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Vox Sanguinis (2014)
ORIGINAL PAPER © 2014 International Society of Blood TransfusionDOI: 10.1111/vox.12215
Febrile non-haemolytic transfusion reaction occurrence andpotential risk factors among the U.S. elderly transfused inthe inpatient setting, as recorded in Medicare databasesduring 2011–2012M. Menis,1 R. A. Forshee,1 S. A. Anderson,1 S. McKean,2 R. Gondalia,2 R. Warnock,2 C. Johnson,2 P. D. Mintz,1
C. M. Worrall,3 J. A. Kelman3 & H. S. Izurieta11Food and Drug Administration, Silver Spring, MD, USA2Acumen LLC, Burlingame, CA, USA3Centers for Medicare & Medicaid Services, Baltimore, MD, USA
Received: 23 July 2014,revised 25 September 2014,accepted 30 September 2014
Background and Objectives Febrile non-haemolytic transfusion reaction (FNHTR)is an acute transfusion complication resulting in fever, chills and/or rigours.Study’s objective was to assess FNHTR occurrence and potential risk factorsamong inpatient U.S. elderly Medicare beneficiaries, ages 65 and older, during2011–2012.
Materials and Methods Our retrospective claims-based study utilized large Medi-care administrative databases. FNHTR was ascertained via ICD-9-CM diagnosiscode, and transfusions were identified by recorded procedure and revenue centrecodes. The study ascertained FNHTR rates among the inpatient elderly overalland by age, gender, race, blood components and units transfused. Multivariatelogistic regression analyses were used to assess potential risk factors.
Results Among 4 336 338 inpatient transfusion stays for elderly during 2011–2012, 2517 had FNHTR diagnosis recorded, an overall rate of 58�0 per 100 000stays. FNHTR rates (per 100 000 stays) varied by age, gender, number of units andblood components transfused. FNHTR rates were substantially higher for RBCs- andplatelets-containing transfusions as compared to plasma only. Significantly higherodds of FNHTR were identified with greater number of units transfused (P < 0�01),for females vs. males (OR = 1�15, 95% CI 1�04–1�27), and with 1-year histories oftransfusion (OR = 1�25, 95% CI 1�10–1�42), lymphoma (OR = 1�22, 95% CI 1�02–1�46), leukaemia (OR = 1�90, 95% CI 1�56–2�31) and other diseases.
Conclusions Our study shows increased FNHTR occurrence among elderly withgreater number of units and with RBCs- and platelets-containing transfusions,suggesting need to evaluate effectiveness of prestorage leucoreduction in elderly.The study also suggests importance of prior recipient alloimmunization andunderlying health conditions in the development of FNHTR.
Key words: administrative databases, elderly, febrile non-haemolytic transfusionreaction, inpatient, Medicare, potential risk factors.
Introduction
Febrile non-haemolytic transfusion reaction (FNHTR) is
one of the most frequently occurring acute transfusion
complications, which results in fever, chills, rigours,
Correspondence: Mikhail Menis, Office of Biostatistics and Epidemiology,Center for Biologics Evaluation and Research, FDA, 10903 NewHampshire Avenue, White Oak Building #71, Silver Spring, MD 20993-0002, USAE-mail: [email protected]
1
headache, nausea and/or vomiting [1–7]. The two known
mechanisms for FNHTR occurrence include an antileuco-
cyte antibody mediated mechanism and accumulation of
pro-inflammatory cytokines during storage of cellular
components. During the immune-based reaction, pre-
formed leucocyte antibodies in the recipients due to prior
alloimmunization (e.g. transfusion, pregnancy) interact
with leucocytes of transfused blood components resulting
in release of endogenous pyrogens (e.g. interleukins,
tumour necrosis factor) and consequently in FNHTR.
Additionally, the storage of cellular components, espe-
cially platelets, results in accumulation of pro-inflamma-
tory cytokines which may cause FNHTR [1, 2, 5, 6, 8–11].
Although FNHTR is non-life-threatening, it causes patient
discomfort and can potentially exacerbate underlying
health conditions as well as result in interruption of
needed transfusions [1, 5, 7]. Specifically, as fever associ-
ated with FNHTR may also be representative of serious
health conditions (e.g. sepsis, haemolytic transfusion
reactions), the life-saving transfusion(s) are likely to be
stopped until reaction investigation is completed [1, 5, 7].
To our knowledge, there have been no published popu-
lation-based studies assessing FNHTR occurrence and
potential risk factors among the inpatient U.S. elderly. As
published literature suggests a disproportionately high
blood utilization among the elderly and the importance
of prior alloimmunizations (e.g. transfusions, pregnancies)
in FNHTR occurrence, the elderly population may be at
an increased risk for FNHTR [1, 10, 12–16]. The Centers
for Medicare & Medicaid Services (CMS) administers
Medicare, a national health insurance that provides cov-
erage to virtually all U.S. elderly persons ages 65 and
older and maintains large administrative databases [17–
19]. The primary objective of our retrospective popula-
tion-based study was to assess FNHTR occurrence and
potential transfusion and recipient risk factors (e.g. blood
components, number of units transfused, demographics,
health conditions) among the inpatient U.S. elderly Medi-
care beneficiaries during 2011–2012, using large CMS
administrative databases.
Materials and methods
This retrospective claims-based study utilized large Medi-
care administrative databases in co-ordination with the
Centers for Medicare & Medicaid Services and under
CBER’s Safe Blood Program within the SafeRx Project.
The study utilized the 100% Inpatient and Medicare
Enrollment Common Working Files (CWF) for calendar
years 2011 and 2012. The Inpatient Files contain inpa-
tient hospital claims with medical services rendered and
include patient diagnoses and procedures. The Medicare
Enrollment Files contain demographic and enrolment
information, and help in ascertaining coverage eligibility.
Transfusions of blood and blood components [e.g. whole
blood, packed red blood cells (RBCs), platelets, plasma,
autologous blood] were identified by recorded Interna-
tional Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9-CM) procedure codes (99.00–99.05,
99.07) and revenue centre codes (0381–0384, 0390–0392,
0399), while FNHTR was ascertained via ICD-9-CM diag-
nosis code 780.66 titled ‘Febrile non hemolytic transfu-
sion reaction’ [20, 21]. Revenue centre units were used to
quantify blood use [21, 22]. Inpatient transfusion stays
for the elderly, defined as inpatient hospital stays with at
least one blood component transfused, and unique by
beneficiary and hospital admission date, were used as
study’s unit of analysis to assess FNHTR occurrence rates
and conduct multivariate regression analyses among the
U.S. elderly. During inpatient hospital stays, the diagnoses
are generally made and recorded into the medical records
by treating physicians and based on patients’ clinical pre-
sentations and laboratory values. Upon discharge, the
diagnoses are coded by medical coders for billing pur-
poses and captured in the large CMS databases. Inpatient
transfusion stays were grouped into ten mutually exclu-
sive blood component categories: RBCs only; Plasma
only; Platelets only; Plasma and Platelets; RBCs and
Plasma; RBCs and Platelets; RBCs, Plasma and Platelets;
Autologous Transfusion only; Non-specific Blood Compo-
nent (i.e. based on non-specific revenue centre codes
only); and Other Transfusion Combinations. Analyses
using blood quantities (i.e. blood units) transfused
excluded transfusion stays with either zero units or 200
units or more recorded, as these were likely due to either
blood quantity reporting or recording errors.
The study evaluated FNHTR rates (per 100 000 inpa-
tient transfusion stays) among elderly Medicare beneficia-
ries, overall and by age, gender, race, number of units
and blood components transfused. Univariate comparisons
of transfusion stays with FNHTR vs. without FNHTR were
conducted by demographic characteristics, admission
type, mechanical ventilation, inpatient mortality, length
of stay, the use of intensive care unit (ICU) and coronary
care unit (CCU). Multivariate logistic regression analyses
were used to assess the effect of potential transfusion
(e.g. blood components, number of units transfused) and
recipient (e.g. age, gender, race, Charlson Comorbidity
Index [23], health conditions) risk factors on FNHTR
occurrence, while controlling for potential confounders.
The final multivariate regression analyses retained char-
acteristics that are likely biologically and clinically
important for FNHTR occurrence and thus essential in
adjustment for the underlying FNHTR risk, including but
not limited to blood components, number of units trans-
fused, age, gender, race, Charlson Comorbidity Index
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
2 M. Menis et al.
Score (CCIS) [23] and underlying health conditions. As
transfusion recipient prior alloimmunization plays an
important role in the development of FNHTR, the regres-
sion analyses also adjusted for history of prior transfu-
sion(s). Health conditions and procedures were
ascertained within 1 year prior to inpatient admission (i.e.
1-year histories) to assure their presence before the stud-
ied outcome, while other potential risk factors (e.g. num-
ber of units, blood components) were assessed as recorded
during inpatient transfusion stay. The Elixhauser Comor-
bidities [24] were used to define health conditions when-
ever available. Charlson Comorbidity Index Score is a
comorbidity burden measure based on 17 underlying
health conditions, with a weighted score assigned to each
comorbid condition depending on the relative risk of 1-
year mortality [23, 25]. Both the Elixhauser Comorbidities
[24] and CCIS [23] were based on the enhanced ICD-9-
CM coding algorithm as described by Quan et al. [25].
The multivariate regression analyses were conducted
overall, by gender and age groups (65–79 vs. >79) to help
better assess their effects on FNHTR occurrence. The sen-
sitivity multivariate regression analyses included age and
CCIS as continuous variables to help quantify their effect
on FNHTR occurrence.
The univariate and multivariate analyses utilized SAS
9.2 (SAS Institute, Cary, NC, USA) to assess associations
between potential risk factors (e.g. blood components,
number of units transfused, recipient demographic char-
acteristics, CCIS [23], underlying health conditions) and
FNHTR occurrence. A priori level of significance was
P < 0�05. Specifically, the unadjusted relative risks (i.e.
rate ratios or RRs) and 95% confidence intervals (CI) were
estimated using SAS. Chi-squared tests were used to com-
pare proportions. Trend analyses of FNHTR occurrence by
age and units transfused were assessed using the Coch-
ran–Armitage statistic. Multivariate logistic regression
analyses were used to estimate adjusted odds ratios (ORs)
and 95% CIs for FNHTR occurrence among the elderly
Medicare beneficiaries with quantifiable number of blood
units recorded during transfusion stays, who were also
continuously enrolled in Medicare Parts A (inpatient
health coverage) and B (outpatient health coverage) and
not C (supplemental non-Fee-For-Service coverage) for at
least 1 year prior to their transfusion stays. The regres-
sion model fit and predictive ability were estimated using
the Hosmer–Lemeshow Goodness-of-Fit test and Area
Under the ROC Curve (AUC) [26, 27]. Multicollinearity
was evaluated using Variance Inflation Factors (VIFs) for
each model covariate. Firth’s method of penalized likeli-
hood was applied to multivariate regression analyses to
account for potential separability issues and help correct
for a possible small-sample bias in the multivariate
regression analyses [28, 29]. As part of sensitivity analy-
ses, multivariate regression splines were implemented in
STATA Version 11 (STATA Corp, College Station, TX,
USA) using software package by Royston et al. [30] to
ascertain potentially nonlinear associations between
FNHTR and continuous variables of blood units trans-
fused, age and CCIS, while controlling for other model
covariates. The continuous variables were categorized into
piecewise polynomial functions (i.e. splined functions),
and adjusted odds of FNHTRs and corresponding 95% CIs
were estimated for each of the continuous covariates.
Results
Among 4 336 338 inpatient transfusion stays for elderly
beneficiaries during 2011–2012, 2517 had FNHTR diagno-
sis code recorded, resulting in an overall rate of 58�0 per
100 000 stays. Table 1 compares unadjusted FNHTR rates
(per 100 000 transfusion stays) by blood component
groups, age, gender, race and number of units transfused.
When compared to plasma only stays, the unadjusted rate
comparisons show significantly increased risk of FNHTR
(P < 0�0001) with RBCs only (RR = 3�1, 95% CI 2�2–4�3),platelets only (RR = 2�6, 95% CI 1�6–4�3), RBCs and
plasma (RR = 2�7, 95% CI 1�8–3�9), RBCs and platelets
(RR = 8�9, 95% CI 6�2–12�8), and RBCs, plasma and plate-
lets (RR = 3�9, 95% CI 2�5–6�1). FNHTR rate was also
found to be significantly higher for females vs. males
(RR = 1�1, 95% CI 1�0–1�2). The unadjusted FNHTR rates
increased significantly with increasing number of units
transfused (P < 0�01), and oppositely, decreased with
advancing age (P < 0�01) (Table 1).
Table 2 shows comparison of transfusion stays with
FNHTR vs. without FNHTR by demographic and other
characteristics. Transfusion stays with FNHTR recorded
were significantly more likely to be female (P < 0�02) andyounger elderly ages 65–79 (P < 0�0001) and admitted on
urgent basis (P < 0�01). In contrast, stays with FNHTR
were significantly less likely (P < 0�0001) to be in the
ICU, 27�1% vs. 41�1%; in the CCU, 9�3% vs. 14�3%; as
well as to have continuous mechanical ventilation, 2�8%vs. 9�5%; and a length of stay of more than 10 days,
19�3% vs. 27�0%, as compared to stays without FNHTR.
Inpatient mortality was also significantly lower for
FNHTR stays vs. non-FNHTR stays, 2�6% vs. 6�9%, respec-
tively (Table 2).
Figure 1 shows the overall multivariate logistic regres-
sion analysis, which assesses potential risk factors for
FNHTR occurrence among inpatient elderly Medicare bene-
ficiaries during 2011–2012. When compared to plasma
only group, the adjusted overall regression results show
significantly elevated FNHTR odds ratios (P < 0�05) for
RBCs only (OR = 2�43, 95% CI 1�63–3�64), RBCs and
plasma (OR = 2�01, 95% CI 1�26–3�20), RBCs and platelets
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
FNHTR occurrence and risk factors in elderly 3
(OR = 3�18, 95% CI 2�04–4�97), RBCs, plasma and platelets
(OR = 2�31, 95% CI 1�31–4�06) and other transfusion com-
binations (OR = 2�51, 95% CI 1�27–4�96). Significantly ele-
vated odds of FNHTR were also identified for stays with 5–
9 units (OR = 1�36, 95% CI 1�15–1�61) and >9 units trans-
fused (OR = 1�39, 95% CI 1�13–1�71) as compared to 1 unit
transfused. In contrast, the results show significantly lower
odds of FNHTR with higher CCIS of 3 or more (P < 0�05).The overall regression analysis also shows significantly
higher odds of FNHTR for females vs. males (OR = 1�15,95% CI 1�04–1�27), as well as for inpatient transfusion
stays with 1-year histories of transfusion (OR = 1�25, 95%CI 1�10–1�42), lymphoma (OR = 1�22, 95% CI 1�02–1�46),leukaemia (OR = 1�90, 95% CI 1�56–2�31), metastatic can-
cer (OR = 1�23, 95% CI 1�04–1�45), blood loss anaemia
(OR = 1�34, 95% CI 1�15–1�56), aplastic anaemia and other
bone marrow failure (OR = 1�47, 95% CI 1�23–1�75), che-motherapy (OR = 1�36, 95% CI 1�13–1�64), and neoplasm
of uncertain behaviour of other lymphatic and hematopoi-
etic tissues (OR = 1�41, 95% CI 1�19–1�68) (Fig. 1)Multivariate regression analyses on FNHTR occurrence
by age (Fig. 2) and gender (Fig. 3) showed generally
Table 1 Comparison of unadjusted febrile non-haemolytic transfusion reaction (FNHTR) rates by blood components, units and demographic characteris-
tics among inpatient transfusion stays for elderly Medicare beneficiaries during 2011–2012
CategoryNumber oftransfusion stays
Number of stayswith FNHTR
FNHTR rate(per 100 000) RRa 95% CIb P-valuec
Overall 4 336 338 2517 58�0Blood Component Groupsd
Plasma only (Reference) 153 279 35 22�8 1�0RBC only 2 193 302 1546 70�5 3�1 2�2–4�3 <0�0001Platelets only 53 245 32 60�1 2�6 1�6–4�3 <0�0001Platelets and Plasma 10 383 4 38�5 1�7 0�6–4�8 0�32RBCs and Plasma 166 771 102 61�2 2�7 1�8–3�9 <0�0001RBCs and Platelets 98 928 201 203�2 8�9 6�2–12�8 <0�0001RBCs, Plasma, and Platelets 46 984 42 89�4 3�9 2�5–6�1 <0�0001Non-specific Blood Componente 1 539 643 525 34�1 1�5 1�1–2�1 <0�0001Autologous Transfusion Only 46 981 8 17�0 0�7 0�4–1�6 0�45Other Transfusion Combinations 26 822 22 82�0 3�6 2�1–6�1 <0�0001
Agef
65–69 (Reference) 799 836 502 62�8 1�070–74 835 434 524 62�7 1�0 0�9–1�1 0�9975–79 856 207 529 61�8 1�0 0�9–1�1 0�8080–84 833 696 475 57�0 0�9 0�8–1�0 0�13≥ 85 1 011 165 487 48�2 0�8 0�7–0�9 <0�0001
Sex
Male (Reference) 1 887 221 1038 55�0 1�0Female 2 449 117 1479 60�4 1�1 1�0–1�2 0�02
Race
Non-White (Reference) 739 783 429 58�0 1�0White 3 596 555 2088 58�1 1�0 0�9–1�1 0�98
Quantifiable Transfusionsg 3 982 634 2318 58�2Number of Units Transfusedf
1 (Reference) 742 201 323 43�5 1�02–4 2 326 874 1273 54�7 1�3 1�1–1�4 <0�00015–9 597 866 460 76�9 1�8 1�5–2�0 <0�0001>9 315 693 262 83�0 1�9 1�6–2�3 <0�0001
aUnadjusted relative risks (i.e. rate ratios) comparing FNHTR rates for a specific category vs. the reference category.b95% confidence intervals.cChi-Squared test to compare proportions.dBlood component groups are mutually exclusive.eThe non-specific blood component group is based on inpatient transfusion stays with recorded non-specific revenue centre codes only (0390, 0391,
0392, or 0399).fChi-Squared tests for FNHTR trend analyses: by age (P < 0�01) and by units transfused (P < 0�01).gQuantifiable transfusions group includes inpatient transfusion stays with nonzero units recorded of <200 units per stay.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
4 M. Menis et al.
similar results, with some exceptions as displayed. Specif-
ically, Fig. 2 shows elevated odds of FNHTR for platelets
only as compared to plasma only group in younger
elderly ages 65–79 (OR = 2�05, 95% CI 0�98–4�28), and in
contrast, non-elevated FNHTR odds in older elderly ages
80 and older (OR = 0�65, 95% CI 0�20–2�12). Figure 2
also shows a significant reduction in FNHTR odds with
CCIS of 5 and above in elderly ages 65 to 79 (OR = 0�71,95% CI 0�57–0�89) and a non-significant reduction
among older elderly (OR = 0�87, 95% CI 0�67–1�13). Fig-ure 3 shows significantly elevated odds of FNHTR for
platelets only group in females (OR = 2�92, 95% CI 1�37–6�21), and in contrast, reduced FNHTR odds in males
(OR = 0�42, 95% CI 0�13–1�37). Figure 3 also shows a sig-
nificant reduction in FNHTR odds among males with CCIS
of 2 (OR = 0�71, 95% CI 0�54–0�92), 3 to 4 (OR = 0�71,95% CI 0�55–0�91) and 5 and above (OR = 0�61, 95% CI
0�46–0�79), and not among females.
Figures 4–6, respectively, show plots of multivariate
regression splines with odds of FNHTR by age, number of
units and CCIS, treated as continuous variables, and while
controlling for other covariates in the final regression
models. Figure 4 shows a linear reduction in the odds of
FNHTR with advancing age. In contrast, Fig. 5 shows a
nonlinear increase in the odds of FNHTR with increasing
number of units transfused and a nonzero FNHTR risk
starting at one unit transfused. Figure 6 shows a linear
reduction in the odds of FNHTR with increasing CCIS.
Figure 7 shows the overall sensitivity multivariate regres-
sion analysis with age and CCIS treated as continuous
variables. The results show a 1% reduction in the odds of
FNHTR with each additional year of transfusion recipi-
ent’s age (OR = 0�99, 95% CI 0�99–1�00, P = 0�069)among elderly Medicare beneficiaries. Similarly, Fig. 7
shows a 4% reduction in the odds of FNHTR for each
additional unit-increase in CCIS (OR = 0�96, 95% CI
0�94–0�99, P < 0�05), thus further suggesting the impor-
tance of underlying health conditions in FNHTR occur-
rence.
Discussion
Our retrospective claims-based study is the first popula-
tion-based nationwide study that assessed FNHTR occur-
rence and potential risk factors among the inpatient
elderly Medicare beneficiaries. FNHTR occurrence among
elderly in the U.S. varied by age, gender, number of units
and blood components transfused as well as by different
other characteristics (e.g. health conditions). Overall, our
population-based study showed a substantially elevated
FNHTR risk for stays with RBCs- and platelets-containing
transfusions. The study also showed an increased FNHTR
risk with greater number of units transfused, especially
with five or more units, for females vs. males, and for
elderly with histories of transfusion, chemotherapy, lym-
phoma, leukaemia and other health conditions (e.g.
malignancies, anaemias). In contrast, our study among
the U.S. elderly suggests a decline in FNHTR occurrence
with advancing age and with increasing CCIS as well as
suggests the lowest FNHTR risk for plasma only and
autologous only transfusions, which need further investi-
gations.
Table 2 Comparison of transfusion stays with febrile non-haemolytic
transfusion reaction (FNHTR) vs. without FNHTR by demographic and
other characteristics among inpatient elderly Medicare beneficiaries dur-
ing 2011–2012
Characteristics
FNHTRN = 2517(%)
No FNHTRN = 4 333 821(%)
UnadjustedORa P-valueb
Sex
Male 41�2 43�5 0�9 0�02Female 58�8 56�5 1�1 0�02
Race
White 83�0 82�9 1�0 0�98Non-White 17�0 17�1 1�0 0�98
Age (years)
65–79 61�8 57�5 1�2 <0�0001>79 38�2 42�5 0�8 <0�0001
Admission typec
Emergency 55�2 56�9 0�9 0�08Urgent 19�6 17�2 1�2 <0�01Elective 24�4 24�8 1�0 0�66
Continuous mechanical ventilation
Overalld 2�8 9�5 0�3 <0�0001<96 h 1�5 5�0 0�3 <0�0001≥96 h 1�4 4�8 0�3 <0�0001
Intensive care unit (ICU)
Yes 27�1 41�1 0�5 <0�0001Coronary care unit (CCU)
Yes 9�3 14�3 0�6 <0�0001Length of stay (days)
1–2 5�5 4�9 1�1 0�183–4 24�9 21�7 1�2 <0�00015–6 25�4 21�6 1�2 <0�00017–10 24�9 24�7 1�0 0�88> 10 19�3 27�0 0�6 <0�0001
Inpatient mortality
Yes 2�6 6�9 0�4 <0�0001
aUnadjusted Odds Ratios comparing the presence of specific characteris-
tics for stays with FNHTR vs. no FNHTR.bChi-Squared test to compare proportions; a priori level of significance is
P<0�05.cThis category may not add up to 100%.dOverall group includes continuous mechanical ventilation of <96 h,
≥96 h, and of unknown duration, which can be recorded within the same
transfusion stay.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
FNHTR occurrence and risk factors in elderly 5
Although currently available literature on FNHTR
occurrence is based on non-population-based studies (e.g.
single-centre studies) and the incidence of FNHTR occur-
rence among the elderly is unknown, the available litera-
ture generally supports our study’s findings of increased
FNHTR risk with RBCs- and platelets-containing transfu-
sions, greater number of units, among persons with prior
alloimmunization (e.g. transfusions, pregnancies), as well
as the importance of underlying health conditions (e.g.
malignancies) [1, 10–12, 31, 32]. Specifically, our study
shows an increased risk of FNHTR with 1-year histories
of blood transfusions, in females as compared to males,
as well as in persons with histories of different oncologi-
cal conditions and chemotherapy. The study’s findings of
significantly elevated odds of FNHTR with RBCs- and
platelets-containing transfusions, greater number of units
and prior alloimmunization suggest the need for further
clinical investigations of prestorage leucoreduction of cel-
lular components as a potential FNHTR prevention strat-
egy among the elderly, which is generally supported by
the literature [32–37]. Additionally, the study’s findings
of decreased FNHTR risk among elderly with advancing
age, with higher CCIS, and with histories of specific
chronic comorbidities (e.g. congestive heart failure, car-
diac arrhythmias, hypertension), suggest potential impor-
tance of underlying immunity among the elderly for
FNHTR occurrence, which needs further clinical evalua-
tions. In support of the literature, our study also suggests
FNHTR to be one of the most frequent transfusion-related
adverse events among the elderly [1, 3–5, 38–41]. As
Fig. 1 The overall multivariate regression analysis to assess potential risk factors for febrile non-haemolytic transfusion reaction occurrence among inpa-
tient elderly during 2011–2012, while controlling for potential confounders.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
6 M. Menis et al.
such, physicians should be aware of FNHTR occurrence
among the elderly, which results in patient discomfort
and therapeutic intervention. FNHTR could also poten-
tially exacerbate underlying comorbidities or suggest
occurrence of serious transfusion-related events (e.g. sep-
sis, haemolytic transfusion reaction), and therefore delay
needed transfusions in the elderly and result in costly
transfusion reaction investigations and potentially in poor
patient outcomes (e.g. morbidity, mortality).
Our large population-based retrospective study to
assess FNHTR occurrence and potential risk factors among
the U.S. elderly used administrative claims databases and
thus limitations include potential under- or misrecording
of transfusion procedures, units and FNHTR diagnosis
code, as well as lack of clinical details to validate the
recorded FNHTR diagnosis. As diagnosis of FNHTR is typ-
ically of exclusion of other transfusion-related events that
may result in fever (e.g. bacterial contamination, haemo-
lytic transfusion reaction, TRALI), under- or misdiagnos-
ing is possible. For example, mild septic reactions or
other transfusion reactions that result in fever may
potentially be misclassified as FNHTR. Additionally, tem-
porality could not be established between all potential
risk factors and FNHTR, and as such additional clinical
investigations are needed to confirm our findings. As the
study was based on claims data, it was not able to evalu-
ate contribution of cellular component storage to the
occurrence of FNHTR among the elderly, potential donor
risk factors (e.g. presence of antileucocyte antibodies,
demographic characteristics), as well as lacked clinical
information to confirm FNHTR diagnosis and could not
evaluate effectiveness of prestorage leucoreduction
among the inpatient elderly. Furthermore, some of the
resulting FNHTR rates may be unstable because of very
small number of events recorded, particularly in associa-
tion with specific blood components, and as such may
result in non-significant associations. As rare events may
bias logistic regression results, especially when adjusting
for multiple confounders, our study used Firth’s method
of penalized likelihood to help correct for potential
small-sample bias [28, 29]. Finally, as our study is the
first population-based study on FNHTR occurrence
Fig. 2 Multivariate regression analyses to assess potential risk factors for febrile non-haemolytic transfusion reaction occurrence among inpatient elderly
ages 65–79 vs. 80 and older, during 2011–2012.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
FNHTR occurrence and risk factors in elderly 7
among the elderly, some of the results may be hypothe-
sis-generating. Therefore, additional clinical and epidemi-
ological investigations are needed to better understand
potential underlying recipient, transfusion and donor risk
factors for FNHTR occurrence as well as their clinical
significance.
Fig. 3 Multivariate regression analyses to assess potential risk factors for febrile non-haemolytic transfusion reaction occurrence among inpatient elderly
by gender, during 2011–2012.
Fig. 4 The overall adjusted odds of febrile non-haemolytic transfusion
reaction (FNHTR) by age, while controlling for covariates in the final
regression model, among elderly Medicare beneficiaries during 2011–
2012.
Fig. 5 The overall adjusted odds of febrile non-haemolytic transfusion
reaction (FNHTR) by number of units transfused, while controlling for co-
variates in the final regression model, among elderly Medicare beneficia-
ries during 2011–2012.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
8 M. Menis et al.
In summary, our retrospective claims-based cohort
study is the first population-based study that assessed
FNHTR occurrence and potential risk factors among the
inpatient U.S. elderly. The study showed a statistically
significant increase in FNHTR occurrence for stays with
RBCs- and platelets-containing transfusions, with five or
more units transfused, as well as for females vs. males,
and in the elderly with histories of transfusions, malig-
nancies and anaemias. As supported by the literature
[32–37] and by the Canadian experience with universal
leucoreduction [42, 43], there may be a need for further
investigations and consideration of universal prestorage
leucoreduction of cellular components for FNHTR
prevention in the elderly, and especially for persons with
potential prior alloimmunizations (e.g. pregnancies, trans-
fusions) who are likely to be at a higher risk for FNHTR
occurrence. The study also suggests potential importance
of underlying immunity among the elderly for FNHTR
occurrence, which needs further clinical evaluations. As
FNHTR is one of the most frequently occurring transfu-
sion-related complications which may delay life-saving
Fig. 6 The overall adjusted odds of febrile non-haemolytic transfusion
reaction (FNHTR) by Charlson Comorbidity Index Score, while controlling
for covariates in the final regression model, among elderly Medicare ben-
eficiaries during 2011–2012.
Fig. 7 The overall sensitivity multivariate regression analysis with age and Charlson Comorbidity Index Score treated as continuous variables to assess
their effects on febrile non-haemolytic transfusion reaction occurrence among inpatient elderly during 2011–2012.
© 2014 International Society of Blood TransfusionVox Sanguinis (2014)
FNHTR occurrence and risk factors in elderly 9
transfusions, our study suggests the importance of physi-
cian awareness of FNHTR occurrence, potential risk fac-
tors and specific prevention strategies among the elderly.
Finally, the study shows utility of large administrative
databases as an additional epidemiological tool in assess-
ment of FNHTR occurrence and potential risk factors and
thus will serve to help reduce the occurrence of FNHTR
and improve public health.
Acknowledgements
All authors made substantial contributions to research
design, or the acquisition, analysis or interpretation of
data and were involved in drafting of the paper or revis-
ing it critically. The manuscript has been approved by all
authors. Authors thank Renata Moldavskaya for her con-
tribution in editing manuscript drafts.
Funding
This study was funded by the U.S. Food and Drug Admin-
istration, Center for Biologics Evaluation and Research.
Conflict of interest
The authors declare that they have no conflict of interests
relevant to the manuscript submitted to Vox Sanguinis.
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