Nitric oxide
Nitric oxide (NO) is a biomarker that can be assessed as nasal NO (nNO) or fraction of exhaled nitric oxide (FeNO), however neither has been routinely used as a biomarker in CFTR modulator studies. A study in the 1990s was done to establish baseline nNO in 19 healthy children, compared to 36 children with asthma and 8 children with CF24. The mean nNO levels were 239 (SD 20) parts per billion (ppb) in the controls, 254 (SD 17) ppb in the asthmatics, and 72 (SD 18) ppb in the children with CF. A separate study found that in adults (mean age 26.9 years), those with CF had a mean nNO of 520ppb (CI, 452-588), which was significantly lower than healthy, non-smoking adult controls (mean nNO 987ppb, CI 959-1015)25. In a recent study of treatment with iva, 8 patients with S1251N (class III gating mutation) with a median age of 16 (range 9-26) years, at one center in the Netherlands showed increases in measurements of median nNO from 220 to 462 ppb after 2 months, with no further increase in those followed for a year (n=4)26. During this time when the nNO was increasing, the authors also demonstrated improvement in sinonasal symptoms, with reduction of CT sinus opacification (blinded Lund-Makay score), symptoms, and nasal endoscopic findings26.
Previous studies of FeNO have not always shown a significant difference in CF compared to healthy controls though there may be a trend toward lower levels27,28. A group in Toronto postulated that FeNO can be used as a clinical biomarker similar to nNO to determine the efficacy of CFTR modulators, as they state it is typically lower in pwCF compared to those without CF29. Their hypothesis was also based on two previous studies, which had shown that 4 weeks of iva increased FeNO levels in pwCF30,31. The mean increase in FeNO with iva in the two studies was from 8.5ppb (SD 5) to 16.2ppb (SD 15.5) in 15 pwCF, and from 6.6ppb (SD 2.19) to 11.8ppb (SD 4.97) in 5 pwCF, respectively30,31. The most recent two-site study in Toronto evaluated 20 patients on iva (8 pediatric/12 adult) and 14 pediatric patients on lum/iva29. The patients on iva had an increase in FeNO compared to their baseline after 4 weeks which was maintained for 24 months. The subjects on lum/iva had no change in their FeNO in the first year of treatment from baseline 10 ppb (range 8-15 ppb); however, some patients (n=5) showed improvement at 2 year follow up (median increase 9 ppb, 95%CI 2.8-15.6ppb, p=0.02). The use of both nNO and FeNO as biomarkers in future studies of modulators could be considered, but their widespread use would require more patient data and investigation.