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\begin{document}

\title{Young Cystic Fibrosis Lung Transplant Recipients: Predisposing Factors
for End-stage Disease}



\author[1]{George Mallory}%
\author[2]{Ernestina Melicoff}%
\author[2]{Fadel  Ruiz}%
\author[1]{Kathleen Hosek}%
\affil[1]{Texas Children's Hospital}%
\affil[2]{Baylor College of Medicine}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: The largest age group among children and adolescents
referred for lung transplantation for cystic fibrosis (CF) have been
those who in the pubertal or post pubertal age range. However, over 100
younger patients with CF have undergone lung transplantation over the
last three decades in the USA. Methods: We performed a retrospective
review of our experience with 18 children with CF who underwent lung
transplantation in our center before the age of 11 years. Results:
Notable findings were a high prevalence of methicillin-resistant
Staphylococcus aureus, a high prevalence of diabetes mellitus and an
impressive prevalence of consolidated lobar or whole lung disease.
Post-transplant outcomes, however, were comparable to those older than
10 years of age in our center. Conclusions: In an era of increasingly
effective medications modifying the natural history of CF,
identification of risk factors for early severe lung disease in CF
remains relevant and potentially more important for effective
intervention in order to extend life.%
\end{abstract}%



\sloppy


\textbf{Youngest Cystic Fibrosis Lung Transplant Recipients:
Predisposing Factors for End-stage Disease}

Melicoff, Ernestina, MD\textsuperscript{1}, Ruiz, Fadel E,
MD\textsuperscript{1}, Hosek, Kathleen, MA\textsuperscript{2}, Mallory,
George B, MD\textsuperscript{1}

Section of Pediatric Pulmonology, Department of Pediatrics, Baylor
College of Medicine and Texas Children's Hospital

Department of Quality Assurance, Texas Children's Hospital

\emph{Corresponding author} : George B. Mallory, Jr., M.D.

\emph{Address} : Section of Pediatric Pulmonology Texas Children's
Hospital

6701 Fannin Street, Suite 1040

Houston, TX 77030 United States of America

Phone: 832-822-3300 Email: gbmallor@texaschildrens.org

None of the authors have a conflict of interest or financial disclosure
of relevance to this manuscript.

Abbreviations: CF = cystic fibrosis

CFTR = cystic fibrosis transmembrane receptor

MRSA = methicillin-resistant \emph{Staphylococcus aureus} CFRD = cystic
fibrosis related diabetes mellitus ECMO = extracorporeal membrane
oxygenation BOS = bronchiolitis obliterans syndrome

Abstract:\emph{Background:} The largest age group among children and
adolescents referred for lung transplantation for cystic fibrosis (CF)
have been those who in the pubertal or post pubertal age range. However,
over 100 younger patients with CF have undergone lung transplantation
over the last three decades in the USA.\emph{Methods} : We performed a
retrospective review of our experience with 18 children with CF who
underwent lung transplantation in our center before the age of 11 years.

\emph{Results} : Notable findings were a high prevalence of
methicillin-resistant \emph{Staphylococcus aureus} , a high prevalence
of diabetes mellitus and an impressive prevalence of consolidated lobar
or whole lung disease. Post-transplant outcomes, however, were
comparable to those older than 10 years of age in our center.

\emph{Conclusions} : In an era of increasingly effective medications
modifying the natural history of CF, identification of risk factors for
early severe lung disease in CF remains relevant and potentially more
important for effective intervention in order to extend life.

Advances in the care of individuals with cystic fibrosis (CF) have led
to a progressive improvement in median survival around the world in
developed countries.\textsuperscript{1-3} Death due to CF advanced lung
disease in childhood is becoming increasingly uncommon, especially in
the earliest decades of life. The factors contributing to this
phenomenon include the introduction of newborn screening for CF in many
countries,\textsuperscript{4,5} advances in nutritional
support\textsuperscript{6} and the institution of aggressive protocols
to prevent and treat pulmonary infections.\textsuperscript{7} An even
greater change in the trajectory of the natural history of cystic
fibrosis lung disease is expected from the most recent formulation of
cystic fibrosis transmembrane receptor (CFTR)
modulators.\textsuperscript{8} Consequently, lung transplantation for
children and adolescents with CF will likely become increasingly less
common in the coming years with the earliest trend recently noted (Table
). Nevertheless, we performed a retrospective review of our experience
in a large pediatric lung transplant center with children 10 years of
age or younger who underwent transplantation in our center since its
inception in 2002 to discern factors that appeared to predispose to
progression of lung disease to end-stage in the youngest CF patients.

{[}Insert Table at this point in the manuscript{]} MATERIALS AND
METHODS: A retrospective review of all patients undergoing primary lung
transplant in our center was performed identifying individuals with a
primary diagnosis of cystic fibrosis from 2002 through 2020. Clinical
data was collected and certain comparisons were made between the younger
cohort (10 years of age and younger) and the older cohort ([?]11 years).
Follow-up information on outcome after lung transplantation was also
obtained from the medical record and the cohorts were compared for
survival. For the comparison of survival after lung transplantation
between age cohorts, we used the Wilcoxon log-rank method of comparison
of survival times (SAS v9.4) in Figure 2. RESULTS: Since 2002, over 220
infants, children, adolescents and young adults have undergone lung
transplantation in our center through December 2020. Of the total, 122
patients (55\%) had underlying CF; 18 of these (14\%) were 10 years of
age or younger at transplant. Among the older cohort, five individuals
underwent liver-lung and one each heart-lung and one heart-liver-lung
transplant; none in the younger cohort had multiple organ transplants.
We did not exclude these individuals from our comparative analysis.
Eighteen children with CF aged 4.2 to 10.9 (median = 8.1) years of age
underwent primary bilateral lung transplantation in our center. Eight
were female and ten were male. Eleven were residents of Texas at the
time of referral, five were from other states and two were from outside
the United States, one from the United Arab Emirates and the other from
Pakistan. Seven had Hispanic ethnicity in at least one parent, one was
African American, nine were Caucasian, one Middle Eastern and one South
Asian in background. Of US citizens, all but four had public insurance
as primary healthcare insurance. Six of the children lived in single
parent households. Two others were in the primary care of their
grandparents due to cessation of parental involvement. Ten lived in two
parent households. Four of the US children had CF care in a satellite CF
Center where continuity of care was not clearly consistent. The two
children from outside the USA did not receive regular hospitalizations
for advanced lung disease.

Clinical characteristics reveal a morbid patient population. Four of the
patients were hospitalized for chronic respiratory failure at the time
of transplantation, all on non-invasive ventilation. Three others were
using non-invasive ventilation via bi-level positive pressure devices at
home at night only prior to transplantation. Four others were
out-patients on oxygen supplementation at the time of transplantation.
Microbiology among these patients included 10 (55\%) of 18 with
methicillin-resistant \emph{Staphylococcus aureus} (MRSA), six
with\emph{Pseudomonas aeruginosa} , three with \emph{Stenotrophomonas
maltophilia} , two with \emph{Achromobacter xylosoxidans} , two with
non-tuberculous mycobacteria (\emph{Mycobacterium avium-intracellure}and
\emph{Mycobacterium abscessus} ), two with significant fungal burdens
(one with Trichosporon species and the other with \emph{Geotrichum
capitatum)} and one each with \emph{Escherichia coli}
and\emph{Burkholderia multivorans.} Eight patients (44\%) had a
diagnosis of CF-related diabetes mellitus (CFRD) prior to transplant.
Nine patients (50\%) had lobar or whole lung consolidation prior to
transplantation and one of those had undergone lobectomy prior to
listing (Figures 1-3).

{[}insert Figures 1, 2 and 3 within or adjacent to the text{]} The
median BMI Z score at evaluation was 0 with a range of +2.05 to -3.96.
Four patients were well below the 1\%ile for height suggesting a history
of chronic malnutrition in earlier childhood. All patients had
gastrostomy tubes at the time of referral except the two international
patients who underwent surgical gastrostomy placement early after
referral due to severe malnutrition. All patients underwent bilateral
lung transplant and survived transplant hospitalization. Three died
within three years of the transplant surgery, one from acute graft
failure of unknown etiology one year after transplant complicated by a
cerebral vascular accident while on extracorporeal membrane oxygenation
(ECMO), two others had early onset chronic lung allograft dysfunction
which fit the criteria of bronchiolitis obliterans syndrome (BOS). Each
of these two children had proven or suspected non-adherence. Five other
patients died at 3.4, 4.5, 5.4, 8.9 and 14.4 years after transplant with
non-adherence noted in three of the five and all met criteria for BOS.
One of the patients with BOS developed post-transplant
lymphoproliferative disease that contributed to her death. Survival of
the cohort compared favorably to the older CF cohort (Figure 2).

DISCUSSION Lung transplantation for pediatric patients with cystic
fibrosis has been a major focus of pediatric lung transplant programs
with \textgreater{}50\% of the total transplant population often
representing CF.\textsuperscript{9} Although the numbers of such
patients are likely to decrease in the years to come (table 2), the CF
community should be informed of those clinical complications or factors
that may lead to more rapid progression of CF-associated lung disease.
In this paper, we present a retrospective cohort of pediatric patients
referred, evaluated and transplanted over the last 18 years. We have
noted common themes derived from this experience that we believe should
be noted in order to prevent progression or lead to early education and
later referral of these patients to transplant centers. We embrace the
concept of modifiable barriers to lung transplantation as recently
published.\textsuperscript{10}

Because respiratory failure associated with chronic infection is the
most common life-threatening complication of CF and a clear indication
for lung transplantation, the microbiology of CF lung disease is a
primary consideration for CF caregivers in terms of indication for
therapeutic intervention. With the exception of a high incidence of
MRSA, the bacteriology of this cohort of patients did not generally set
them apart from other patients within their own CF centers with a few
exceptions. One patient had \emph{Burkholderia multivorans} and two had
fungal pneumonias, both of which were challenging to treat.
Interestingly, the \emph{Pseudomonas aeruginosa} isolates in this cohort
were not multi-drug resistant despite the prevalence of such organisms
in our center.\textsuperscript{11} Of note, six of eight individuals
with major lung consolidation, which we will subsequently address, were
chronically infected with MRSA. Two patients had serious fungal
infections which have been described but are unusual in CF
patients\textsuperscript{12} -- one with transient \emph{Geotrichum
capitatum} infection and the other with chronic Trichosporon infection.
However, we conclude that there does not appear to be a clear or obvious
microbiologic signature that signals a poor prognosis for young CF
patients. It may be important to distinguish MRSA with small colony
variants as a more virulent and less treatable subset of MRSA and may
require a different antimicrobial strategy. An unexpected finding in our
cohort was the high prevalence of chronic lobar or lung consolidation
associated with volume loss. Lobar collapse has been described in the CF
literature for decades but has not been interpreted as a prelude to
advanced lung disease.\textsuperscript{13,14} Whole lung consolidation
has led in the past to pneumonectomy and single lung
transplantation.\textsuperscript{15} Our surgeons were able to perform
bilateral pneumonectomy with full size bilateral lung transplants in all
of our recipients. As noted above, six of the eight children with lobar
or lung collapse were chronically infected with MRSA. Staphylococcal
empyema was not seen in this subset of patients as a complication of
transplant surgery.

CFRD is unusual in pediatric CF patients prior to puberty. Prevalence in
children has been estimated at 2\% in the prepubertal age group and a
recent Canadian study suggested that there has been no increase in
incidence over time.\textsuperscript{16} Almost 50\% of our cohort had
CFRD requiring daily insulin therapy prior to transplant. It has been
known for years that CFRD is a risk factor for more rapid progression of
lung disease.\textsuperscript{17} Thus, early detection and treatment
for diabetes in the sickest of prepubertal CF patients may be indicated
and important in preventing relentless progression of advanced lung
disease. Frank nutritional deficiency with the exception of our
international patients was not common in our patients at the time of
referral with only two patients with BMI Z scores more than two standard
deviations below normal at initial evaluation. The median BMI Z score at
evaluation was, in fact, zero. Almost all patients were below the
50\%ile for height and four were well below the 1\%ile for height which
we interpreted as consistent with chronic undernourishment earlier in
life. Poor nutritional status affects overall exercise capacity and
immunity and has been clearly associated with worsened lung function in
CF patients.\textsuperscript{6,18}

Other investigators have delineated risk factors in children with CF for
severe lung disease. We will review our findings in this cohort in light
of selected previous publications. Recent experience suggests that MRSA
may be a greater risk for severe early lung
disease.\textsuperscript{19}McColley utilizing a large patient database
in a proximate era identified female gender, public health insurance,
minority ethnicity, chronic Pseudomonas infection, and low weight for
height status as risk factors for early mortality.\textsuperscript{20}
Aurora and colleagues in the UK suggested that resting tachycardia,
hypoalbuminemia and anemia in addition to low lung function and
hypoxemia at rest were predictive of CF mortality in
childhood.\textsuperscript{21} In a meta-analysis in 2016 by
VanDeventer, meconium ileus, early lung disease, radiographic evidence
of ``irreversible lung disease'' early in life and decreased access to
routine CF Center care were identified as factors predisposing to early
progression of lung disease.\textsuperscript{22}In consideration of
these findings from investigators who evaluated large populations of CF
children, we find notable consistencies and inconsistencies. In terms of
modifying clinical factors associated with progression in childhood lung
disease in CF, we believe that careful testing for respiratory
microbiology is prudent and aggressive treatment of early chronic
infection with particular attention to MRSA may be merited. Nutritional
intervention with oral nutritional supplements with early consideration
of gastrostomy tube has become the standard of care in many CF Centers
in the USA. All but one of our transplant recipients had a gastrostomy
tube which was used for supplemental nutrition. CFRD was surprisingly
common in our cohort but was only listed as a risk factor in one of the
studies referenced above. Although screening for CFRD is not recommended
until age 10 years at this time in the CF Foundation clinical
guidelines,\textsuperscript{23} we believe that patients with early
nutritional deficits and/or signs of early lung disease should be
screened for glucose intolerance and treated aggressively if CFRD is
detected. The advent of continuous glucose monitors and continuous
insulin pumps may be difficult to use in young children but our
experience suggests its consideration.

Early signs of focal lobar or unilateral pulmonary disease may or may
not be amenable to therapy. The largely anecdotal published literature
provides no definitive guidance. Aggressive antibiotic therapy and mucus
clearance therapies make logical sense. We are not inclined to recommend
early resection of lobes although we believe that there is anecdotal
evidence that such surgery may be beneficial in selected patients.
Nonetheless, we believe that our cohort suggests to the CF community for
the first time that this development should label such patients as high
risk for progression of disease to transplantation or mortality.
Publications on predictors of mortality in CF date back to the earliest
period of lung transplantation. Kerem and colleagues emphasized the
importance of lung function as a primary indicator of mortality in
1992.\textsuperscript{33} However, other than gender and age, Kerem did
not specify clinical characteristics of individuals with low lung
function.

Lastly, the evidence of the association of lower socioeconomic status
(SES) and early progression of lung disease has become convincing. CF
cuts across all classes of people. In a series of publications dating
back over 20 years, Schecter has documented this
association.\textsuperscript{24-26} Our cohort certainly provides
corroboration of this association. Virtually every CF center in the USA
accepts patients with public insurance so ``limited access to care'' is
not a cogent explanation. There are host of environmental and behavioral
factors that are more common in the homes of children with lower SES
including parental mental health disorders (treated and untreated), less
hygienic home environments including exposure to tobacco smoke,
difficulties in arranging transportation to access CF care and to
community pharmacies, less access to healthful foods, and limited
understanding of the importance of adherence to an often complex and
onerous home treatment program. It is imperative that CF caregiving
teams reach out to these families and discern -- without judgment -- how
barriers to effective CF care and treatment can be modified or
eliminated.

We would like to highlight one other particular finding in our study. In
terms of post-transplant survival, despite identified risk factors prior
to transplant which might predispose to lower survival, this cohort of
children has actually fared favorably compared to our older patients,
many of whom are transplanted in the throes of adolescence (Figure 2).
There is a well-documented literature in liver, kidney, and heart
transplantation of a notable decline in survival after transplant in the
adolescent age group.\textsuperscript{27,28} Non-adherence remains a
huge challenge for clinicians managing adolescents. With respect to lung
transplantation where allograft rejection is more common and more severe
than in other transplanted organs, the risk of death from sustained
non-adherence to immunosuppression is high. Perhaps, if CF patients
undergo lung transplantation in the preadolescent age period, they may
be more easily educated and trained, prior to puberty, to keep the
responsibilities of transplant care in perspective, especially during
the critical first two years after surgery when acute allograft
rejection is most common. CONCLUSIONS: We join the broad CF community in
hoping that advances in therapy and knowledge will continue to lead to a
progressive decline in the early onset of severe lung disease in
children with CF. We have presented our own experience in a limited
cohort of prepubertal CF patients over the last two decades and have
identified the factors that were associated with life-threatening
disease progression with the hope that in future patients, they might be
detected early as an opportunity for modification.

\emph{Acknowledgements} : The authors are indebted to the transplant
nurse coordinators who organized and documented clinical information for
all lung transplant recipients in our program. As well, we appreciate
the devotion of patients and their families to the rigors of this
experience and for the enormous trust they place in our caregiving team.
Lastly, we deeply appreciate the expertise and support of our transplant
surgeons, Drs. McKenzie, Morales and Heinle, during this era in our
program.

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