Predictive meaning of Fractional Exhaled Nitric Oxide (FeNO) in the diagnosis of asthma for epidemiological purposes – an 8-year follow-up study

doi:10.21203/rs.3.rs-2745805/v1

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Predictive meaning of Fractional Exhaled Nitric Oxide (FeNO) in the diagnosis of asthma for epidemiological purposes – an 8-year follow-up study

https://doi.org/10.21203/rs.3.rs-2745805/v1

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Background:Asthma-like symptoms such as dyspnoea, wheezing, and chronic cough are common health problems. Chronic neglected symptoms at the early stages of the disease may herald serious respiratory diseases in the future. On the population level, the respiratory symptoms in children can be estimated via cross-sectional. However, such methods need objective support like the measurement of FeNO. The aim of the study was to analyze if the FeNO value measured at baseline can have predictive meaning for asthma-like symptoms after 8 years of measurement.

Methods: The follow-up included 128 (out of 447) children 70 girls and 58 boys. The FeNO was measured at baseline only. The prevalence of asthma-like symptoms was measured with the adopted version of the ISAAC questionnaire.

Results:After 8 years from FeNO measurement, 5 new cases of asthma have occurred, 2 cases of attacks of dyspnoea, 1 case of wheezy in the chest, and 18 cases of allergic rhinitis. The FeNO values, measured at the baseline of the study, for new cases of the above diseases, were 53.4±75.9 ppb, 11±1.5 ppb, 12.0 ppb, and 16.3±12.4 ppb, respectively. The best diagnostic accuracy parameters were found in the new cases of asthma where the sensitivity was 40.0%, the specificity was 98.6% and AUC was 66.6% and the diagnostic odds ratio was 46.9 when considering FeNO cut-off >35 ppb.;

Conclusions: The FeNO measurement is an objective method for asthma prognosis in early school-aged children with asthma-like symptoms measured on the population level and needs further confirmation on the clinical level with more accurate diagnostic tools.

Asthma

FeNO

Prediction

Follow-up study

Epidemiology

Children

In Poland, the prevalence of asthma in children is around 9% [1, 2]. The asthma-like symptoms like wheezy in the chest, attacks of dyspnoea, atopic rhinitis, and atopic dermatitis occur more often in school-aged children. Thus, this suggests that some of the symptoms are a herald of more serious health issues or underdiagnosis of respiratory diseases. In Poland, the prevalence of allergic rhinitis increased from 51.2–62.1% between 2008 and 2015 and decreased to 52% in 2018, in children aged 7–8 years. In young adults (aged 16–17), the prevalence of allergic rhinitis decreased from 63.9–35.8% in the same period 2008-2018.2 Regarding the prevalence of asthma in children aged 7–10 years, asthma was noted in 3.4–12.6% of children between 1993 and 2014 [3]. The prevalence of attack of dyspnoea in the last 12 months was reported in 11.2% of children aged 6–15 and the episode of wheezing was 9.6% in the last 12 months in 2018 [4].

Most of the studies use questionnaires for assessing asthma-like symptoms at the population level which is a commonly accepted method [5]. However, the accuracy of questionnaires might be unsatisfactory. The International Study of Asthma and Allergies in Childhood Questionnaires (ISAAC) questionnaire that is used for respiratory symptoms assessment in children has an accuracy from 26–76.9% depending on assessed symptoms [6]. The respiratory diagnosis on the populational level needs supportive and more objective methods of assessment. One of such method which is safe, inexpensive, and easy to perform is a measurement of FeNO, the marker of eosinophilic inflammation in airways [7]. The biomarker which is commonly used for asthma diagnosis and managing the treatment process of asthma in children [8]. Current literature shows that FeNO is linearly associated with the age in children aged 6–14 years, but, it is not fully understood how FeNO varies within the physiological changes across age and sex [9]. Moreover, the predictive meaning of it is as well not studied yet [10].

The aim of the study was to assess the predictive meaning of the FeNO measurement in school-aged children in relation to respiratory symptoms after 8 years from the first FeNO measurement.

The baseline of the study included 447 children from the randomly selected primary classes in 4 located schools (in cities: Bytom, Chorzów, Tychy and Zabrze) in the Silesia Voivodship, Poland. The characteristic of the population is described in the previous publication [11]. The follow-up included 128 (out of 447) children because only that number of parents or legal guardians signed informal consent, and responded via a traditional post on the letter with the questionnaire. FeNO measurement was performed only at baseline with an electrochemical NIOX MINO device (Circassia, Stockholm, Sweden), because respondents were not willing to participate in the FeNO measurement. The measurement followed the recommendations formulated by ERS/ATS [12] and was made by a trained and certified researcher. The asthma-like symptoms such as asthma, allergic rhinitis and atopic dermatitis ever diagnosed by physician and symptoms of chest wheezy and attacks of dyspnoea reported by parents, were noted within the adopted version of ISAAC [13].

The diagnostic odds ratio (DOR) was calculated with the following formula [14]: DOR = Sensitivity(1-Sensitivity) + (1-Specificity)Specificity

The frequency of true positive (TP) and false negative (FN) was described according to asthma-like symptoms considering the three defined thresholds of FeNO values suggested by ATS/ERS and other researchers (20, 25, 35 ppb), as well. [8, 15]. Moreover, the diagnostic accuracy formulas included as well sensitivity and specificity [16]. The area under the curve (AUC) was calculated to present FeNO accuracy as a continuous variable [17] for each diagnosis/symptom.

Statistical analysis

The results for quantitative variables were expressed as the arithmetic mean and standard deviation, for the qualitative variables the number (frequency) of cases was used. The differences between the 4 defined groups (group 1: baseline negative and follow-up negative, group 2: baseline negative and follow-up positive, group 3: base-line positive and follow-up negative, group 4: baseline positive and follow-up positive) were calculated with the Kruskal-Wallis test with correction for multiple comparisons.

The Wilcoxon test was used to assess the differences in age between the two groups (sexes).

All analyses were performed using the SAS statistical package (SAS Institute Inc., Cary, NC, USA, version 9.4.

Reported respiratory symptoms (baseline vs. follow-up).

In the study, there were 128 children who participated in the follow-up. There were 45% (n = 58) boys and 55% (n = 70) girls. The children did not differ significantly according to age (p = 0.6) between sexes in the follow-up. Regarding the symptoms from the respiratory system, there were 86,7% (n = 111) children without any asthma at baseline and after follow-up, 2/128 children without asthma at baseline but reported asthma during the follow-up, 1 child had asthma at the baseline but denied asthma diagnosis at follow-up, and 3/128 children had asthma confirmed by a physician at the baseline of the study and at the follow-up of the study. Lack of asthmatic tendency (defined as symptoms of wheezy in the chest and dyspnea reported in the last 12 months) at baseline and at the follow-up was reported by 95% (n = 122) of parents, 1/128 children had no symptoms of asthmatic tendency at baseline and reported asthmatic tendency during follow-up, 4/128 children had symptoms of asthmatic tendency at the baseline of the study and denied those symptoms during follow-up. One child had an asthmatic tendency at the baseline and at the follow-up. The symptoms of dyspnea on the day were not reported at the baseline and during follow-up in 96.8% (n = 124) children, no symptoms of dyspnea at baseline but during follow-up were reported in 3/128 children, while in only 1/128 children there were symptoms of dyspnea at baseline but no during the follow-up. None of the children had symptoms of dyspnea during the day at baseline and at the follow-up of the study. While considering the dyspnea attack during the night, 96.8% (n = 124) had no such symptoms at baseline and during the follow-up, the remaining 4 children in this group had episodes of dyspnea during the night at the baseline of the study but not during the follow-up. The lack of dyspnea induced by physical activity was reported in 92.1% (n = 118) children at baseline and follow-up. Lack of this symptom at baseline and its occurrence at follow-up was reported in 2/128 children, 5/128 had episodes of dyspnea induced by physical activity at baseline but not during the follow-up, while 2/128 children had such symptom at baseline and at follow-up. The lack of occurrence of wheezing currently on in the past 6 months was reported in 86.7% (n = 111) children, no symptoms of wheezing at baseline but during the follow-up was reported in 1/128 child. At baseline but not during the follow-up there 12/128 children with wheezing episodes, in 4/128 children the wheezing was reported at the baseline and during the follow-up of the study.

Reported allergic symptoms (baseline vs. follow-up).

Lack of allergic rhinitis at the baseline and during the follow-up was noted in 63.2% (n = 81) children, no symptoms of allergic rhinitis were reported at baseline but no during the follow-up was reported in 14% (n = 18), the occurrence of allergic rhinitis at the baseline but lack of allergic rhinitis during follow-up was reported in 16.4% (n = 21), the occurrence of allergic rhinitis at baseline and during follow-up was noted in 5/128 children. In 82% (n = 105) of children there were no symptoms of atopic dermatitis at baseline and during the follow-up, no atopic dermatitis at baseline but reported during follow-up was noted in 3/128 children, atopic dermatitis was reported at baseline but no during the follow-up was noted in 10.1% (n = 13), while in 7/128 children atopic dermatitis was reported at the baseline and at the follow-up of the study. The frequency of the symptoms at the baseline and during the follow-up with the mean FeNO values measured only at baseline are described in Table 1.

Table 1

The mean FeNO value in the relation to the status of the diagnosis at baseline and after 8 years from FeNO measurement (n = 128).
		1	2	3	4	P value
Disease/Symptoms		Baseline:(-) Follow-up:(-)	Baseline:(-) Follow-up:(+)	Baseline:(+) Follow-up:(-)	Baseline:(+) Follow-up:(+)	P value
Asthma	FeNO [ppb]	12.8 ± 6.6	53.4 ± 75.9	21.0	37 ± 23.4	1 vs. 2 = 0.2 1 vs. 3 = n/a 1 vs. 4 = 0.09
Asthma	n	119	5	1	3	1 vs. 2 = 0.2 1 vs. 3 = n/a 1 vs. 4 = 0.09
Attacks of dyspnoea	FeNO [ppb]	14.5 ± 17.2	11 ± 1.5	25.8 ± 20.9	29.0 ± 32.5	1 vs. 2 = 0.8 1 vs. 3 = 0.3 1 vs. 4 = 0.9
Attacks of dyspnoea	N	119	2	5	2	1 vs. 2 = 0.8 1 vs. 3 = 0.3 1 vs. 4 = 0.9
Wheeze	FeNO [ppb]	12.6 ± 6.6	12.0	21.0 ± 14.5	66.7 ± 81.3	1 vs. 2 = n/a 1 vs. 3 = 0.02 1 vs. 4 = 0.09
Wheeze	n	111	1	12	4	1 vs. 2 = n/a 1 vs. 3 = 0.02 1 vs. 4 = 0.09
Allergic rhinitis	FeNO [ppb]	13.3 ± 6.5	16.3 ± 12.4	12.4 ± 9.3	41.4 ± 65.3	1 vs. 2 = 0.6 1 vs. 3 = 0.1 1 vs. 4 = 0.4
Allergic rhinitis	n	81	18	21	7	1 vs. 2 = 0.6 1 vs. 3 = 0.1 1 vs. 4 = 0.4
Atopic dermatitis	FeNO [ppb]	13.1 ± 7.1	13.0 ± 1.7	20.0 ± 15.8	36.7 ± 66.2	1 vs. 2 = 0.5 1 vs. 3 = 0.2 1 vs. 4 = 0.7
Atopic dermatitis	n	105	3	13	7	1 vs. 2 = 0.5 1 vs. 3 = 0.2 1 vs. 4 = 0.7
Legend: “-“ – negative status of the disease; “+” – positive status of the disease; n/a – not available

The accuracy of FeNO in children who developed asthma was calculated in contrast to children without any considered health burden (77 children). The sensitivity (SEN) was 40% (2/5) specificity (SPE) 81.9% (59/72), positive predictive value (PPV) 95.1% (59/62), negative predictive value (NPV) 13.3% (2/15) for FeNO cut-off 20ppb, the SEN for the recommended high FeNO cut-off (> 35ppb) was 40% (2/5), SPE 98,6% (71/72) PPV 66.7% (2/3) and NPV 95.9% (71/74). Table 2.

Table 2

Diagnostic accuracy of FeNO at follow-up.
New case of outcome	FeNO [ppb]	SEN	SPEC	TP	FN	DOR	AUC
Asthma n = 5	> 20	40.0%	81.9%	13.3%	95.1%	3.01	0.610
	> 25	40.0%	94.4%	33.3%	95.7%	11.2	0.672
	> 35	40.0%	98.6%	66.6%	95.9%	46.9	0.693
Allergic rhinitis n = 18	> 20	16.6%	94.4%	42.8%	79.7%	3.3	0.507
	> 25	16.6%	94.4%	42.8%	81.9%	3.3	0.556
	> 35	11.1%	98.6%	66.7%	81.6%	8.7	0.549
Atopic dermatitis n = 3	> 20	0	81.9%	0	95.1%	n/a	0.590
	> 25	0	94.4%	0	95.7%	n/a	0.528
	> 35	0	98.6%	0	95.9%	n/a	0.507
Legend: AUC – area under curve; DOR – diagnostic odds ratio; FN– false positive; TP– true positive; SPEC – specificity SEN – sensitivity

The aim of the study was to analyze results of FeNO levels and reported lack or occurrence of the respiratory/allergic symptoms measured at baseline and confronta-tion them with reported results of lack or occurrence of the respiratory/allergic symp-toms reported at follow-up in children after 8 years from the FeNO measurement. The results of this study suggest that children, aged 6–9 years, with asthma-like symptoms and FeNO values > 35 ppb have the highest chance of having respiratory disease in the future. The diagnostic odds ratio resulted in almost 47 score which according to the test value has an extremely good predictive meaning [18]. However, in this study, the other diagnostic indicators like AUC or sensitivity, specificity, and true positive values don’t support the value of the diagnostic odds ratio. The FeNO had the best accuracy in relation to asthma. The sensitivity was 40% with 95% confidence interval (95%CI) ranging from 0 to 83% for each analyzed FeNO cut-off (> 20 ppb, > 25 ppb and > 35 pbb). The specificity was 81.9% (95%CI 73%-90%), 94.4% (95%CI 89%-100%) and 98.6% (95%CI 96%-100%) for each FeNO cut-off. The true positive indicators for FeNO cut-offs were 13.3% (95%CI 9%-30%),33.3% (95%CI 0–71%) and 66.6% (95%CI 27%-100%), respectievely.The results of false negative indicators for FeNO cut-offs were 95.1% (95%CI 90%-100%), 95.7% (95%CI 91%-100%), 95.9% (95%CI 91%-100%), respectively. Such findings are consistent with the results reported in systematic re-view and meta-analyses from cross-sectional studies [19].

The other issue that cannot be omitted is the question, if whether the children with increased FeNO values were not yet diagnosed with asthma (underdiagnosis of asthma). From a total group of children (n = 447), there were 22 cases of asthma. In the group of children who participated in the follow-up part, at baseline there were 4 cases of asthma (mean FeNO: 33.0 ppb; range: 10–52 ppb) and 8 cases of asthma (mean FeNO: 47.2 ppb; range: 6-186 ppb) during follow-up. One child from baseline asthma had excluded asthma after 8 years so in total there were 5 new cases of asthma (mean FeNO: 53.4 ppb, range: 6-186 ppb). That probably suggests that children with elevated FeNO levels (> 34 ppb) have not been diagnosed by a physician. In the 5 new cases of asthma, 2 children had attacks of dyspnoea, 3 children had wheezy in the chest and in all 5 cases, there were symptoms of allergic rhinitis and atopic dermatitis. In the study performed by Caudri et. all the FeNO was used as a predictor of asthma in preschool children from PIAMA cohort. It shows FeNO as a significant predictor of asthma-like symptoms such as wheezing and steroid use in the future [20]. However, the study was performed in the clinical field and in children with any asthma-like symptoms, so the conditions of the study differed from the methodology of the presented study. Moreo-ver, the presented study was performed in children who were free of respiratory symptoms as well.

More studies focused on the accuracy of FeNO in the diagnosis of asthma rather than the prediction of FeNO in asthma diagnosis. Some studies showed that FeNO (> 15.8 ppb) diagnostic accuracy (area under the curve ROC = 0.53) was poor in children with symptoms suggesting asthma [21]. The different results were shown in a study performed by Malberg. Children with probable asthma had higher FeNO concentra-tions in comparison to healthy controls. Moreover, the same study showed the discri-minant accuracy of FeNO with a sensitivity of 86% and specificity of 92% [22]. That corresponds with the conclusions suggested by Pijnenburg. It seems that the measure-ment of FeNO in preschool children might be more accurate for asthma diagnosis in children and respiratory symptoms, particularly in atopic children [10].

Moreover, the in the author’s previous study, the conclusion considered FeNO measurement as not a good screening tool for pediatric asthma in a community setting [23]. However, the current results of this study show that children with asthma-like symptoms and elevated FeNO levels are at increased risk of asthma and need further investigation, such results have been presented in the cross-sectional screening study conducted by Prasad et. all [15].

The predictive meaning of FeNO needs to be controlled according to the determi-nants of FeNO. In the study performed by See and Christiani, ethnicity, height, self-reported rhinoconjunctivitis, and household smoke exposure were responsible for 10.3% of FeNO variability in children aged 6–11. [24]. According to their study, they based the symptoms from the respiratory system on the responses from the question-naire The lack of validated diagnosis probably decreased the explained variability of FeNO, however, their study reflected the study performed in the epidemiological con-ditions [23]. In the study performed by Garcia-Marcos, the variability of FeNO was ex-plained in 27%. The 20% of the variability was explained by age, rhinoconjunctivitis, positive skin prick test and removal of cat and/or dog from the house [25]. The internal variability (within the group) of FeNO seems to be stable according to current litera-ture [26, 27] and should not impact the differences between the status of children.

It seems that the predictive meaning of FeNO for asthma diagnosis is dependent on a couple of crucial factors. First, it is the level of FeNO which is influenced by a lot of determinants that need to be clearly explained [28, 29]. Moreover, the exact refer-ence FeNO values like for spirometry should be developed. Current literature results imply that baseline FeNO levels seem to be a good predictor of a greater risk of moder-ate to severe asthma exacerbations, especially in uncontrolled asthma. Such results in-crease the meaning of FeNO measurement for community-setting [30].

And finally, for the epidemiological purpose, it is necessary to accurately assess the respiratory status of children. The questionnaire is a very important tool but needs additional support to increase its accuracy since it seems that the level of it is not sati-factionary. In the study performed by Kim et. al. the ISAAC questionnaire sensitivity, specificity, and accuracy for allergic rhinitis were 39.8%, 76.9%, and 63.4, respectively [31].

Study limitations

The study has a couple of limitations. The most important is that children in the follow-up did not willing for the FeNO measurement. Measurement at follow-up could improve the results of the questionnaire and verify if children have elevated FeNO levels, especially in those who had asthma previously. Another limitation is related to the small number of new cases of asthma, more cases of asthma could improve the in-vestigation of current symptoms and FeNO levels in this specific group. A further problem is related to the nature of the study, the cross-sectional study on the popula-tional level should be marked with limited trust since all symptoms are declared by legal guardians. The study has a potential strength. According to the author’s knowledge, it is the first study that considers FeNO levels and confronted them with asthma-like symptoms during follow-up. Most studies, consider prospective methods but according to the assessment of the relation of FeNO to the treatment control of asthma.

The FeNO measurement is an objective method for asthma prognosis in early school-aged children with asthma-like symptoms measured on the population level and needs further confirmation on the clinical level with more accurate diagnostic tools and physician decisions. Moreover, the method needs to be adjusted for factors influencing FeNO levels such as sex, age, and allergic diseases other than asthma.

Ethics approval and consent to participate

The study was conducted in accordance and approved by the Institutional Review Board - Ethics Committee of the Medical University of Silesia in Katowice (Decision No. KNW/0022/KB1/37/IV/14/16/17/; 14 November 2017) for studies involving humans.

All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).

Availability of data and materials

The data of this study are available upon reasonable request sent to the author (Kamil Barański) of the manuscript

Competing interests

The author declares no conflict of interest.

Funding

This research was funded by the Medical University of Silesia in Katowice, grant number PCN-1-057/N/1/O

Authors’ contributions

Conceptualization, KB; methodology, KB; investigation, KB; data curation, KB; writing—original draft preparation, KB; supervision, KB

Informed Consent Statement: Written informed consent has been obtained consent from a parent and/or legal guardian was obtained for study participation.

Consent to Publish Statement: Not applicable

Acknowledgements

I would like to thank all the participants for their valuable contribution. I thank Students Bartłomiej Nowak and Piotr Nakiela from the Medical School of Medicine in Katowice for data entry

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No competing interests reported.

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Predictive meaning of Fractional Exhaled Nitric Oxide (FeNO) in the diagnosis of asthma for epidemiological purposes – an 8-year follow-up study

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