The profiles of FeNO level and B-Eos count in asthmatic patients and the accuracy of these two biomarkers in the diagnosis of asthma are unclear. In the present study, we provide a large-cohort analysis of the relationship among FeNO, B-Eos, and asthma in Chinese patients. According to receiver operating characteristic (ROC) curve analysis,
combining FeNO and B-Eos counts can improve diagnostic efficacy for asthma. Another interesting finding was that the risk of having asthma increased progressively with a gradual increase in FeNO or B-Eos count. Notably, patients with moderately elevated biomarkers (FeNO > 40 ppb and B-Eos > 300 cells/µl) could be diagnosed with asthma, as diagnostic specificity is > 95% and the PLR > 10. Although diagnostic sensitivity was reduced to 30.59%, these patients benefited from avoiding BPTs, especially since the simultaneous increase in FeNO and B-Eos count is associated with higher bronchial hyperresponsiveness,[18] which may trigger an acute exacerbation of asthma.
At present, in order to avoid underdiagnosis or overdiagnosis, objective tests must be conducted to confirm the diagnosis of asthma.[5] However, there are several limitations to objective tests.[6] The BPT is time consuming, has a risk of triggering asthma attack, and is generally not available in primary care; the BDT has limited value for distinguishing asthma from chronic airway diseases; and variable peak expiratory flow requires good cooperation and adherence.[26–28] Conspicuously, the UK National Institute for Health and Care Excellence (NICE) recommends that FeNO, a potential indirect predictor of Th2 airway inflammation in asthma, should be measured in all suspected asthma patients.[29] Our data indicated that the optimal cutoff level for FeNO in the diagnosis of asthma was 38 ppb, in line with the recommendation by Japanese Respiratory Society (JRS),[30] who recommend using a FeNO cutoff value of 35 ppb to diagnose asthma. Meanwhile, GINA conservatively points out that measurement of FeNO alone is insufficient to determine or rule out asthma.[1] This is because diagnostic cutoff values for FeNO are mostly concentrated in the intermediate range (25–50 ppb), and these levels can overlap extensively between asthma and other diseases.[31, 32] Therefore, many guidelines recommend that FeNO should be combined with other objective evidence to identify inflammatory respiratory diseases.[1, 26, 29, 33]
B-Eos count, another promising and easy-to-measure biomarker, is more attractive as a means of diagnosing asthma.[6, 34] In this study, we found that the optimal diagnostic cutoff level was 203 cells/µl for B-Eos to identify asthma. Consistent with previous reports,[13, 35] our data indicated that FeNO or B-Eos count alone had only moderate accuracy for diagnosing asthma, so using a single biomarker for this purpose will yield many false negatives and false positives. In all suspected asthma cases, as B-Eos count gradually increased, the risk of having FEV1 < 80% of the predicted value significantly increased. In addition, previous studies have demonstrated that high B-Eos counts are related to poor asthma control, risk of exacerbations, and response to maintenance of inhaled corticosteroids.[36–38] It is becoming crucial that the measurement of blood eosinophils adds predictive and prognostic information to airway disease.[39]
Although FeNO and B-Eos are part of the Th2 inflammation cascade, these two biomarkers are regulated by different inflammatory pathways.[11] Activation of the Th2 inflammatory cascade leads to secretion of various cytokines, including interleukin-4 and − 13 (IL-4, IL-13), which activate nitric oxide synthase to increase FeNO in bronchial epithelial cells. IL-5 acts on IL-5 receptor subunit α (IL5RA), causing eosinophilia.[10] Similar to a previous report by Malinovschi et al.,[16] FeNO was weakly correlated with B-Eos count in this study, but our data also revealed that the correlation between FeNO and B-Eos count was stronger in asthma patients than in non-asthma patients. These results suggested that the combination of FeNO and B-Eos count could help diagnose asthma. Based on ROC curve analysis, the AUC of asthma diagnosis based on both biomarkers combined was higher than that based on single biomarker alone. Since positive and negative predictive values depend on the prevalence of the disease irrespective of the sensitivity and specificity,[25, 40] when we seek threshold levels for a diagnosis of asthma using both biomarkers, the goal is to achieve an ultrahigh PLR (> 10). When linking the different thresholds of these two biomarkers, the appropriate folding point is found at a FeNO of 40 ppb and a B-Eos count of 300 cells/µl.
Notably, our entire study population included patients with suspected early asthma who underwent the BPT and those with severe symptoms who underwent the BDT, which is more representative of suspected asthma patients of all adult ages. The advantage of this study was the large number of asthmatic patients who were evaluated by spirometry and standardized clinical examination. However, this study also had some limitations. Due to the large proportion of incomplete data, we repeated the main analysis on this incomplete data and examined the risk of selection bias. The results of these secondary analyses were similar to those of our primary analysis. Since the smoking status of the study population was unknown, we calculated the diagnostic accuracy of these two biomarkers in women (who rarely smoke in China[24]), and the results did not change significantly. This indirectly indicated that smoking status had a limited effect on the diagnostic efficiency of these two biomarkers. As this was a retrospective study, although we followed a uniform inclusion procedure, there were still potential selection biases. Moreover, the atopic statuses and comorbidities of patients in this study were not fully known, which might have affected the efficiency of these two biomarkers in diagnosing asthma. These issues are worthy of further evaluation in prospective studies.
In conclusion, there was no difference in diagnostic accuracy for asthma between FeNO and B-Eos count, but the combination of these two biomarkers could improve diagnostic efficacy. Notably, patients with moderately elevated biomarkers (FeNO > 40 ppb and B-Eos > 300 cells/µl) could be diagnosed with asthma, which can be applied as a practical diagnostic tool for asthma in primary care.