Analysis of induced sputum has advantages over determination of exhaled NO that recently was deemed to be of little value as a guide to treatment interventions in asthma [
128]. Studies involving sequential sampling of sputum in stable disease suggest that leukocyte counts in induced sputum samples may exhibit acceptable repeatability [
129,
130]. These data support the use of induced sputum in monitoring disease severity and evaluating anti-inflammatory treatments in stable asthma and COPD. Of significant interest is the possibility that sputum indices can predict disease exacerbations. This is an area where sputum analysis has fared better than a clinical strategy involving symptoms and spirometry [
131‐
135]. Since the first successful study of inhaled steroids half a century ago sputum eosinophilia has shown its value in predicting which patients will benefit from treatment with these drugs. In a matter of days to weeks after instituting steroid treatment both airway wall and lumen eosinophils will be much reduced. Adjusting the steroid dose to keep sputum eosinophil counts low successfully reduces the exacerbation rate in asthma [
131‐
133]. However, as stated by Jayaram et al [
133] "the observation that treatment to control sputum eosinophilia reduced eosinophilic exacerbations may not be a surprise, since treatment was designed to prevent these" (in this case by keeping sputum eosinophils < 2%). It might also be expected that the exacerbations that follow from tapering steroid doses can be predicted by sputum eosinophils[
134,
135]. Interestingly, loss of control of asthma following rapid withdrawal of steroids was associated with increased sputum neutrophils [
136]. Reduced sputum neutrophilia was also helpful as an index of therapeutic effects of clarithromycin in refractory asthma [
137]. It is of note that sputum data, even better than bronchial biopsy data, have identified individuals with regard to risks for exacerbation [
138]. This observation may reflect the fact that sputum samples represent cumulative events over a large surface area involving also more peripheral airways than those available to biopsies. At growing inflammation, the airway wall is increasingly infiltrated with cells. A portion of these cells will migrate into the lumen. In this situation the epithelial transmigration does not reflect a resolving airway inflammation. However, a 'spill-over' of cells would be recorded in sputum samples as a sign of an arriving exacerbation. Future studies specifically addressing the relationship between airway lumen and airway wall eosinophils in developing exacerbations are warranted to further elucidate this possibility.
Leukocytes in the bronchial lumen in asthma and COPD may differ between large and small bronchiolar-alveolar airways. In accord there are differences as regards the relative proportions of different leukocytes occurring in sputum specimens and broncho-alveolar lavage (BAL) fluids, respectively [
139,
140]. This is a concern since much of the pathology of asthma and COPD resides in the small airways. Tillie-Leblond and colleagues [
141] further noted that only half of ten studies on the subject could demonstrate a relationship between eosinophils in induced sputum samples and symptoms of asthma. Caution is also advised in interpretation of sputum data since airway tissue and lumen may differ as to which granulocyte, eosinophil or neutrophil [
81,
82], and which T lymphocyte, especially Tc1 or Tc2 [
116,
142‐
144], is predominant. Irrespective of such differences, it is commonly assumed that numbers of leukocytes in sputum samples reflect intensity of cell-mediated inflammatory processes in diseased bronchial tissues. The present hypothesis infers that the timing of obtaining samples in relation to developing and resolving disease conditions is crucial. Thus, during development of inflammation the cell content of sputum samples may underestimate bronchial tissue cellularity. Reversely, during an active resolution phase when cells are being eliminated from the airway wall the sputum samples could grossly overstate the numbers of airway wall cells. Awareness of this confounding possibility may improve interpretation of sputum data.
We have introduced a dual induction method [
66] whereby inhalation of histamine first induces a prompt bronchial plasma exudation response. About an hour later a second induction, this time of sputum, is employed. The induced sputum then retrieves the exuded plasma together with other mucosal interstitial proteins that the travelling plasma may have picked up. This technique can improve the protein yield of induced sputum and be employed to examine the pharmacology of plasma exudation and the occurrence of exudative hyperresponsiveness. Although the laying down of exuded plasma proteins (including fibronectin and fibrin) may pave the way for cell traffic cells cannot be expected to migrate into the airway lumen along with the bulk plasma. Perhaps other inhalational challenges than histamine can be developed that safely will bring cells into the airway lumen to improve the cellular yield of a subsequent sputum induction. As a bonus this work could lead to discovery of interventions that will speed up resolution of airway wall inflammation.