RESULTS |
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METHODS
RESULTS
DISCUSSION
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Intubation Tracheal Aspirates
The median number of neutrophils and eosinophils in the first tracheal aspirates collected within 12 h of intubation ("intubation tracheal aspirates") from the asthmatic patients was significantly higher than in the control patients (Table 2, Figure 1). Neutrophils constituted the majority of the cells (> 50%) from seven of the 10 asthmatic patients, whereas eosinophils constituted the majority cell type in only one patient. No eosinophils were identifiable in the intubation tracheal aspirates from two asthmatic patients. There was a strong trend for a significant positive correlation between the number of neutrophils in the intubation tracheal aspirates from the asthmatic patients and the duration of intubation (rs = 0.64, p = 0.06). However, no such correlation existed for eosinophil number and the duration of intubation (rs = 0.4, p = 0.26). There was a trend for a higher percentage of neutrophils in the traceheal aspirates from the subjects with a preceding upper respiratory tract infection than those without (80.1 ± 8.8 versus 47.3 ± 11.8%, p = 0.09). There was no significant difference in the percentage of eosinophils in these two subgroups (5.0 ± 3.4 versus 17.3 ± 9.7%, p = 0.34).
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Three of our study patients were already receiving cortico- steroids at the time of intubation. There was no significant difference in the number or percentage of neutrophils in the intubation samples from these patients and the other asthmatics. The number and percentage of neutrophils and eosinophils was similar in the tracheal aspirates from the four asthmatic subjects intubated within 3 h of symptoms and those with longer prodromes.
IL-8 levels were significantly higher than normal in the intubation tracheal aspirates from the asthmatic subjects (Table 3), and the IL-8 levels correlated significantly with the number of neutrophils in these samples (rs = 0.77, p = 0.03). In addition, IL-8 levels in the intubation aspirates correlated positively and
significantly with the number of hours of mechanical ventilation (rs = 0.75, p = 0.03) (Figure 2). Furthermore, the levels of IL-8 were higher in the aspirates from patients with gradual worsening of asthma versus those with acute worsening (median,
range): 141, 95 to 168 versus 52, 9 to 136; p < 0.04). No such
correlations existed for the levels of free neutrophil elastase,
TNF-, IL-6, or ECP. However, free neutrophil elastase activity, TNF- levels, and ECP levels were all significantly higher
than normal in the intubation tracheal aspirates from the asthmatic subjects (Table 3).
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Extubation Tracheal Aspirates
In the asthmatic patients the median number and percentage of neutrophils was significantly higher in the extubation tracheal aspirates than in the intubation tracheal aspirates, whereas the median number and percentage of eosinophils in the extubation tracheal aspirates and significantly lower (Table 1, Figure 1).
The time course of the change in neutrophil and eosinophil percentages in tracheal aspirates from the asthmatic subjects can be seen from analyses of tracheal aspirates collected every 12 to 24 h from two patients who were intubated for 7 to 9 d (Figure 3). In these patients the eosinophil percentages decreased to almost zero within 48 h even though intubation for mechanical ventilation was required for another 5 to 7 d. In contrast, the neutrophil percentages increased during the period of mechanical ventilation, despite improvement in airway obstruction, and successful weaning from the mechanical ventilator. The changes in eosinophil number and neutrophil number paralleled the changes in eosinophil and neutrophil percentages (Figure 3).
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The levels of IL-8, free neutrophil elastase activity, and
TNF- were significantly higher in the extubation tracheal aspirates than in the intubation aspirates; the levels of ECP and
IL-6 changed little (Table 3).
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DISCUSSION |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The main findings of this study are that the neutrophil is the dominant inflammatory leukocyte in airway secretions from patients with acute severe asthma requiring mechanical ventilation, and that IL-8 levels in airway secretions collected close to the time of intubation correlate positively with the degree of neutrophilia and with the severity of the asthma exacerbation. These findings suggest an important role for neutrophils and IL-8 in life-threatening attacks of asthma and should prompt consideration of specific targeting of this cell and cytokine in new treatment strategies for acute severe asthma.
In these severely ill asthmatic patients, the number of neutrophils in the tracheal aspirates collected within 12 h of intubation was approximately 10-fold higher than normal and was approximately 8-fold higher than the numbers of eosinophils in the same samples. Associated with this increase in neutrophils was an increase in free neutrophil elastase activity. The accumulation of neutrophils in the airway may have been mediated by interleukin-8 because markedly elevated levels of IL-8 were found in the tracheal aspirates, and there was a positive correlation between IL-8 levels and neutrophil number in the intubation tracheal samples. Furthermore, the levels of IL-8 correlated significantly and positively with the length of time these patients received mechanical ventilation suggesting that the severity of the acute asthma exacerbation was related to the degree of hypersecretion of IL-8. The data do not identify the cellular sources of IL-8 in the airway, but airway epithelial cells are a likely source because secretion of IL-8 by epithelial cells in response to a wide variety of airway injuries has been reported (7).
The pathophysiologic role of the neutrophil in acute severe asthma in an important question raised by our study and by other recent studies that have documented the presence of neutrophils in airway secretions and airway tissue from patients with acute severe asthma (2, 10, 11). There are at least three possible physiologic roles for the neutrophil in acute severe asthma. First, neutrophil proteases, especially neutrophil elastase, are important mucin secretagogues for goblet cells and submuscosal gland cells (12, 13). Thus, neutrophils may be important mediators of the prominent mucous hypersecretion seen in acute severe asthma. Second, neutrophil products may be important mediators of epithelial cell activation and heightened vascular permeability in acute severe asthma (14, 15). Third, neutrophil proteases can activate eosinophils (16). Thus, a mechanism for acute airway obstruction in severe asthma is that injury-induced secretion of IL-8 by epithelial cells leads to IL-8-directed neutrophil accumulation in the airway, increased levels of free elastase in the airway, and elastase-mediated eosinophil activation, mucous hypersecretion, and plasma extravasation. Similarly important roles for IL-8 and neutrophils have been proposed for virus-induced nasal inflammation in asthmatic subjects (17, 18).
There was considerable variability in the percentages of eosinophils in tracheal aspirates from different asthmatic patients at the time of intubation. For example, no eosinophils were identified in two patients, whereas eosinophils constituted 64% of the cells in one patient. Overall, eosinophil numbers were 8-fold less than neutrophil numbers in the asthmatic samples. Unlike neutrophils, the numbers of eosinophils decreased during the period of intubation. The high dose corticosteroid treatment received by all asthmatic patients in the most likely explanation for the decrease in eosinophils. Corticosteroids have multiple actions that reduce airway eosinophilia, including inhibitory effects on the permissive effects of GM-CSF and IL-5 on eosinophil survival (19, 20) and promotion of eosinophil apoptosis (21). The coincidence of clinical improvement and reduction in eosinophil numbers in the tracheal aspirates in the asthmatic patients argues for an important role for eosinophils and their products in the airway obstruction of acute severe asthma. However, a contrary argument is the finding that two of 10 asthmatic patients had no identifiable eosinophils in their aspirates at the time of intubation and the finding that another patient had marked reduction in airway eosinophilia several days before extubation was possible.
Although eosinophil numbers decreased significantly during the period of mechanical ventilation in the asthmatic subjects, the levels of ECP did not, perhaps because ECP originated from cell sources other than eosinophils. For example, there has been a recent report of ECP localizing to neutrophils (22), and neutrophils have been reported to take up and store ECP released by neutrophils (23).
Surprisingly, the number of neutrophils and the levels of
neutrophil elastase and TNF- were significantly higher in the
extubation samples than in the intubation samples from the
asthmatic patients. These increases occurred despite sufficient
improvement in airway obstruction to allow extubation in nine
of the 10 asthmatic subjects. The high dose intravenous glucorticosteroid treatment likely explains these findings. Glucocorticoids promote neutrophil survival (24), and a steroid-mediated delay in neutrophil apoptosis in a plausible explanation
for the 6-fold increase in neutrophil number observed in the
extubation tracheal aspirates compared with the intubation samples. The steroid effect on neutrophil survival in turn
could explain at least in part the increases seen in neutrophil
elastase, TNF-, and IL-8 since all of these mediators are secreted by neutrophils (25). In contrast, IL-6 levels decreased
in the extubation samples, perhaps because IL-6 is not secreted by neutrophils, but by other cells such as airway epithelial cells, monocytes/macrophages, lymphocytes, and endothelial
cells, which may be more steroid-sensitive than neutrophils.
Another possible cause for the increased neutrophils in the extubation samples is that the neutrophilia represents a response
to prolonged intubation, mechanical ventilation, and repeated
tracheal aspiration with suction catheters. Arguing against this
mechanism as the principal reason for the airway neutrophilia at the time of extubation are the data of Lambin and colleagues (3). These investigators compared the cell differential
of BAL from asthmatic patients receiving mechanical ventilation for acute severe asthma with that of control patients without preexisting respiratory disease who required prolonged
mechanical ventilation. They found that the number and percentage of neutrophils in the asthmatic patients receiving mechanical ventilation was significantly higher than those in control patients; the corticosteroid treatment being given to the
asthmatic patients may again explain the difference.
The paradox of improving clinical function in the asthmatic patients at the same time that many inflammatory mediators increased in the tracheal aspirates may be explained by the effects of corticosteroids on the response structures in the airway mucosa that contribute to severe airway narrowing. Specifically, in vitro and animal studies have demonstrated that corticosteroids render goblet cells, submucosal gland cells, and blood vessels less responsive to mediators such as neutrophil proteases, eosinophil granule products, mast cell products, and various cytokines (26). Through these mechanisms, corticosteroids might promote the early resolution of airway obstruction in acute severe asthma, even though proinflammatory mechanisms may remain upregulated for prolonged periods.
One of the 10 asthmatic patients died because his acute asthma attack was complicated by rhabdomyolysis, acute renal failure, hemodynamic instability, and acute ischemic colitis necessitating total colectomy. Although unusual, rhabdomyolysis, acute necrotizing myopathy, and acute renal failure have all been described previously in association with acute severe asthma in several case reports (31). Interestingly, acute ischemic colitis has also recently been described as a complication of acute severe asthma (35).
In summary, analysis of tracheal aspirates from asthmatic patients close to the time of intubation for acute severe asthma reveals more neutrophils than eosinophils and high levels of IL-8 that correlate positively with the number of neutrophils and with the number of hours of mechanical ventilation subsequently required. We conclude that neutrophils are the dominant inflammatory leukocyte characterizing airway inflammation in acute severe asthma that requires mechanical ventilation, and that IL-8 is an important mediator of this neutrophilia. Surprisingly, neutrophils numbers, neutrophil elastase activity, and elastase and IL-8 levels all increased significantly in tracheal aspirates collected just before extubation. This effect is most likely explained by the high doses of corticosteroid treatment received by these patients and the nonspecific effects of intubation and mechanical ventilation.
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Footnotes |
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Correspondence and requests for reprints should be addressed to John V. Fahy, M.D., Box 0111, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail: jfahy{at}itsa.ucsf.edu
(Received in original form December 8, 1998 and in revised form October 4, 1999).
Acknowledgments: The writers are indebted to Brian Daniel and Richard Kallet for assistance in patient identification and for collecting tracheal aspirates, and to Jane Liu and Eunice Tam for expert technical assistance with differential cell counting and immunoassays.
Supported in part by Grant HL-61662 from the National Institutes of Health.
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References |
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REFERENCES
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