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\begin{document}

\title{Lung clearance index short-term variability in cystic fibrosis. A
pre-post pulmonary exacerbation study.}



\author[1]{M. De Marchis}%
\author[1]{Enza Montemitro}%
\author[1]{A. Boni}%
\author[1]{A. Federici}%
\author[2]{Daniele Di Giovanni}%
\author[1]{L. Cristiani}%
\author[1]{Renato Cutrera}%
\author[1]{A.G. Fiocchi}%
\affil[1]{Ospedale Pediatrico Bambino Gesu}%
\affil[2]{Universita degli Studi di Roma Tor Vergata Dipartimento di Ingegneria Industriale}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Multiple Breath washout (MBW) represents an
important tool to detect early a possible pulmonary exacerbation
especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI)
is the most commonly reported multiple breath washout (MBW) index and in
the last years was used as management measure for evaluation. Our aim
was to analyze clinical utility of LCI index variability in pulmonary
exacerbation in CF. \textbf{Methods:} A single-center study was
conducted at CF Unit of Bambino Ges\selectlanguage{ngerman}ù Children's Hospital among
hospitalized \textgreater{} 3 years patients for pulmonary exacerbations
and treated with antibiotic intravenous treatment for 14 days. MBW and
spirometry were evaluated within 72 hours of admission to hospital and
at the end of hospitalization. Descriptive analysis was conducted and
correlations between quantitative variables were investigated.
\textbf{Results:} Fifty-seven patients (M22/F35) with an average age
18.56 (± 8.54) years were enrolled. LCI 2.5 was significantly reduced at
the end of antibiotic treatment in both pediatric and adult populations
with an average improvement of -6\% in 37/57 patients. 26/57 are stable
in LCI values. A significant elevation of +7.30\% was found for FEV1\%.
4/57 (7.02 \%) had a significant deterioration in LCI values at the end
of IV antibiotic treatment. A positive good correlation among LCI 2.5
and Scond (rho= +0.615, p=0.000) and LCI 2.5 and Sacin (rho=+0.649,
p=0.000) and a negative strong correlation between FEV1\% and LCI 2.5
were found in post treatment period. A better increase of LCI 2.5 in
\textless{} 18 years (-10.27\% vs -4.57\%) than adult was noticed.
\textbf{Conclusions:} LCI may have a role in the routine clinical care
of CF patients as a good tool to assess response to intravenous
antibiotic therapy.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Lung clearance index short-term variability in cystic fibrosis.
A pre-post pulmonary exacerbation study.}

\textbf{Authors:} M. De Marchis
\textsuperscript{1,2},\emph{matteo.demarchis@opbg.net}

E. Montemitro\selectlanguage{ngerman}¹,\emph{enza.montemitro@opbg.net}

A. Boni¹,\emph{alessandra.boni@opbg.net}

A. Federici¹,\emph{alessandra.federici@opbg.net}

D. Di
Giovanni\textsuperscript{3,4},\emph{daniele.di.giovanni@uniroma2.it}

L. Cristiani¹,\emph{luca.cristiani@opbg.net}

R. Cutrera¹,\emph{renato.cutrera@opbg.net}

A.G. Fiocchi\textsuperscript{5}\emph{agiovanni.fiocchi@opbg.net}

Affiliations:

\emph{1 Pneumology and Cystic Fibrosis Unit, Bambino Gesù Children's
Hospital IRCCS, Rome, Italy}

\emph{2 University of Magna Graecia of Catanzaro, Italy}

\emph{3 Industrial Engineering Department, University of Rome Tor
Vergata, Rome, Italy}

\emph{4 Unicamillus, Saint Camillus International University of Health
Sciences, Rome, Italy}

\emph{5 Allergy Division, Bambino Gesù Children's Hospital IRCCS, Rome,
Italy}

\textbf{Abstract}

\textbf{Background:} Multiple Breath washout (MBW) represents an
important tool to detect early a possible pulmonary exacerbation
especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI)
is the most commonly reported multiple breath washout (MBW) index and in
the last years was used as management measure for evaluation. Our aim
was to analyze clinical utility of LCI index variability in pulmonary
exacerbation in CF.

\textbf{Methods:} A single-center study was conducted at CF Unit of
Bambino Gesù Children's Hospital among hospitalized \textgreater{} 3
years patients for pulmonary exacerbations and treated with antibiotic
intravenous treatment for 14 days. MBW and spirometry were evaluated
within 72 hours of admission to hospital and at the end of
hospitalization. Descriptive analysis was conducted and correlations
between quantitative variables were investigated.

\textbf{Results:} Fifty-seven patients (M22/F35) with an average age
18.56 (± 8.54) years were enrolled. LCI 2.5 was significantly reduced at
the end of antibiotic treatment in both pediatric and adult populations
with an average improvement of -6\% in 37/57 patients. 26/57 are stable
in LCI values. A significant elevation of +7.30\% was found for FEV1\%.
4/57 (7.02 \%) had a significant deterioration in LCI values at the end
of IV antibiotic treatment. A positive good correlation among LCI 2.5
and Scond (rho= +0.615, p=0.000) and LCI 2.5 and Sacin (rho=+0.649,
p=0.000) and a negative strong correlation between FEV1\% and LCI 2.5
were found in post treatment period. A better increase of LCI 2.5 in
\textless{} 18 years (-10.27\% vs -4.57\%) than adult was noticed.

\textbf{Conclusions:} LCI may have a role in the routine clinical care
of CF patients as a good tool to assess response to intravenous
antibiotic therapy.

Background

CF is the most common life-limiting autosomal recessive disease in
Caucasian population, and is a complex multisystemic disorder caused by
mutations in the gene encoding the cystic fibrosis transmembrane
conductance regulator (CFTR), an ion channel which primarily regulates
anion transport through cell surface. To date, more than 2000 mutations
have been identified \textsuperscript{1}. Functional failure of CFTR
leads to multisystemic dysfunction, involving lungs, gastrointestinal
tract, liver and pancreatic gland. Impaired mucociliary clearance and
dense secretions primarily result in chronic pulmonary inflammation and
infections, irreversible lung architecture modification, respiratory
failure and death \textsuperscript{2}.

In the last decade, LCI started to be used in CF management as an
efficacy endpoint in interventional trials thanks to its ability to
effectively assess small airways disease both in preschool and
middle-age children, when forced expiratory volume in 1 second (FEV1) is
generally within normal range and CF lung disease still
mild\textsuperscript{3-5}.

LCI is the most commonly reported MBW index in the pediatric literature
and it is defined as the number of functional residual capacity lung
turnovers required to reduce the alveolar concentration of a tracer-gas
to a given fraction of its starting value, historically 1/40 (2.5\%). A
particular advantage of LCI in pediatric population is feasibility by
passive cooperation and minimal coordination across all the pediatric
age ranges \textsuperscript{6}.

Horsley et al. described Lung clearance index as a sensitive, repeatable
and practical measure of airways disease also in adults with cystic
fibrosis

Despite being the gold standard for the assessment of pulmonary function
in CF lung disease, FEV1 measurement through spirometry has been shown
to be less sensitive than LCI in detecting early abnormalities and
peripheral airways disease in CF \textsuperscript{8}. LCI is an early
marker of ventilation inhomogeneity, reflecting initial airways
dysfunction in CF population with normal pulmonary function
tests\textsuperscript{9-10} and is being recognized as a useful
surrogate pulmonary outcome measure, especially in the new era of CFTR
modulators, where new disease trajectories will require adequate
clinical markers to characterize clinical phenotypes and monitor the
efficacy of treatments\textsuperscript{11-14}\textsubscript{.}

LCI is a sensitive and feasible measures index (LCI) with strong
intra-test and iter-test repeatability \textsuperscript{15}.

In CF, pulmonary exacerbations are crucial events which progressively
determine a loss of respiratory function, worsening of the quality of
life and negatively impact overall survival. According to studies, lung
function fails to return to baseline value in up to 25\% of CF pulmonary
exacerbations, despite a prompt antibiotic
treatment\textsuperscript{16-17}. In contrast to studies in which FEV1
was used as primary outcome, consistently showing a positive treatment
effect\textsuperscript{18-21}, studies addressing LCI as outcome measure
obtained heterogeneous results \textsuperscript{22-24}. LCI
significantly increases in patients with a pulmonary exacerbation, but
LCI response to therapy for pulmonary exacerbations is heterogeneous and
not completely clear in literature .

Our primary aim was to evaluate LCI index short-term variability in
pulmonary exacerbation after antibiotic intravenous therapy. We also
aimed to analyze the possible correlations between spirometry and LCI
values post therapy course to support treatment variability.

\textbf{Methods}

Study design

A pre-post single-center retrospective study according to STROBE
statement checklist was conducted at the CF Centre of Bambino Gesù
Pediatric Hospital, from September 2020 to February 2021. Fifty-eight
consecutive CF patients with a Pulmonary exacerbation (PE) were
enrolled. PE with intravenous (IV) antibiotic need was defined according
to standard Fuchs' criteria with an inadequate/absent clinical response
to a standard 14-day oral treatment. We included patients starting from
3 years of age. Exclusion criteria were an advanced lung disease with a
FEV1 \selectlanguage{english}[?] 40 \% of predicted and chronic Burkholderia cepacia complex and
Nontuberculous Mycobacteria (NTM) airways infection. All study
participants performed coupled multiple breath washout test and
spirometric assessment within 72-hours from hospital admission for
pulmonary exacerbation and at the end of IV antibiotic course. IV
treatment was conducted entirely in hospital, according to the CF
guidelines, providing 14 days of intravenous processing with standard
chest daily physiotherapy pulmonary rehabilitation \textsuperscript{26}.
The study protocol was approved by the local ethics committee of Bambino
Gesu (2819\_OPBG\_2022). A written informed consent was obtained from
all eligible subjects or from their parents/guardians when necessary.

\textbf{Sample Size}

We conducted sample size calculations starting from previous study of
Sonneveld N. et al \textsuperscript{25}. To detect a difference of 0.3,
considering 0.8 SD of differences, given a type I error of 0.05\% and
80\% power, 58 subjects were required for the analysis. To stratify the
response, we divided the population in two group: pediatric and
pre-adult age (PPaa) with \textless{} 18 years age and adult population
with \textgreater{}18 years age.

\textbf{Multiple-breath-washout}

MBW measurements were performed with a flow, volume and molecular mass
measurement analyzer (EXHALYZER D, Ecomedics, Switzerland), according to
ERS/ATS Consensus Guidelines \textsuperscript{27}. A minimum of two
satisfactory LCI results were obtained for each patient. Normal cut-off
value of LCI was set at 7.81. Scond and Sacin, two MBW test secondary
indexes of conductive airways and acinar zone respectively, collected
during the measurements, were included in the analysis

\textbf{Spirometry}

FEV1, forced vital capacity (FVC) and forced expiratory flow~25--75\%
(FEF25-75) were measured using standard spirometry following the ATS/ERS
guidelines\textsuperscript{28} with an ultrasound spirometer (Ecomedics,
EXHALIZER-D software 3.3.1). Data were expressed in \% predicted using
the normative data from the Global Lung Function Initiative software
(GLI 2012, Global Lung Function Initiative Task Force).

\textbf{Statistical analysis}

The collected data, related to demographic and clinical characteristics
of patients, were presented as counts and proportions (categorical data)
or mean, median, standard deviation (continuous data). The t-Student
test was used to compare normally distributed continuous data and
Wilcoxon tests for data that are not normally distributed. In line with
the secondary objectives of the study, correlations between quantitative
variables were investigated using Pearson's (parametric) or Spearman's
(nonparametric) correlation coefficient. A P-value \textless{}0.05 was
considered statistically significant for all analyses. The statistical
elaboration of the data was performed using IBM SPSS Statistics (version
25).

\textbf{Results}

Fifty-seven patients with CF (M/F 22/35) were recruited; their mean age
(+-DS) was 18.56 +- 8.7 years for females and 18.57 +- 8.5 years for males.
PPaa patients were 28/57 with a median age of 11,23 +- 3.95 years, and
adult patients were 29/57 with a median age of 25,65 +- 5.01 years. The
majority of the population was pancreatic insufficient and \selectlanguage{greek}Δ\selectlanguage{english}F508
homozygous. Pseudomonas colonization was present in 44\% of patients and
17\% of population were treated by CFTR modulators. The demographic and
anthropometric characteristics of the entire study population are shown
in Table 1.

Considering respiratory function at baseline, population had a moderate
impairment with median FEV1\% of 73.48 (\selectlanguage{ngerman}±21,19) and median LCI 2.5 of
12.85 (±3.86) as shown in Table 2. Modification after antibiotic IV
therapy was statistically significative for FEV1\% (p=0.000), FVC\%
(p=0.000) and for LCI 2.5 (p=0.001) and LCI5 (p=0.030). No differences
were found for Sacin (p=0.33) and Scond (p=0.38).

FEV1\% variation post antibiotic IV treatment was + 7.30\%, FVC \%
variation was + 5.46\%. An improvement of LCI2.5 was found in 37/57
patients (-6.99\%), while in 20/57 it remained stable or worsened. Among
the total of study population, 4/57 patients showed a deterioration
\textgreater{} 15\% in LCI after antibiotic therapy.

All differences in the measured pre and post antibiotic IV therapy
respiratory parameters are shown in Table 2.

\textbf{TABLE 1} \textbf{Demographic and clinical characteristics of the
study population}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Demographic / clinical characteristic} &
\textbf{Value}\tabularnewline
Sex (M/F) & 22/35\tabularnewline
\selectlanguage{greek}Δ\selectlanguage{english}F508 homozygous (\%) & 15\tabularnewline
\selectlanguage{greek}Δ\selectlanguage{english}F508 heterozygous (\%) & 85\tabularnewline
Age (yrs) \selectlanguage{ngerman}± SD & 18.56 (8.54)\tabularnewline
Height (cm) \selectlanguage{ngerman}± SD & 150.16 (20.63)\tabularnewline
Weight \selectlanguage{ngerman}± SD & 46.11 (16.87)\tabularnewline
BMI \selectlanguage{ngerman}± SD & 19.69 (3.49)\tabularnewline
Chronic pseudomonas aeruginosa colonization (\%) & 44\%\tabularnewline
Pancreatic insufficiency (\%) & 96.5 \%\tabularnewline
Patients on CFTR modulator (\%) & 17 \%\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 2} \textbf{Spirometry and multiple breath washout
parameters of the study population (mean value)}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Multiple Breath washout average values} & \selectlanguage{ngerman}\textbf{Pre (mean ±
SD)} & \selectlanguage{ngerman}\textbf{Post (mean ± SD)} & \textbf{Variation pre-post
(\%)}\tabularnewline
LCI 2.5 & 12.85 (3.86) & 12.01 (4.05) & -6,99\tabularnewline
LCI 5 & 7.72 (1.98) & 7.34 (2.03) & -5,18\tabularnewline
Scond & 0.08 (0.10) & 0.07 (0.04) & -14,29\tabularnewline
Sacin & 0.223 (0.16) & 0.246 (0.20) & +9,35\tabularnewline
\textbf{Spirometric parameters} & \selectlanguage{ngerman}\textbf{Pre (mean ± SD)} &
\selectlanguage{ngerman}\textbf{Post (mean ± SD)} &\tabularnewline
FEV1 (liters) & 2.08 (0.85) & 2.23 (0.89) & +6,73\tabularnewline
FEV1 \% & 73.48 (21,19) & 79.27 (20.21) & +7,30\tabularnewline
FVC (liters) & 2.70 (1.06) & 2.83 (1.13) & +4,59\tabularnewline
FVC \% & 81.83 (16.67) & 86.56 (16.43) & + 5,46\tabularnewline
FEF 25-75 (Liters/second) & 1.99 (1.14) & 2.07 (1.12) &
+3,86\tabularnewline
FEF 25-75 \% & 62.3 (33.0) & 67.2 (31.5) & +7,29\tabularnewline
\bottomrule
\end{longtable}

Regarding sub-classification of population, we noticed a similar
modification after IV antibiotic treatment for PPaa vs. adult population
in FEV1\% (p=0.002), FVC\% (p=0.000) and LCI 2.5 (p=0.014). We
registered a better increase of LCI 2.5 in PPaa population (-10.27\% vs
-4,57\%) than adult one. On the contrary, in adult population we
recorded significative differences in FVC\% after treatment (p=0.065).

Considering correlation, we noticed a positive good correlation among
LCI 2.5 and Scond (rho= +0.615, p=0.000) and Sacin (rho=+0.649, p=0.000)
in post treatment period. FEV1\% and LCI 2.5 showed a negative strong
correlation (rho= -0.78 with p=0.000) after IV antibiotic therapy.

\textbf{Discussion}

According to our results, LCI values appear to significantly vary during
the course of a pulmonary exacerbation in people with CF as an important
tool to monitor response to antibiotic therapy. In particular, we
demonstrate a significant correlation between the gold standard CF lung
function parameter FEV1\% and a small airways inhomogeneity index such
as LCI 2.5.

Hatziagorou et al. investigated the use of LCI to assess intravenous
antibiotic treatment response in pulmonary exacerbation with a
significant improvement in most lung function parameters: LCI
(p=0.0001), FEV1\% (p=0.05), FEV1 z-score (p=0.033) and FEF25-75
(p=0.046). LCI decreased by a mean of 1.77 lung turnovers with an
average decrease in LCI of 26\% (p=0.001) and average increase in FEV1\%
of 10.36\% (p=0.05)\textsuperscript{29}. These data are more encouraging
than ours but the caseload is much smaller (13 patients).

Our data are more in line with Robinson et al. that reported a LCI2.5
mean decrement of 0.48 lung turnovers with a 3.8\% change and with Eef
Vanderhelst that had described a significant decrease of 4.5\% among CF
adult patients \textsuperscript{23}.

We might hypothesize that in the pre-school population there is a
greater variation in LCI post antibiotic treatment, with an average
treatment effect of -15.5\% (95\% CI -25.4 to -5.6). Interestingly, in
that population no distinction was made between PE requiring oral or IV
therapy \textsuperscript{30}. In fact, also in our population we notice
a better increase of LCI 2.5 in \textless{} 18 years patients, perhaps
mirroring a less pronounced structural and functional lung damage.

As reported in literature, under clinical stability conditions, the
inter-individual variability of LCI was of 16\%. Our data suggest the
hypothesis that this variability during PE is reduced for the presence
of inflammation, mucus and increased
broncostriction\textsuperscript{31}.

Sacin and Scond are two values that are becoming more studied in
literature, especially Sacin that reflects alveolar functionality,
starting point of lung damage in CF disease. In contrast to Vanderhelst,
our data demonstrate that LCI 2.5 correlates with both Sacin and Scond
emphasizing how much in CF-PE both proximal and distal airways are
affected \textsuperscript{23}.

In our setting, LCI2.5 and FEV1 are concordant in showing a
statistically significant amelioration of lung function after an IV
antibiotic therapy. Despite its limits, we suggest that LCI may be
adopted as an additional biomarker to assess lung function response to
antibiotic therapy, during a pulmonary exacerbation.

According our experience, we focuse attention on 4 patients who showed a
greater drop in LCI 2.5 (\textgreater{} 15\%) and analyzing their
clinical conditions we try to explain this anomalous trend. One of these
patients had Allergic Bronchopulmonary Aspergillosis, spirometric
indexes improved but LCI value did not respond; one pediatric patient
did not respond probably for her severe anatomic compromission, with TC
confirming severe atelectasis in upper lobe of the right lung. Two adult
women patients from starting to the end of hospitalization preserved
more or less the same spirometric values, including FEF 25-75\% for
small airways, despite primary value of LCI 2.5 and secondary
inhomogeneity parameters had a severe worsening.

A major limitation to our study is the lack of a baseline LCI 2.5
assessment due to SARS-CoV-2 pandemic and the routine availability of
Exhalyzer --D in our center only after March, 2020. Among limitations
were the lack of knowledge about aerosol therapy treatment (Dornase
alfa, hypertonic solution, bronchodilators) performed during the
hospitalization for IV antibiotic treatment, and the typology of chest
physiotherapy administered by respiratory therapists.

Sovrainfections could represent another possible bias factor that
prevented improvements of LCI 2.5 values. Even it was possible that
patients had allergies to intravenous antibiotics and this clinical
aspect could influence value at the end of IV antibiotic treatment.

The variability of LCI response for each patient could be explained by
the different clusters of bronchopulmonary flare-ups in CF adult
patients, as recently reported in the literature, but further studies
are needed to prove this hypothesis \textsuperscript{32}.

In conclusion, our study shows that LCI is a valid tool to monitor
antibiotic responses in PE in CF in the same way as the FEV1\%, with the
advantages of being easy to perform especially in pediatric population.
We can assume that LCI will be used in conjunction with the clinic, to
be evaluated halfway through the antibiotic cycle to make any treatment
implementations or total changes.

Future long-term studies are needed to confirm these findings.

\textbf{List of abbreviations:}

Multiple Breath washout (MBW)

Cystic Fibrosis (CF)

Lung clearance index (LCI)

Forced expiratory volume in 1 second (FEV1)

Cystic fibrosis transmembrane conductance regulator (CFTR)

Pulmonary exacerbation (PE)

Intravenous (IV)

Forced vital capacity (FVC)

Forced expiratory flow~25--75\% (FEF25-75)

Pediatric and Pre-adult age (PPaa)

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\textbf{Acknowledgements} None.

\textbf{Authors' contributions} MDM, EM and LC conceived the study. MDM
and AB wrote the manuscript. MDM ,LC and AF collected data. RC and AGF
conceived and directed the work thanks to their knowledge of the subject
matter. All authors analyzed and interpreted patients' data, read and
approved the final manuscript.

\textbf{Funding} None

\textbf{Availability of data and materials} The datasets used and/or
analysed during the current study are available from the corresponding
author on reasonable request.

\textbf{Ethics approval and consent to participate} Local ethics
committees approved the study (n° 2819\_OPBG\_2022). Parental consent
was not required because this is a retrospective study and data were
anonymized.

\textbf{Consent for publication} Not applicable.

\textbf{Competing interests} The authors declare that they have no
competing interests.

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