ICU Hospitalization
Intensive care hospitalization in the first 100 days was necessary for
75 (22%) patients, with a median of 29 days (IQR 11-54) between HSCT
and ICU hospitalization. For allogeneic HSCT patients, there was a 1.65
(95% CI 1.15-2.35; p=0.006) fold increased risk of ICU hospitalization
for every doubling of pre-HSCT glucose CV. There was no association
among autologous HSCT patients. Because 53% of patients requiring ICU
hospitalization did so before day 30, associations between day 0-30
variability and time-to-ICU could not be evaluated.
Discussion
This retrospective cohort study demonstrates that GV is common in
pediatric patients undergoing HSCT, and that it is associated with
increased risk of infection and critical illness. These associations are
consistent with research describing malglycemia as a whole, both in
adult and pediatric HSCT patients.1-3 Associations
between GV and mortality were less clear.
Roughly one third of patients both pre- and post-HSCT had glucose CVs
that were in the range of adults who are either obese or have diabetes,
with a striking 8-10% of pediatric patients having glucose CVs above
the proposed cutoff for poor control in patients with type 1
diabetes.5 This suggests that the physiologic stress
or iatrogenic exposures prior to and during HSCT, such as pre-HSCT
asparaginase, radiation and preparative chemotherapy, or post-HSCT
intravenous fluids, TPN, immunosuppressive agents, and steroids, appears
to lead to abnormal insulin secretion or sensitivity, resulting in
pediatric HSCT patients experiencing a pathologic level of GV.
In the pre-HSCT period, non-malignant diagnosis and prior treatment with
asparaginase were associated with increased glucose CV. Asparaginase has
known associations with pancreatitis and hyperglycemia, so this finding
is not surprising.11-13 However, the reason for an
association between non-malignant HSCT indications and higher glucose CV
is unclear, as no patients in this group had disorders with known
associations with glucose intolerance, and no patients had existing
diabetes mellitus.14 It is possible that patients with
malignant underlying diagnoses were more tolerant of the stress
associated with HSCT preparation due to their prior treatment with
chemotherapy, while for nonmalignant HSCT patients, HSCT preparation may
have been more disruptive. While our prior research evaluating risk
factors for pre-HSCT malglycemia identified underlying malignant
diagnosis and adolescent age as risk factors, these were not associated
with pre-HSCT glucose CV; thus, these findings were likely driven by
hyperglycemia and not variability.3 Additionally,
several other hypothesized risk factors, such as being overweight/obese,
having prior steroid exposure, or having prior insulin needs, were not
significant risk factors for increased pre-HSCT glucose CV. This may
suggest that stress and exposures associated with HSCT result in these
patients having similar glucose tolerance to an obese adult, regardless
of BMI. The number of obese/overweight patients was small, so further
studies to confirm this relationship are needed.
Consistent with prior literature on malglycemia or hyperglycemia,
post-HSCT glucose CV was increased for patients who underwent allogeneic
HSCT or who were treated with post-HSCT steroids or
TPN.1,3,15-19 Prior insulin needs and any pre-HSCT
radiation to the pancreas were associated with post-HSCT but not
pre-HSCT increased glucose CV, suggesting that either the
stress/exposures of undergoing a conditioning regimen levels out these
factors pre-HSCT, or that post-HSCT, patients are more sensitive to
their prior exposures.
The high prevalence of elevated glucose CV in this study, and risk
factors for it, are notable because increased glucose CV was associated
with adverse HSCT outcomes. Specifically, there was nearly a 5-fold
increased risk of infection with doubling of pre-HSCT glucose CV, after
adjusting for HSCT type. As can be visualized in Figure 1, median
glucose CVs spanned a wide range, so differences in glucose CV of this
magnitude (for example from 15% to 30%) are not an uncommon
occurrence. Fortunately, there was not a similar association for
patients who underwent autologous HSCT, which may be related to lower
risk of early death.
While glucose CV was associated with viremia among allogeneic HSCT
patients, our analysis did not demonstrate significant associations with
SBI or fungal infection. This could be due to the confounding factor of
the potential for multiple infections of different subtypes and
inability to explore time-to-infection subtype, or due to the low number
of fungal infections in our cohort. While potential underlying
pathophysiology is detailed more below, future studies are needed to
explore the mechanisms underlying the association between GV and
viremia, including an evaluation of additional factors such as
conditioning regimens (e.g. T-cell depletion), and lymphocyte function
and microenvironment. As may be expected given the associations between
GV and risk of infection, there was also an association between glucose
CV and ICU hospitalization, but only among allogeneic HSCT patients.
While we did not evaluate for an association between GV and relapse
based on lack of association between malglycemia and relapse in our
prior study, future studies may evaluate this specifically, and should
also consider the association between GV and rarer events, such as graft
failure, sinusoidal obstructive syndrome, and thrombotic
microangiopathy. This study was not able to evaluate the latter two of
these events not only because of anticipated low numbers of events, but
because diagnosis and treatment of these events changed drastically over
the course of this observation period. Of note, in addition to adjusting
for treatment with steroids, HSCT type and other potential confounders
when able, for all analyses, glucose values after the time of the event
were censored. By doing so, any GV preceded the associated event.
demonstrating temporality, which is critical in considering potential
causation.
While the underlying pathophysiology of the association between
hyperglycemia and adverse outcomes is more clearly hypothesized to be
related to known immunologic effects such as increased inflammation and
impaired leukocyte function, the possible pathophysiologic relationship
between GV and outcomes is less well
described.1,15,20-23 However, several studies have
demonstrated associations between wide glucose fluctuations and both
oxidative stress and endothelial cell apoptosis, which may lead to
microvascular damage, inflammatory milieu, and disruption of normal
immune function.24-26. In addition to these potential
mechanisms, hyperglycemia is known to 1) impair neutrophil activity
including chemotaxis, formation of reactive oxygen species, and
phagocytosis; 2) impair lymphocytes by increasing apoptosis, suppressing
proliferation and attenuating antibody production and function; and 3)
increase pro-inflammatory state cytokines such as IL-6 and
TNF-α.1,15,20,21,27-29 These changes, if true of
variability as well, may explain the association between GV and viral
infections, particularly through lymphocyte dysfunction. Further, if GV
potentiates post-HSCT inflammatory milieu, increased risk for HSCT
complications, more generally, may be expected.
Understanding the degree and mechanism by which GV contributes to HSCT
complications and, potentially, mortality, and how these might be
modifiable with improved glycemic control, is critical. If these are
strengthened with future prospective studies, patients may benefit from
supportive care interventions (e.g. enteral feeding instead of TPN,
selection of immunosuppressive agents, insulin therapy) aimed at
reducing GV. It is important to note, that multiple pediatric and adult
studies evaluating the benefit of improved glucose control in non-HSCT
patients in the intensive care setting were disappointing, often due to
high risk of hypoglycemia.30-34 However, diabetes
technology has progressed since these studies, and safe, intensive
glucose control is increasingly feasible. Further, HSCT patients, who
are likely to be at risk for longer than typical ICU patients, may find
more benefit.
Even if there is no causal link, GV may serve as a useful biomarker for
risk of post-HSCT complications such as infection or critical illness;
predicting abnormal glucose control based on pre-HSCT characteristics
may be useful for tools such as the pre-transplant comorbidity
prognostic index.35 However, prior to assessing the
utility of adjusting such tools or performing glucose interventions in
patients, additional prospective work is needed.
This study has several limitations that must be considered when
discussing implications and future studies. As with any retrospective
study, causality cannot be determined. Prospective studies are necessary
to confirm our results, as well as re-evaluate for associations between
GV and mortality. Further, outcomes such as invasive fungal infection
and GVHD relied on correct international classification of diseases
(ICD) diagnostic coding and manual review and therefore have potential
for misclassification bias. While this is unlikely to bias the data as
classification challenges would be true across all patients, it may have
resulted in decreased statistical power due to underreporting. Most
limiting was our previously mentioned inability to evaluate for
associations between post-HSCT GV and outcomes that tended to occur
early in the post-HSCT period, such as infection and ICU
hospitalization. As such, it is possible that this study missed a true
underlying association between post-HSCT GV and increased infection or
ICU stays. Additionally, while this study aims to highlight correlations
between GV and adverse events, any biological causes are hypothetical
and require prospective human and animal model-based studies. To this
end, future work will use continuous glucose monitoring to prospectively
describe GV, its risk factors, and associated outcomes. While this study
demonstrated relationships between stress GV immediately preceding and
following HSCT and outcomes; future work should evaluate whether GV that
predates HSCT-related stress is also associated with adverse outcomes.
In summary, GV is a common occurrence in the pediatric HSCT population
and is associated with increased risk of infection and critical illness
in HSCT patients. Because GV is subtle and may be more easily overlooked
than hyperglycemia or hypoglycemia by care teams, special attention to
understanding its incidence, risk factors, and implications, is
necessary.
Conflicts of Interest
G.P.F. has served as a consultant for Abbott Diabetes Care, an advisory
board member for Dexcom, and conducts research sponsored by Medtronic,
Dexcom, Bigfoot, Tandem, Insulet, and NovoNordisk. MRV has served as a
consultant for Fate Therapeutics and B-mogen. All other authors declare
no competing financial interests.
Acknowledgements
This work was supported by the National Institutes of Health (grant
NIDDK 2K12DK094712-06). Contents are the authors’ sole responsibility
and do not necessarily represent official NIH views.
Data Sharing
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Correspondence: Jenna Sopfe, Center for Cancer and Blood Disorders,
Department of Pediatrics, University of Colorado School of Medicine,
13123 E. 16th Ave, B115, Aurora, Colorado, 80045;
email: jenna.sopfe@cuanschutz.edu