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.