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\begin{document}

\title{Cost Utility of Fractional Exhaled Nitric Oxide Monitoring for the
Management of Children Asthma}



\author[1]{jefferson buendia}%
\author[2]{Ranniery Acuña-Cordero}%
\author[3]{Carlos Rodriguez-Martinez}%
\affil[1]{University of Antioquia}%
\affil[2]{Hospital Militar Central}%
\affil[3]{School of Medicine, Universidad El Bosque}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Introduction Fractional exhaled nitric oxide (FeNO) is a simple,
noninvasive measurement of airway inflammation with minimal discomfort
to the patient and with results available with a few minutes. This study
aimed to evaluate the cost-effectiveness of the Fractional exhaled
nitric oxide in asthma. Methods A markov model was used to estimate the
cost-utility of FeNO versus standard treatment (control group) an infant
with mild to moderate allergic asthma. Cost data were obtained from a
retrospective study on asthma from tertiary center, in Medellin,
Colombia, while utilities were collected from the literature. The
analysis was carried out from a societal perspective. Results The model
showed that FeNO, was associated with lower total cost than SC (US
\$1333 vs US \$1452 average cost per patient), and higher QALYs (0.93
vs. 0.92 average per patient); showing dominance. The probability that
MS provides a more cost-effective use of resources compared with
standard therapy exceeds 99\% for all willingness to pay thresholds
Conclusion FeNO was cost-effective for the hospital treatment of an
infant with infant with mild to moderate allergic asthma. Our study
provides evidence that should be used by decision-makers to improve
clinical practice guidelines and should be replicated to validate their
results in other middle-income countries.%
\end{abstract}%



\sloppy


\textbf{Cost Utility of Fractional Exhaled Nitric Oxide Monitoring for
the Management of Children Asthma}

Short running title: Fractional Exhaled Nitric Oxide in Asthma

Jefferson Antonio Buend\selectlanguage{ngerman}ía, MD,MSc, PhD \textsuperscript{1} , Ranniery
Acuña-Cordero MD\textsuperscript{2} , Carlos E. Rodriguez-Martinez MD,
MSc, PhD(c)\textsuperscript{3,4}

Department of Pharmacology and Toxicology, School of Medicine, Research
group in pharmacology and toxicology (INFARTO). Universidad de
Antioquia, Medellín, Colombia.

Departamento de Neumología Pediátrica, Hospital Militar Central,
Departamento de Pediatría, Facultad de Medicina, Universidad Militar
Nueva Granada, Bogotá, Colombia

Department of Pediatrics, School of Medicine, Universidad Nacional de
Colombia, Bogota, Colombia

Department of Pediatric Pulmonology and Pediatric Critical Care
Medicine, School of Medicine, Universidad El Bosque, Bogota, Colombia

Corresponding author: Jefferson A. Buendía, MD, Ph.D., Facultad de
Medicina, Universidad de Antioquia, Carrera 51D \#62-29, Tel: +574
2196046; Medellín, Colombia. E-mail: jefferson.buendia@gmail.com.
E-mail: JAB: jefferson.buendia@gmail.com

\textbf{Introduction}

Fractional exhaled nitric oxide (FeNO) is a simple, noninvasive
measurement of airway inflammation with minimal discomfort to the
patient and with results available with a few minutes. This study aimed
to evaluate the cost-effectiveness of the Fractional exhaled nitric
oxide in asthma.

\textbf{Methods}

A markov model was used to estimate the cost-utility of FeNO versus
standard treatment (control group) an infant with mild to moderate
allergic asthma. Cost data were obtained from a retrospective study on
asthma from tertiary center, in Medellin, Colombia, while utilities were
collected from the literature. The analysis was carried out from a
societal perspective.

\textbf{Results}

The model showed that FeNO, was associated with lower total cost than SC
(US \$1333 vs US \$1452 average cost per patient), and higher QALYs
(0.93 vs. 0.92 average per patient); showing dominance. The probability
that MS provides a more cost-effective use of resources compared with
standard therapy exceeds 99\% for all willingness to pay thresholds

\textbf{Conclusion}

FeNO was cost-effective for the hospital treatment of an infant with
infant with mild to moderate allergic asthma. Our study provides
evidence that should be used by decision-makers to improve clinical
practice guidelines and should be replicated to validate their results
in other middle-income countries.

Keywords: health economics, public health, healthcare

\textbf{Introduction}

The high proportion of patients without adequate control of asthma
generates permanent challenges worldwide. For example, in Latin America,
only 2.4\% of the patients with this disease have total asthma control
(1). The periodic assessment and the early management of airway
inflammation are the principal strategies, to prevent hospitalizations,
recommended for international and local clinical guidelines (2, 3). In
this sense, the frequent measure of airway inflammation during the
follow up plays an important role to anticipate the exacerbations and
optimize the use of biological and corticosteroids drugs.

Since early of the nineties, the measure of fractional exhaled nitric
oxide (FeNO) has been used as a surrogate marker for type 2 airway
inflammation(4). FeNO is a simple, noninvasive measurement of airway
inflammation with minimal discomfort to the patient and with results
available with a few minutes. FeNO correlates with airway eosinophilia
in biopsy and bronchoalveolar lavage fluid (5). Indeed, a meta-analysis
of eight clinical trials in children found that FeNO guided treatment
reduced asthma exacerbations (6). The National Institute for Health and
Care Excellence (NICE) since 2014 recommended FeNO testing in children
when asthma diagnosis unclear. However, the routine used of FeNO in
asthma, and in children, is not uniformly adopted by all countries,
especially those developing countries.

The main barriers to adopting new technologies, from policymakers, are
always doubts about their efficiency in scenarios with scarce health
resources. Different economic evaluations of the use of FeNO during
asthma management in developed countries have been demonstrated that
FeNO monitoring to guide asthma management was cost-effective in Spain,
Germany, UK, and US (7-10). In this paper, we aimed to evaluate the
cost-utility of FeNO monitoring to guide asthma management in Children
in a middle-income country from a societal perspective.

\textbf{Material and methods}

\textbf{Economic model}

A Markov simulation model with three mutually exclusive nonabsorbent
states was used to compare the estimated cost and outcomes associated
with asthma management using standard care (SC) or SC with FeNO
monitoring to guide asthma management in Children (FeNO-SC)
(\textbf{Figure 1} ). This model and according to the natural history,
have three health states were defined: ``no symptoms'', ``suboptimal,
control, no exacerbation'', and ``asthma exacerbation'' with a cycle
length of 1 week. All patients entering the model are children with no
symptoms, diagnosed with mild to moderate allergic asthma, and receiving
inhaled corticosteroids as maintenance therapy. The effectiveness
outcome was the quality-adjusted life years (QALYs). The analysis was
carried out from a societal perspective (included direct and indirect
costs). The analytic horizon was 12 months. Given the short time
horizon, no type of discount to costs or results was applied. The study
protocol was reviewed and approved by the Institutional Review Board of
University of Antioquia (No 18/2015).

\textbf{Intervention}

These were obtained from a systematic review of published randomized
clinical trials and systematic reviews of randomized clinical trials
(RCT). Searches of computerized databases (MEDLINE, EMBASE, CENTRAL, and
LILACS) and references cited in published literature identified the
potentially applicable studies. The structured literature searches in
these databases were made using the following criteria: (asthma OR
wheeze) and (``Nitric Oxide''{[}tiab{]} or FeNO or eNO ``exhaled
NO''{[}tiab{]}). The searches yielded 493 citations, and a total of 34
studies were examined in full text. Included studies comparing
adjustment of asthma medications based on FeNO levels versus management
based on clinical symptoms or current asthma guidelines or both. We
excluded studies with the following comorbidities/ characteristics:
eosinophilic bronchitis, asthma-related to underlying lung disease such
as bronchiectasis and chronic obstructive pulmonary disease or
diagnostic categories such as 'cough variant asthma' and 'wheezy
bronchitis'. After applying these criteria, data from 8 studies were
included. A random-effect meta-analysis of the 8 eligible studies was
performed to summarize their results. The meta-analysis was based on the
model of Dersimonian and Laird. The analysis found a reduction of risk
of exacerbation (RR 0.76 CI0.63-092, I\textsuperscript{2} 39\%), between
the exacerbation rates observed in the FeNO-SC arm and SC arm
(\textbf{figure 2} ). The evidence on the usage of inhaled
corticosteroids is based on a systematic review that found an
approximately 20\% average reduction in use of ICS when FeNO monitoring
was applied in pediatrics patients (11-12)

\textbf{Transition Probabilities and utilities}

Utilities and transition probabilities of pediatric patients with
mild-moderate asthma treated with inhaled corticosteroids as maintenance
therapy of the model were extracted from a local previous study that
evaluates the cost-utility of inhaled steroids in pediatric asthma
within national guidelines for pediatric asthma (3, 13), \textbf{Table
1} .

\textbf{Cost analysis:}

To estimate the cost of each health state defined in the model we
extracted all costs of infants less than two years of age admitted on a
tertiary center, in Medellin, Colombia due to asthma according to the
national clinical guideline of asthma in children from January 2018 to
December 2018. All costs and use of resources were collected directly
from medical invoices and electronic medical records. The direct costs
considered in the analysis include medical consultation at the emergency
room, specialist referrals, chest physiotherapy, diagnosis support
(laboratory, electrocardiogram, x-ray, etc), medication (oxygen,
nebulization, antibiotics, corticosteroids, bronchodilators, etc.),
medical devices, hotel services at intensive care unit, hotel services
in a general medical ward, \textbf{Table 2} . Our country has been
characterized by having a very small price variation in the last 10
years, especially in health services between the different clinics and
over time (14). Moreover, the proportions of each of the costs remain
relatively constant, which, with few variations in their composition in
the last ten years (14). We use US dollars (Currency rate: US\$ 1.00 =
COP\$ 3,000) (15) to express all costs in the study. For the valuation
of the indirect costs associated with the loss of productivity of
parents, the human capital method was used, assuming everyone receives
an income of at least a legal minimum wage for formal or informal work.
The cost-opportunity of the productivity loss at the workplace and the
caregiver was assessed based on the minimum wage without including the
transportation assistance for the year 2019 (U\$ 229.81 per month). The
legal minimum wage approved by the government was taken as a reference
and not an average or median wage thereof, given that in Colombia more
than 75\% of the population has this value as income(16). Because all
patients with asthma included were children, we assumed that at least
one family, member accompanies the patient permanently during
hospitalization, since pediatric hospitals in the country usually allow
only one companion per patient in the hospital. The cost associated with
transportation and food (does not include a stay), was assumed to
correspond to 50\% of the minimum wage per day.

\textbf{Sensitivity analyses}

To explore parameter uncertainty of the model inputs, a probabilistic
sensitivity analysis was conducted by randomly sampling from each of the
parameter distributions (beta distribution in the case of relative risk,
and utilities, Dirichlet distribution for multinomial data in the case
of transition probabilities, and gamma distribution in the case of
costs). The expected costs and expected QALYs for each treatment
strategy were calculated using that combination of parameter values in
the model. This process was replicated one thousand times (i.e.,
second-order Monte Carlo simulation) for each treatment option resulting
in the expected cost-utility. Decision uncertainty is represented in the
cost-effectiveness acceptability frontiers, which plot the probability
that the treatment strategy with the maximum expected net monetary
benefit is the most cost-effective over a range of willingness-to-pay
threshold values. Net monetary benefit was calculated by multiplying
effect by societal willingness to pay and subtracting cost, with
willingness to pay set at a ratio of US\$ 20,000 per QALY. We estimated
the expected value of perfect information (EVPI). The EVPI is the
maximum value that the health care system would be willing to pay for
additional evidence to inform the reimbursement decision in the future.
The population expected value of perfect information (PEVPI) was
calculated to inform the expected cost of uncertainty (expected
opportunity loss surrounding the decision) (17). Microsoft Exel ®was
used in all analyzes.

\textbf{Results}

The model showed that FeNO-SC, was associated with lower total cost than
SC (US \$1333 vs. US \$1452 average cost per patient), and higher QALYs
(0.93 vs 0.92 average per patient); showing dominance. A position of
dominance negates the need to calculate an incremental
cost-effectiveness ratio (\textbf{Table 2} ).

\textbf{Sensitivity analyses}

One-way showed that the probability of hospitalization has the highest
impact on the outcome, but MS was the dominant strategy in all range of
probabilities analyzed. The results of PSA are graphically represented
in the cost-effectiveness plane, \textbf{figure 3} . 53.82\% of
simulations were graphed in quadrant 2 (lower cost, high QALYs), and
45.97\% in quadrant 1 of this plane (high cost, high QALYs). The 95\% CI
for the cost per patient treated with FeNO-SC, and with SC were US\$
1331 to 1335 and US\$ 1449 to 1454. The 95\% CI for QALYs per patient
was 0.93 to 0.94 and 0.91 to 0.92 respectively. The net monetary
benefits of FeNO-SC was higher than SC (US\$ 16591 vs US\$ 16885). The
expected net benefit with perfect information US\$ 16885.9 and the
expected value of perfect information were: US\$ 0.074. The
Cost-effectiveness acceptability curve shows that the probability that
FeNO-SC provides a more cost-effective use of resources compared with
standard therapy exceeds 99\% for all willingness to pay thresholds. The
population expected value of perfect information (EVPIP) for the
threshold of US\$ 20 was US\$ 1030015.

\textbf{Discussion}

Our study suggests that FeNO-SC achieving better outcomes at a lower
cost over standard treatment without FeNO in children with mild to
moderate allergic asthma. These better outcomes are due to reductions in
the probabilities of asthma exacerbation and sub-optimal control of the
disease, with the consequent increase of patients well controlled. The
magnitude of annual cost savings for the health system (US\$ 118 per
patient ) is no negligible if we consider that this disease affects
between 10 to 13\% of children and only 2.4\% of them meet the criteria
for total asthma control in Colombia. The findings constitute a new
argument to include the FeNO-SC in clinical practice guidelines of
pediatric asthma.

Our findings are in line with previous studies in the literature
evaluating the economic value of FeNO of inserting FeNO monitoring into
asthma management, some of them enrolling pediatric patients.
Beerthuizen et al. assessed the cost-effectiveness of web-based monthly
monitoring and of 4-monthly monitoring of FeNO as compared with standard
care. The economic evaluation was performed alongside a multicentre RCT
with a 1-year follow-up, and included 272 children aged between 4 and 18
years of age. The FeNO-based strategy had 83\% chance of being most
cost-effective at \textbackslash{}euro40 000/QALY from a societal
perspective (18). Berg et al. assessed the cost-effectiveness of FeNO
measurement with NIOX MINO in the diagnosis of asthma and in optimizing
asthma management using the expected reimbursement price of the device.
In this study, the use of FeNO measurement in treatment decisions was
less costly than asthma management based on standard guidelines (while
in mild to severe patients, asthma management with FeNO measurement
instead of standard guidelines resulted in cost-savings of
\textbackslash{}euro30 per patient and year, in more severe population,
management with FeNO measurement would save costs of
\textbackslash{}euro160 per patient) and provided similar health
benefits (7). Brooks et al. examined the impact of FeNO monitoring on
the cost-effectiveness of asthma management compared with management
without FeNO. FeNO in conjunction with current standard of care
guidelines had decreased expected per-patient annual expenditure
(US\$2,228) and increased expected per-patient annual QALYs (0.844)
compared with current standard of care alone (US\$2,637 and 0.767)(9).
Price et al. determined the cost-effectiveness of FeNO measurement using
a hand-held monitor (NIOX MINO), at a reimbursement price of £23, for
asthma diagnosis and management in the UK. Asthma management using FeNO
measurement instead of lung function testing resulted in annual
cost-savings of £341 and 0.06 QALYs gained for patients with mild to
severe asthma and cost-savings of £554 and 0.004 QALYs gained for those
with moderate to severe asthma(19). Sabatelli et al. evaluated the
cost-effectiveness and budget impact of FeNO monitoring for management
of adult asthma in Spain over a 1-year period. Adding FeNO to standard
asthma care saved \textbackslash{}euro62.53 per patient-year and
improved QALYs by 0.026 per patient-year. The budget impact analysis
revealed a potential net yearly saving of \textbackslash{}euro129
million if FeNO monitoring had been used in primary care settings in
Spain.8 Similarly, Harnan et al. assessed the cost-effectiveness of the
hand-held electrochemical devices NIOX MINO® (Aerocrine, Solna, Sweden),
NIOX VERO® (Aerocrine) and NO breath® (Bedfont Scientific, Maidstone,
UK) for the diagnosis and management of asthma. The de novo management
model indicated that the ICER of guidelines plus FeNO monitoring using
NO breath compared with guidelines alone in children is expected to be
approximately £45,200 per QALY gained, concluding that FeNO-guided
management has the potential to be cost-effective, although this is
largely dependent on the duration of effect(10)

The last version of the Global Initiative for Asthma refers to children
`` FeNO-guided treatment significantly reduces exacerbation rates
compared with guidelines-based treatment (Evidence A). However, further
studies are needed to identify the populations most likely to benefit
from FeNO-guided treatment, and the optimal frequency of FeNO
monitoring''(2). However, in the references that support this statement
included only RCTs and not economic evaluations were revised. The
dynamics between clinical research in the effectiveness and research of
efficiency of the allocation of health resources must be coordinated,
synchronous of the moment to make a recommendation from individual to
public health level. It is clear the complexity of the transferability
of economics evaluations, but this situation highlights the need to
assess the health technologies in the clinical guidelines no only
evaluating effectiveness or safety but also review economical topics to
increase the level of recommendation in clinical guidelines.

A very important aspect of our model is that it was robust to changing
the values \selectlanguage{english}\selectlanguage{english}of the model's utilities, probabilities, and costs using
oneway and probabilistic sensibility analysis of a Markov model. FeNO-SC
was always the cost-effectiveness strategy in all ranges of values of
utilities, probabilities, and costs. Even more, FeNO-SC was always the
cost-effectiveness strategy in all ranges of thresholds evaluated with a
low population EVPI. These findings in the sensibility analysis have
cardinal importance in our study because many of the inputs were
extracted from literature, which all were hospital-based and undertaken
in affluent countries; also allow decision making with an estimated
degree of uncertainty in each cost parameter or QALYs per strategy.

Our study has some limitations. The cost data were collected
retrospectively. Asthma treatment and the costs in question, including
hospital prices, did not markedly change to our days. Furthermore, our
country has been characterized by having a very small price variation in
the last 10 years, especially in health services (14). Additionally, we
use utilities extracted from the literature and not estimated directly
from our population. As was mentioned previously, the reliability and
robustness of the results were evaluated by sensitivity analyses.

In conclusion, the FeNO-SC was cost-effective for infant with asthma
moderate or severe. Our study provides evidence that should be used by
decision-makers to improve clinical practice guidelines and should be
replicated to validate their results in other middle-income countries.

\textbf{References}

1. Neffen H, Fritscher C, Schacht FC, Levy G, Chiarella P, Soriano JB,
et al. Asthma control in Latin America: the Asthma Insights and Reality
in Latin America (AIRLA) survey. Rev Panam Salud Publica.
2005;17(3):191-7.

2. Global Iniciative for Asthma Management and Prevention 2020
{[}Available from: \emph{www.ginaasthma.org} .

3. Colciencias MdSyPS-. Guia de Practica Clinica Para el diagnostico,
atencion integral y seguimiento de ninos y ninas con diagnostico de
Asma. Guia No. 01 2014 {[}Available from:
,\emph{http://gpc.minsalud.gov.co/gpc\_sites/Repositorio/Conv\_500/GPC\_asma/GPC\_Comp\_Asma.pdf}
.

4. Silvestri M, Sabatini F, Spallarossa D, Fregonese L, Battistini E,
Biraghi MG, et al. Exhaled nitric oxide levels in non-allergic and
allergic mono- or polysensitised children with asthma. Thorax.
2001;56(11):857-62.

5. Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen
G, et al. Relationship of exhaled nitric oxide to clinical and
inflammatory markers of persistent asthma in children. J Allergy Clin
Immunol. 2003;112(5):883-92.

6. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide
treatment for children with asthma. Cochrane Database Syst Rev.
2016;11:CD011439.

7. Berg J, Lindgren P. Economic evaluation of FE(NO) measurement in
diagnosis and 1-year management of asthma in Germany. Respir Med.
2008;102(2):219-31.

8. Sabatelli L, Seppala U, Sastre J, Crater G. Cost-effectiveness and
Budget Impact of Routine Use of Fractional Exhaled Nitric Oxide
Monitoring for the Management of Adult Asthma Patients in Spain. J
Investig Allergol Clin Immunol. 2017;27(2):89-97.

9. Brooks EA, Massanari M. Cost-Effectiveness Analysis of Monitoring
Fractional Exhaled Nitric Oxide (FeNO) in the Management of Asthma.
Manag Care. 2018;27(7):42-8.

10. Harnan SE, Tappenden P, Essat M, Gomersall T, Minton J, Wong R, et
al. Measurement of exhaled nitric oxide concentration in asthma: a
systematic review and economic evaluation of NIOX MINO, NIOX VERO and
NObreath. Health Technol Assess. 2015;19(82):1-330.

11. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE,
Gadomski AM, et al. Clinical practice guideline: the diagnosis,
management, and prevention of bronchiolitis. Pediatrics.
2014;134(5):e1474-502.

12. Morphew T, Shin HW, Marchese S, Pires-Barracosa N, Galant SP.
Phenotypes favoring fractional exhaled nitric oxide discordance vs
guideline-based uncontrolled asthma. Ann Allergy Asthma Immunol.
2019;123(2):193-200.

13. Rodriguez-Martinez CE, Sossa-Briceno MP, Castro-Rodriguez JA.
Cost-utility analysis of the inhaled steroids available in a developing
country for the management of pediatric patients with persistent asthma.
J Asthma. 2013;50(4):410-8.

14. Estadisticas DAN. Indice de Precios al Consumidor - IPC 2020
{[}Available
from:\emph{https://www.dane.gov.co/index.php/estadisticas-por-tema/precios-y-costos/indice-de-precios-al-consumidor-ipc}

15. la Bd, Republica. Tasa Representativa del Mercado (TRM - Peso por
dolar) 2019 {[}cited 2020. Available
from:\emph{https://www.banrep.gov.co/es/estadisticas/trm}.

16. Departamento, Nacional, (DANE) DE. Archivo Nacional de Datos 2019
{[}Available from:\emph{https://sitios.dane.gov.co/anda-index/}.

17. Felli JC, Hazen GB. Sensitivity analysis and the expected value of
perfect information. Med Decis Making. 1998;18(1):95-109.

18. Beerthuizen T, Voorend-van Bergen S, van den Hout WB,
Vaessen-Verberne AA, Brackel HJ, Landstra AM, et al. Cost-effectiveness
of FENO-based and web-based monitoring in paediatric asthma management:
a randomised controlled trial. Thorax. 2016;71(7):607-13.

19. Price D, Berg J, Lindgren P. An economic evaluation of NIOX MINO
airway inflammation monitor in the United Kingdom. Allergy.
2009;64(3):431-8.

20. Buendia JA. {[}Attitudes, knowledge and beliefs of patient about
anti-hypertensive drugs{]}. Biomedica. 2012;32(4):578-84.

\textbf{Abbreviations}

Fractional exhaled nitric oxide (FeNO)

SC with FeNO monitoring to guide asthma management in Children (FeNO-SC)

quality-adjusted life years (QALYs)

randomized clinical trials (RCT)

\textbf{Acknowledgements :} none

\textbf{Funding:} Own fundings

\textbf{Conflict of interest statement for all authors :} All authors
declare that they do not have any conflict of interest in this
publication.

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