These studies support the concept that events in the upper airway that cause airway obstruction in VCD are not related to generalized airway inflammation. Among patients presenting with intermittent or reversible airway obstruction, patients with VCD can be distinguished from those with asthma by the minimum or absence of inflammation in their sinuses as shown by CT scan and by the absence of elevated eNO, peripheral blood eosinophilia, and normal circulating total IgE concentrations. Our results confirm the presence of a highly significant association between sinus abnormalities seen on CT and asthma.6–8
However, the results also make it clear that it is essential to use a scoring system and to compare CT results to a “normal range,” as minor abnormalities are present in a large proportion of the controls. Using our definition of extensive disease (CT score ≥12), sinusitis was present in 23 of 74 (31.1%) acute asthmatic patients presenting to the ER but not in any of the VCD subjects. Further, in comparison to the study controls, fewer VCD subjects demonstrated minor abnormalities in their sinus disease. This may plausibly reflect the frequent use of systemic corticosteroids in these subjects who are frequently placed on these therapies after being misdiagnosed with asthma. Our results confirm a previous suggestion made by Newman et al,3
using standard anterior-posterior radiography of the sinuses, that VCD subjects demonstrate less evidence for sinus disease and diminished eosinophilia than those with asthma.
In the present study we found very little relationship between questionnaire results and sinus CT changes. These results confirm previous published evidence that clinical symptom scores are not predictive of either the presence or extent of sinus disease in most cases.6–8,16
This is not surprising insofar as many of the symptoms that are used to evaluate sinus disease such as headache, posterior pharyngeal drainage, purulent nasal drainage, nasal congestion, and toothache are not specific for this disease. These symptoms are more reflective of the presence of nasal disease including all of the causes of perennial rhinitis. Similarly, frontal headaches have numerous causes and the source of this discomfort can not be localized by the patient with any accuracy to the sinuses. In the current study, neither fever nor neutrophil leukocytosis was associated with the presence or extent of sinus disease. We assume that most of the sinus opacification represents some form of inflammation including goblet cell hyperplasia and mucus hypersecretion, but also cellular infiltration of the tissues with eosinophils, lymphocytes, monocytes, basophils, and mast cells.17–19
This opacification will also reflect the fibroblast hyperplasia, collagen deposition, and fibrosis associated with this chronic inflammatory process. However, it is likely that chronic sinusitis represents numerous disease processes including those with more prominent eosinophilic inflammation and those more characterized by either mononuclear inflammatory cells or alternatively mucous hyperplasia without prominent active inflammation. This inflammation in many or perhaps most cases does not seem to be related to the presence of a bacterial infection.20,21
Similar to the questionnaire results, in our retrospective analysis, no association was observed between the decision of the ER physician to discharge two of the patients on an antibiotic for acute sinusitis with findings suggestive of acute sinusitis on their CT scan. Unfortunately, other than the screening CT scan, no readily accessible methodology exists to assist in the diagnosis of acute bacterial sinusitis.
In our study, three individuals who presented to the ER with acute asthma and also three of the subjects recruited from the clinic with non-acute asthma had late-onset, severe asthma associated with intolerance to aspirin or other non-steroidal anti-inflammatory drugs. As has been previously published,14
each of these six cases had very extensive CT changes (CT score ≥23). In contrast, the majority of the patients with extensive sinus abnormalities (score ≥12) had the features of extrinsic asthma and the mean total IgE in this group was strikingly elevated. The association between elevated IgE and extent of sinus disease has been reported in chronic sinusitis, but not previously in relation to asthma.6,22
Our results do not define how much of the changes seen were related to the acute episode. We have previously published that repeat CT on 13 of these cases after 4 to 6 months found a significant decrease in score but the changes were very variable.14
Similarly, the generally lower CT scores observed in our non-acute asthmatic patients suggests that some of the severity of the sinus disease observed in the ER cohort may have been related to the acute process responsible for the asthma exacerbation. It is tempting to propose that acute viral infection among patient would precipitate increased sinus changes and an exacerbation of asthma.23–25
Further understanding of the relationship between sinus disease and exacerbations of asthma will need prospective studies in which the change in sinus CT at the time of an attack can be related to evidence of viral infection, allergen exposure, and inflammation. However, the problem will remain difficult to resolve without better understanding of the immunologic mechanisms that lead to persistent eosinophil-rich inflammation in the sinuses.17–19
Other evidence related to inflammation in the lower and upper airways can be obtained from eNO, nasal or blood eosinophils, and most recently, from condensates of exhaled air.10,26–28
Although we were unable to confirm a linkage of asthma to elevated circulating soluble IL-2 receptor or to IL-13, these studies did confirm a significant elevation of eNO and blood eosinophils (or the associated eosinophil marker, ECP) in asthma. Although sinusitis is associated with dramatically elevated NO production, our technique for measuring eNO should have been able to exclude NO derived from the sinuses.12
Consistent with the sinus CT results, airway obstruction in VCD is not related to generalized airway inflammation. As such, in addition to the absence of significant sinusitis, VCD is not associated with elevations either in IgE, eosinophil counts, or eNO, and these parameters were identical to those observed in nonallergic subjects ().
A final, very important outcome of this study is the observation that VCD is not a rare condition and is a frequent presentation in the non-referral ER population. Patients were identified in the ER as having probable VCD on the basis of history and a flow-volume loop demonstrating inconsistency and evidence for fixed extrathoracic obstruction. Twelve of these patients underwent laryngoscopy, and the diagnosis of VCD was confirmed in five. Although it is well recognized that some patients with VCD also have asthma and sinus disease, many have vocal cord abnormalities without
In the present study, these VCD subjects were subsequently shown to have low total IgE, absolute eosinophil counts ≤100/μL, and, in the four subjects who subsequently had CT scans, scores of 0, 1, 4, and 5 (ie, they had no evidence for an inflammatory process). Thus, the investigations used here could provide a basis for identifying VCD and distinguishing VCD from asthma. A large portion of patients with VCD are inappropriately treated with oral steroids.3
Given that over a million patients are treated for asthma in the ER annually, and that this is a major, if not the only, way in which socio-economically disadvantaged patients present, investigation of these patients should be normal practice. Identifying these cases of VCD in the ER presents a challenge. However, investigations similar to those reported here can provide the information necessary to identify those patients who should be considered for specific treatments of VCD including speech therapy, heliox, and psychologic counseling. Although screening CT scans may be expensive to perform (approximately 600 to $800), and this expense will generate reticence among third-party payers to their approval, clearly this expense is much less than the cost of the misdiagnosis of asthma.