This is the first proof-of-concept study comparing measurements of TB-nNO between stationary
and hand-held analysers. NIOX MINO® Nasal is, to our knowledge, currently one of very few commercially available hand-held devices, but so far no guidelines exist for their use in PCD work-up. Non-VC-nNO measurement such as TB-nNO technique is easy to perform even in young children
and has previously been found to discriminate significantly between PCDs and HS and between PCD and CF using stationary nNO analysers
In this study, hand-held TB-nNO measured at a flow rate of 5 ml/s showed very promising results, was simple to perform with high feasibility and high success rate even in the youngest children, and exhibited excellent discriminative capacity between HS and PCDs, and between PCD and CF. Discrimination was comparable to TB-nNO measurements using stationary analysers and in concordance with published TB-nNO results using stationary equipment
. The discriminative power of TB-nNO measured by MINO5 was comparable to nNO measured by the recommended VC-sampling techniques
, and in addition with higher success rate and feasibility. Furthermore, MINO5 exhibited superior within-subject repeatability, and comparable agreement with stationary analysers.
MINO5 was superior to MINO2 in terms of success rate (100% vs. 96.5%), false positives (specificity 100% vs. 90.5%), within-subject repeatability (CV% of 10% vs. 19.3%), and agreement with stationary reference method (NIOX Flex). In addition, to our experience, cooperation to 2 minutes of sampling, which is required by MINO2 sampling, was much to difficult for especially the young children. Thus the results of this study strongly suggest that hand-held TB-nNO should be measured at a sampling rate of 5 ml/s, abandoning sampling at 2 ml/s.
As expected, hand-held TB-nNO was more feasible compared to VC-nNO by hand-held equipment in terms of overall success rate including successful measurements down to 3.9 years of age. Moreover, hand-held TB-nNO showed superior success rate to VC-nNO in PCD and CF patients probably because TB-technique is less exhausting.
The concept of using a hand-held device for nNO measurement to discriminate between PCD, CF and HS has already been addressed by Montella and coworkers
. However, they employed a substantially different and more demanding method, not likely feasible in young children. They did assessments by nasal aspiration/insufflation via one nostril or by nasal silent exhalation through a facemask and also during humming and found it as effective as the stationary analyzer for assessing nNO during silent and humming exhalation.
A simple primary test is definitely needed in the attempt to achieve early diagnosis in children with PCD, since secondary confirmatory tests (ciliary beat pattern and frequency analysis together with evaluation of ciliary ultrastructure) are time consuming and often require repeated unpleasant nasal brushings or scrapings. The motivation for introducing hand-held nNO measurement, as first-in-line tool in the diagnostic work-up for PCD is the markedly lower cost compared to conventional stationary analysers, which make them affordable even to small PCD centres and secondary paediatric centres. Secondly, they are very simple to use with need of minimal training of staff, and with minute demand of maintenance and lack of need for calibration.
A recently published questionnaire survey including 194 centres (26 countries) handling PCD patients across Europe, disclosed that only 46% used nNO as the primary test in PCD work-up, whereas as many as 36% used the saccharin test
despite the latter being obsolete and abandoned in international recommendations
. The explanation for choosing saccharin test over nNO could be well explained both by the high cost of stationary nNO equipment and the high maintenance-costs. The same survey showed that PCD care is widely decentralised in Europe, with an average number of only four PCD patients per centre and with the need for smaller centres to refer patients to larger centres for diagnostic work-up
. For such small centres, a more widespread use of nNO may be enhanced by the current availability of cheap hand-held nNO-analysers. Furthermore, it is assumed that hand-held FeNO measurements, now widely recommended in certain aspects of asthma management
, are already becoming increasingly implemented in pulmonary and paediatric centres across Europe and US. This will likely pave the way for the additional and optional tool for nNO measurements.
Limitations of hand-held equipment
There are some limitations to the hand-held analyser used in this study, since e.g. even short interruptions during sampling result in measurement error. Hence, sniffing and crying may require multiple attempts (>3) or even make measurements impossible in an unwilling child. Moreover, especially the 2 full minutes of required TB-nNO sampling by MINO2, made cooperation difficult in the youngest children.
Furthermore, our results clearly demonstrates that TB-nNO measurement as such and by any equipment does not precisely cover the full range of nNO from the very high levels in HS to the extremely low levels in PCDs. Indeed, it seems that precision of TB-nNO, compared to the gold standard using VC-nNO sampling, increases inversely with lower levels of nNO. A phenomenon favouring its use for targeting possible PCDs, but potentially invalidates the use of TB-nNO in patients with e.g. allergic rhinitis.
Limitations, precautions and future perspectives
In this study, the groups of subjects were highly selected enrolling only definitive PCDs and CF patients diagnosed prior to inclusion. Indeed, the discriminative capacity in a random population of referred patients was not investigated. Furthermore, only few young children were included. Hence, this study provided proof-of-concept for the method as such, but did not provide sufficient data concerning young and none regarding newly referred children. Indeed, in our previous published study of TB-nNO measured using stationary analyser we reported a considerable fraction of false positive cases among newly referred young children
, which raises questions for future studies. Hand-held TB-nNO applied on a similar less well-defined cohort of mixed referrals for PCD work-up, including a higher number of young children and potentially also infants, might face a similar overlap between groups. Moreover, normal or even high nNO values in PCD has been previously described, although this is rare
. With respect to these previous findings, we believe that a high index of clinical suspicion of PCD should always lead to further investigational tests - despite above-cut-off level of nNO.
It must be emphasized that nNO measurements have no place in diagnosis of CF. In this study these measurements only further strengthened the proof-of-concept by demonstrating that hand-held devices completely reflect the intermediate levels of nNO in CF patients (between HS and PCDs), which has been also shown with stationary devices
Hand-held TB-nNO may hold promising potential as targeted case-finding tool for PCD in contrast to a formal screening tool, which is much more comprehensive and currently not realistic with the available methods. Introduction
as a primary test in combination with thorough clinical assessment and the very essential history may provide quick assessment and guidance as to either rule out PCD, or refer for confirmatory diagnostic tests in specialised centres. Hence, delay of referral may diminish, and early PCD diagnosis and prevention of missed diagnoses will hopefully come a step closer. However, although it may seem attractive to implement hand-held nNO devices in primary or secondary paediatric centres, some precautions need to be addressed: hand-held TB-nNO needs validation in a real-life scenario among primary and specialised centres with the very heterogeneous population of a large number of referrals with upper and lower respiratory disease involvement. Experiences from such studies may subsequently develop into an algorithm to be used in primary centres to interpret specific levels of nNO values and to determine when to repeat tests, when to refer or when to rule out PCD. Moreover, specific TB-nNO cut-off levels are needed for infants and young children. Finally, optimising the technology behind hand-held nNO could be desirable. From the experience of this study, the ideal nNO hand-held analyser should be simple to use with substantially shorter sampling time requirements and accepting short pauses during measurements, and preferentially also provide real time display of measurement quality.
In conclusion, hand-held TB-nNO discriminates significantly between highly selected groups of PCD, CF and HS, and has equal discriminative power compared to both TB-nNO using stationary analysers and to VC-nNO measurements. Hand-held TB-nNO was in excellent alignment with stationary TB-nNO and more feasible than VC-nNO in both young children and in patients with PCD and CF. TB-nNO measured by sampling rate of 5 ml/s was superior to sampling at 2 ml/s, and we suggest a sampling rate of 5 ml/s to be used in both children and adults. Hand-held TB-nNO exhibits promising potential as a targeted case-finding tool for PCD.