FeNO Values Linked to ICS Therapy Response Rates in Patients With Chronic Cough

A systematic review showed that a high fractional exhaled nitric oxide (FeNO) value before starting inhaled corticosteroid (ICS) therapy may be associated with higher response rates in patients with chronic cough.

The results of a meta-analysis published in Annals of Medicine showed that a high fractional exhaled nitric oxide (FeNO) value before starting inhaled corticosteroid (ICS) therapy could be linked to higher treatment response rates in patients with chronic cough.

The authors also noted that FeNO values can help predict steroid responsiveness and have a better performance at higher cut-off values.

Defined as a cough lasting more than 8 weeks, chronic cough has a global prevalence of 9.6% and can impair quality of life.

“Up to 44% of diagnostic and therapeutic failures have been documented among patients with chronic cough, thus leading to the new paradigm of a neuropathic syndrome with its own pathophysiology, known as cough hypersensitivity syndrome (CHS),” the study authors wrote. “In parallel, such diagnostic and therapeutic challenges called for the development of specific guidelines for chronic cough aimed at improving the current management strategies.”

The authors added that such guidelines rely on a common principle based on the identification and treatment of the disease potentially responsible for CHS. There are multiple diseases that can cause it, including asthma, eosinophilic bronchitis, pulmonary fibrosis, gastroesophageal reflux disease, postnasal drip syndrome, chronic obstructive pulmonary disease, and respiratory tract infections (RTIs). External factors such as exposure to cigarette smoke or environmental pollution or use of blood pressure medications could also be potential causes.

To conduct this systematic review, researchers included 2237 studies that reported the rate of ICS response in people with chronic cough with high and low FeNO, later narrowing it down to 9 articles with a total of 740 participants with chronic cough.

The mean age among all studies ranged from 39.8 to 59.2 years, and the mean body mass index ranged from 25.7 to 30.1 kg/m2. Asthma was documented in 0% to 54.8% of patients, atopic status was documented in 5.2% to 100%, recent RTI was documented in 0% to 13%, and smoking history was documented in 0% to 51.9%.

“Mean values of [forced expiratory volume in 1 second (FEV1)] ranged from 86.2% to 113.2% predicted, while the FEV1/[forced vital capacity] ratio was between 72.8 and 88.9,” the authors noted. “Data on the use of [angiotensin-converting enzyme inhibitors] and on the proportion of steroid naïve patients lacked in most included studies.”

The response rate to ICS was 87.4% in 317 patients with chronic cough and a high FeNO, and 46.3% in 423 patients in the control group. The researchers noted an attributable proportion of 47.0% and a corresponding odds ratio of 9.1 (95% CI, 3.7-22.4: P < .001). There was significant heterogeneity among the studies that was not reduced by the exclusion of one study at a time.

A pooled analysis of diagnostic indexes demonstrated a sensitivity of 68.5% (95% CI, 46.7%-84.4%) and a specificity of 81.9% (95% CI, 63.0%-92.3%). It also showed a positive likelihood ratio of 3.79 (95% CI, 1.24-7.47) and a negative likelihood ratio of 0.38 (95% CI, 0.22-0.66).

The authors also found that, among 6 studies, 321 patients with chronic cough responding to ICS therapy showed significantly higher FeNO values compared with 240 nonresponders.

“The analysis of the funnel plot for studies evaluating FeNO levels among responders and nonresponders to ICS suggested the absence of publication bias for this additional analysis, also confirmed by the Egger’s test (P = .917),” the authors noted.

The authors concluded that high FeNO values in patients with chronic cough prior to starting ICS therapy may be associated with a higher response rate.

“These findings are supported by sensitivity and meta-regression analyses, showing no impact of several clinical and demographic variables on the observed results, including those related to cough aetiology and duration,” they said. “Furthermore, this meta-analysis offers interesting insights into the identification of the optimal FeNO cut-off for predicting response to steroids.”

They also mentioned that FeNO has recently emerged as a useful and noninvasive method to identify chronic inflammation of airway diseases, and it is successful in monitoring adherence to steroid treatment in patients with asthma.

“Considering that steroids are able to reduce eosinophilic inflammation documented in most asthma phenotypes, FeNO is the perfect biomarker for monitoring steroid response in this clinical setting,” the authors said. “Further studies are needed to evaluate the real usefulness of this biomarker to guide cough therapy and optimise strategies in different healthcare settings (community, hospital, rehabilitation).”


Ambrosino P, Accardo M, Mosella M, et al. Performance of fractional exhaled nitric oxide in predicting response to inhaled corticosteroids in chronic cough: a meta-analysis. Ann Med. 2021;53(1):1659-1672. doi:10.1080/07853890.2021.1979242

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