Youngest Cystic Fibrosis Lung Transplant Recipients:
Predisposing Factors for End-stage Disease
Melicoff, Ernestina, MD1, Ruiz, Fadel E,
MD1, Hosek, Kathleen, MA2, Mallory,
George B, MD1
Section of Pediatric Pulmonology, Department of Pediatrics, Baylor
College of Medicine and Texas Children’s Hospital
Department of Quality Assurance, Texas Children’s Hospital
Corresponding author : George B. Mallory, Jr., M.D.
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 Staphylococcus aureus CFRD = cystic fibrosis related diabetes mellitus
ECMO = extracorporeal membrane oxygenation
BOS = bronchiolitis obliterans syndrome
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.
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.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,4,5 advances in nutritional
support6 and the institution of aggressive protocols
to prevent and treat pulmonary infections.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.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 Staphylococcus aureus (MRSA), six withPseudomonas aeruginosa , three with Stenotrophomonas
maltophilia , two with Achromobacter xylosoxidans , two with
non-tuberculous mycobacteria (Mycobacterium avium-intracellureand Mycobacterium abscessus ), two with significant fungal burdens
(one with Trichosporon species and the other with Geotrichum
capitatum) and one each with Escherichia coli andBurkholderia 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
>50% of the total transplant population often representing
CF.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.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 Burkholderia multivorans and two had
fungal pneumonias, both of which were challenging to treat.
Interestingly, the Pseudomonas aeruginosa isolates in this cohort
were not multi-drug resistant despite the prevalence of such organisms
in our center.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
patients12 – one with transient 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.13,14 Whole lung consolidation has led in the
past to pneumonectomy and single lung
transplantation.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.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.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.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.19McColley 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.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.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.22In 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,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
1992.33 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.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.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.
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.