The relationship between FEF25-75 and skin test sensitization, nasal inflammation, and bronchial hyperreactivity in young subjects without asthma
I Cirillo, A Vizzaccaro, G Marseglia, C Klersy, M Tosca, G Ciprandi
bronchial hyperreactivity, eosinophils, fef, rhinitis, sensitization, small airways disease, spirometry
I Cirillo, A Vizzaccaro, G Marseglia, C Klersy, M Tosca, G Ciprandi. The relationship between FEF25-75 and skin test sensitization, nasal inflammation, and bronchial hyperreactivity in young subjects without asthma. The Internet Journal of Asthma, Allergy and Immunology. 2004 Volume 4 Number 1.
Despite the fact that asthma prevalence is increasing worldwide (1), asthma is still underdiagnosed, especially in children and young adults (2,3).
A close association between allergic rhinitis and asthma has been reported (4). Moreover, allergic rhinitis has been demonstrated to be a strong risk factor for the onset of asthma in adults (5).
Asthma is characterized by a reversible airflow obstruction and small airways are involved in the pathogenesis of asthma (6). The forced expiratory flow at the 25 and 75% of the pulmonary volume (FEF25-75) might be considered as a measure of the caliber concerning distal airways, particularly in subjects with normal FEV1 (7). Thus, FEF25-75 may be envisioned as a possible marker of early bronchial impairment, as recently described by ourselves in patients with allergic rhinitis alone (8,9,10). Therefore, small airways disease (SAD) as defined by a reduction in FEF25-75 and normal spirometry (normal FEV1 and FVC) may be a marker for early allergic or inflammatory involvement of the small airways in subjects with allergic disease and no asthma. On the other hand, bronchial hyperreactivity (BHR) is a paramount feature of asthma and may be observed in a high proportion of rhinitics, sensitized to perennial allergens (9), pollens (10), or both (8). In addition, Th2-dependent cytokines and eosinophilic inflammation are related to nasal and bronchial airflow impairment in rhinitics (11,12).
The aim of the present study was determine if there was a relationship between SAD, the outcome variable, and allergic predictors in healthy as Naval conscripts without asthma but with allergic disease.
Materials and Methods
The Review Board approved the study and an informed consent was obtained from each subject.
The diagnosis of allergic rhinitis was made on the basis of a history of nasal symptoms and a positive skin prick test according to validated criteria (4).
The most important perennial allergens in our geographic area are: house dust mites (i.e.
It should be noted that all 58 subjects included in this study had no symptoms of lower airway disease or asthma. Military service is not allowed for those with asthma or those with other known lung diseases.
Nobody had assumed nasal or oral corticosteroids, and antihistamines within the previous 4 weeks.
Rhinitis was considered according with TSS grade as mild (TSS=<6), moderate (TSS=6-8), and severe (TSS=>9). Subjects with no symptom were considered as normal.
Smears were stained with Diff Quik stain and were analysed by optic microscope (Olympus U-SPT). The number of inflammatory cells was expressed as a mean of 10 optical fields at 100x magnification. Samples were examined in a blinded fashion.
SAD was defined as a normal FEV1, FVC and FEV1/FVC ratio with a reduction of the FEF25-75 below 80%.
The test was interrupted and considered positive when FEV1 value was reduced by more or equal than 20% of control or a maximal cumulative dose of 1,590 µg/ml was achieved. The threshold dose causing a 20% fall of FEV1 (PD20) was calculated.
To assess the role of allergic characteristics for predicting reduced FEF25-75, logistic models were fitted; odds ratios (OR) and their 95% confidence intervals (95%CI) were calculated. A multivariate was fitted, not including eosinophils due to multicollinearity.
Stata 8 (StataCorp, College Station, TX) was used for computation. A 2-sided p-value<0.05 was considered statistically significant.
Patients characteristics are summarized in Table 1. Age ranged from 21 to 24; only a 3 recruits were female. None of them smoked. Most subjects did not elicit symptoms. Among those with symptoms, 2 had score 2, 3 had score 4 and 5 had score 5. Slightly more than 50% had moderate eosinophil infiltration. The BHR challenge was positive in half of the case series, at a median dose of 170 µg/ml (25 th -75 th 90-420). Fifteen percent of patients showed mono and 50% poly-sensitivity at skin prick test. FEV1 and FVC were normal (>80%) in all cases, while 34% of patients had a reduced FEF25-75 (all of them showed reversibility).
It is of note that subjects without a positive skin prick test (ie nonatopic) do not have any of the other manifestations of allergic disease. In other words, only those with a positive skin prick test are positive for nasal eosinophils, nasal symptoms, have a positive BHR test, or a reduced FEF25-75.
Predictors of depressed FEF
A mean value of FEF25-75 of 70.3 (SD 8.5) was measured in patients with a reduced FEF, while it was 108.0 (SD 14.3) in those with preserved FEF25-75. All the candidate allergic predictors appeared to be strongly associated with a reduced FEF25-75, as shown in Table 2. The proportion of subjects with reduced FEF25-75 appeared to increase with increasing severity of the allergic predictors, and correspondingly the mean value of FEF25-75 appeared to decrease.
Moderate to severe BHR and poly-sensitivity appeared to be independent predictors of a reduced FEF25-75 at multivariate analysis.The independent role of eosinophil infiltration could not be evaluated due to multicollinearity with the remaining predictors.
Evaluating substantially healthy subjects with slight spirometric anomalies, we showed that all the candidate allergic predictors, such as nasal symptoms, nasal eosinophils, sensitizations, and bronchial hyperreactivity, appeared to be strongly associated with a reduced FEF25-75. Moreover, the proportion of subjects with reduced FEF25-75 appeared to increase with increasing severity of the allergic predictors, and correspondingly the mean value of FEF25-75 appeared to decrease.
It is well known that eosinophilic infiltration is the hallmark of allergic inflammation, as Th2-derived cytokines account for recruiting and activating eosinophils in airways.
The presence of nasal eosinophils in sensitized subjects here reported was in agreement with the observation that these cells and their mediators were found in nasal secretions of subjects allergic to mites, even in symptom-free periods (16,17).
In this study, nasal eosinophils were recovered from sensitized subjects only. Consistent with previous studies, eosinophil number was related to nasal symptom severity (10,11).
We also found a significant association between nasal involvement and BHR. The relationship between allergic inflammation and airway hyperreactivity or airflow obstruction is still controversial (18). However, significant correlations have been reported between total serum IgE or blood eosinophils and BHR to methacholine (19), and between the decrease in circulating eosinophils following allergen inhalation challenge, and the degree of late asthmatic response and changes in BHR to histamine (20) in allergic patients.
Our findings are in agreement with those observed in allergic children (17) and furthermore support the concept of a link between allergic inflammation and increased bronchial reactivity in sensitized subjects.
Moreover, it is noteworthy that the lowest FEF25-75 values were present in those subjects with nasal symptoms, severe BHR and more intense eosinophilic infiltration. In addition, FEF25-75 impairment and BHR were demonstrated in sensitized subjects only. This finding was even more evident in polysensitized subjects. Therefore, in sensitized subjects, mainly rhinitics, with normal FVC and FEV1 values, impaired FEF25-75 values (i.e. <80% of predicted) suggest the presence of SAD. Therefore, SAD may be a marker for early allergic or inflammatory involvement of the small airways in subjects with allergic disease and no asthma. This idea is consistent with the associations seen but needs to be validated with longitudinal studies comparing those with nonasthmatic allergic disease and SAD with those with allergic disease without asthma and no SAD to determine if progression to frank asthma actually occurs, relative to those without SAD.
Thus, the present study provides evidence, relevant to clinical care, that spirometry should be performed in all rhinitics who will perform strenuous physical exercises or risky works.
In conclusion, we retain that these data may be considered convincing proof of the close link existing between atopy and airway disorders.
Giorgio Ciprandi, M.D. Allergologia - U.O. ORL Dipartimento Regionale Testa-Collo Padiglione Specialità (piano terzo) Ospedale San Martino Largo R. Benzi 10, 16132 Genoa, Italy Phone 00 39 10 5552124 FAX 00 39 10 5556682 E-mail email@example.com