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Research Article

Eosinophilia in routine blood samples and the subsequent risk of

hematological malignancies and death
Christen Lykkegaard Andersen,1,2* Volkert Dirk Siersma,2 Hans Carl Hasselbalch,1 Hanne Lindegaard,3
Hanne Vestergaard,4 Peter Felding,5 Niels de Fine Olivarius,2 and Ole Weis Bjerrum6
Eosinophilia may represent an early paraclinical sign of hematological malignant disease, but no reports
exist on its predictive value for hematological malignancies. From the Copenhagen Primary Care Differen-
tial Count (CopDiff) Database, we identified 356,196 individuals with at least one differential cell count
(DIFF) encompassing the eosinophil count during 2000–2007. From these, one DIFF was randomly chosen
and categorized according to no (<0.5 3 109/L), mild (0.5–1.0 3 109/L) or severe (1.0 3 109/L) eosino-
philia. From the Danish Cancer Registry and the Danish Civil Registration System, we ascertained hemato-
logical malignancies and death within 3 years following the DIFF. Using multivariable logistic regression
odds ratios (ORs) were calculated and adjusted for previous eosinophilia in a DIFF, sex, age, year, month,
C-reactive protein, previous cancer, and comorbidity. ORs for developing Hodgkin’s lymphoma (HL) was
significantly increased in individuals exhibiting severe eosinophilia, OR 5 9.09 (C.I. 2.77–29.84), P 5 0.0003.
The association with classical myeloproliferative neoplasms (cMPNs) showed an increasing risk with
OR 5 1.65 (1.04–2.61) P 5 0.0322 and OR 5 3.87 (1.67–8.96) P 5 0.0016 for mild and severe eosinophilia.
Eosinophilia was in a similar fashion associated with chronic lymphatic leukemia (CLL), OR 5 2.57 (1.50–
4.43), P 5 0.0006 and OR 5 5.00 (1.57–15.94), P 5 0.0065, and all-cause death, OR of 1.16 (1.09–1.24),
P < 0.0001 and 1.60 (1.35–1.91), P < 0.0001. We confirm associations between eosinophilia and HL and
cMPNs, and in addition for the first time demonstrate a dose-dependent association between eosinophilia
and CLL as well as death. Unexplained eosinophilia should prompt clinicians to consider conditions where
early diagnosis may improve prognosis. Am. J. Hematol. 88:843–847, 2013. V C 2013 Wiley Periodicals, Inc.

Introduction eosinophils are present to a varying extent and are part of

Human eosinophilic granulocytes (eosinophils) originate the clonal disease [12], in particular polycythemia vera [13]
from multipotent hematopoietic stem cells, circulate in the and chronic myeloid leukemia [14]. The 2008 WHO classifi-
blood stream, and constitute less than 5% of the total white cation defines clonal disorders with eosinophilia according
blood cell count in healthy individuals [1]. The eosinophil is to their platelet-derived growth factor receptor (PDGFR)
a multifunctional cell, which can store and secrete biologi- alpha—and PDGFR beta abnormalities [4,12]. Hence,
cally active substances relevant for its effects in infections, blood eosinophilia may in some cases represent an early
allergy, and inflammation [2,3]. An increased number of paraclinical sign of hematological malignant disease, but no
eosinophils in peripheral blood (eosinophilia, >0.5 3 109/L) reports exist on the predictive value of eosinophilia for hem-
may accompany various conditions like invasive parasitic atological malignancies. Such a study may prove helpful for
disease, asthma, drug reactions, connective tissue dis- physicians to interpret eosinophilia and aid them to make
eases, or malignancies. Under these circumstances, the early diagnosis and targeted treatment of underlying
eosinophilia is termed secondary or reactive. Rare cases of morbidities.
eosinophilia are classified as primary or non-reactive and The aim of this study was, therefore, to investigate eosin-
arise from an autonomous cell production, caused by clonal ophilia in routine blood samples as a potential risk marker
disorders of lymphoid or myeloid origin. A residual small for the development of hematological malignant disease
group of patients are termed idiopathic because the sus-
1
pected clonal origin is missing [3–5]. Irrespective of the Department of Hematology, Roskilde University Hospital, Denmark; 2The
Research Unit for General Practice and Section of General Practice,
cause of eosinophilia, activation of eosinophils may cause Department of Public Health, University of Copenhagen, Denmark; 3Depart-
a diverse organ involvement [3,5,6]. Thus, blood eosino- ment of Rheumatology, Odense University Hospital, Denmark; 4Department
philia may arise from intrinsic eosinophilic disorders caused of Hematology, Odense University Hospital, Denmark; 5Copenhagen
by cytogenetic mechanisms or extrinsic eosinophilic reac- General Practitioners’ Laboratory, Copenhagen, Denmark; 6Department of
Hematology, Copenhagen University Hospital, Denmark
tions caused by cytokines [3–5,7,8]. Hodgkin’s lymphoma
(HL) is a classic example of a hematologic, extrinsic disor- Conflict of interest: The study has received no financial support or other
benefits from commercial sources and no authors have any financial inter-
der accompanied by blood eosinophilia in about 15% of ests, which could create potential conflicts of interest
cases. This observation appears to be associated with a
survival advantage in patients with mixed cellularity and *Correspondence to: Christen Lykkegaard Andersen MD, Dept. of Hematol-
ogy, Roskilde Hospital, Koegevej 7, 4000 Roskilde, Denmark.
nodular sclerosis histology in some [9], but not all studies E-mail: [email protected]
[10]. Eosinophilia in non-HL (NHL) is primarily confined to
Grant sponsor: Eva & Henry Frænkels’ Memorial Foundation and Axel
T-cell disorders, and may in these cases contribute to the Muusfeldts Memorial Foundation.
clinical presentation as a reactive, non-clonal phenomenon Received for publication 8 April 2013; Revised 31 May 2013; Accepted 4
[4,11]. In some rare lymphoproliferative disorders associ- June 2013
ated with Fibroblast growth factor receptor 1 abnormalities, Am. J. Hematol. 88:843–847, 2013.
the eosinophilia may be part of the clone [4] and in both Published online 13 June 2013 in Wiley Online Library
Philadelphia (Ph)-positive and Ph-negative, classical myelo- (wileyonlinelibrary.com).
proliferative disorders (cMPNs), an increased number of DOI: 10.1002/ajh.23515

C 2013 Wiley Periodicals, Inc.

V
American Journal of Hematology 843 http://wileyonlinelibrary.com/cgi-bin/jhome/35105
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research article
TABLE I. Patient Characteristics

Baseline patient characteristics

Gender
Male 180,578 (50.2)
Female 179,372 (49.8)
Age (years) 48.3 6 16.7
Eosinophilia
No (<0.5 3 109/L) 341,790 (96.0)
Mild (0.5–1.0 3 109/L) 13,118 (3.7)
Severe (1.0 3 109/L) 1,288 (0.3)
Previous eosinophilia (<6 months)
Only negative tests 30,104 (8.4)
At least one positive test 2,371 (0.7)
No blood test 327,475 (91.0)
Charlson’s Comorbidity Index [1] 0.22 6 0.77
C-reactive protein
Normal 181,162 (50.4)
Increased [2] 48,349 (13.5)
No blood test 129,755 (36.1)

Values are numbers (column-%) or means (SD). [1] Calculated on previous

hospital contacts (<3 years), [2] >10 mg/L

cal procedures performed [17]. To adjust for possible confounding by

comorbid conditions, we computed Charlson’s comorbidity Index (CCI)
[18] from the hospital contacts recorded in the NPR within 3 years
before the index DIFF.
Outcomes were 3-year all-cause mortality (taken from the CRS) and
incidence of hematological malignancies as defined by the International
Classification of Diseases (ICD) version 10 over the 3-year period fol-
lowing the DIFF: HL, NHL, and other malignant immunoproliferative
diseases (C81, C82-C85; C883-C889, and ICD for Oncology (ICD-O)
morphological codes within the range: 9590/3/6/9 - 9729/3/6/9), multi-
ple myeloma (C90; C880-C882), acute lymphatic leukemia (C910;
C918), chronic lymphatic leukemia [(CLL) C911; C913-C914; C916-
C917; C919], acute myelogenous leukemia (C920; C923-C926; C928;
C930; C940; C942-C944), cMPNs (D45; D473-D474; D46; D470-D471;
D475; C921; C931), and monocytic leukemia (C93).
Figure 1. Flowchart. CGPL, Copenhagen General Practitioners’ Laboratory;
CopDiff, Copenhagen Primary Care Differential Count Database; CRS, The Dan-
Statistical analysis
ish Civil Registration System; DIFF, differential count; GP, general practitioner. We used multivariable logistic regression to compute odds ratios
(ORs) with 95% confidence intervals (CIs) for the 3-year incidence of
hematological malignancies and all-cause death following the index
DIFF. The ORs were adjusted for sex, age (quadratic), year, month,
and death using a comprehensive primary care cohort in a CCI, CRP, and previous eosinophilia. Individuals with previous cancer
prospective design. (n 5 1.234) were omitted from the analyses. To account for multiple
statistical testing, P-values less than 0.0271 were regarded to be sig-
nificant as this controls the false discovery rate at 5% using the method
Methods of Benjamini-Hochberg [19]. All analyses and calculations were per-
The Copenhagen General Practitioners’ Laboratory (CGPL) is the formed with SAS version 9.2 (SAS Institute Inc., Cary, NC).
laboratory for all general practitioners in the Copenhagen area covering
approximately 1.1 million inhabitants. CGPL has International Organi-
zation for Standardization (ISO) accreditation and has registered all Results
analytical results since 1. 5. 2000. The Copenhagen Primary Care Dif- In the total cohort of 356,196 individuals from a primary
ferential Count (CopDiff) Database contains results from all differential care setting there was a balanced sex-distribution and a
cell counts (DIFF) requested by general practitioners in Copenhagen mean age of 48.3 years (Table I). 14,406 individuals (4%)
from 1.5.2000 to 25.1.2010. From each of the 359,950 unique individu- exhibited eosinophilia and 1,234 (0.3%) had experienced a
als (aged 18–80 years) with at least one DIFF in the period 1.1.2001 to hematological malignancy prior to the index DIFF. In the
31.12.2007, one DIFF encompassing the eosinophil count was subsequent 3-year period, 956 patients developed a hema-
randomly chosen by computer-generated random numbers
tological malignancy of which 71 exhibited eosinophilia in
(n 5 356,196) (Fig. 1). The individuals were categorized according to
no (<0.5 3 109/L), mild (0.5–1.0 3 109/L), or severe eosinophilia
the index differential count. The incidence of hematological
(1.0 3 109/L). Where available the level of C-reactive-protein (CRP), cancer was 89/100,000 person-years. Compared with nor-
categorized as “increased” (10 mg/L) vs. “normal” (<10 mg/L) was mal eosinophil counts, the risk of subsequent hematological
also obtained from the database. Furthermore, we recorded whether cancer increased with increasing levels of eosinophilia with
another DIFF was made during 6 months before the request and ORs (95% C.I.) of 1.74 (1.26–2.40, P 5 0.0008) and 5.43
whether eosinophilia was present in this DIFF. In April 2011, the Cop- (3.04–9.74, P < 0.0001) for mild and severe eosinophilia,
Diff database was linked to the following three nationwide registers: (i) respectively (Table II and figure 2).
The Danish Civil Registration System (CRS) listing everyone living in ORs for developing HL was significantly increased in
Denmark with a permanent and unique personal identification number,
patients exhibiting severe eosinophilia, 9.09 (2.77–29.84,
which gives information on vital status and enables linkage between
study populations and all national registries [15], (ii) the Danish Cancer
P 5 0.0003), but not in cases with mild eosinophilia and no
Registry (DCR), containing data on all malignancies in Denmark since association was found to NHL. The risk of cMPNs also
1942 and to which reporting is mandatory [16], and (iii) The Danish increased with eosinophilia with ORs of 1.65 (1.04–2.61,
National Patient Register (NPR) including information on all contacts P 5 0.0322) and 3.87 (1.67–8.96, P 5 0.0016) for mild and
with hospitals in Denmark, inclusive of discharge diagnoses and surgi- severe eosinophilia, respectively. Eosinophilia was also

844 American Journal of Hematology

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research article
TABLE II. The Association Between Eosinophilia and 3-Year Incidence of Hematological Malignancies (n 5 356,196)

Previous malignancy
Incident malignancy
Eosinophilia (since 1977)
n (%) n (%) Odds ratio (95% CI) P-value

All cancer in the lymphatic and hematopoietic tissue

No (<0.5 3 109/L), n 5 341,790 1,172 (0.3) 885 (0.3) 1.00 <0.0001a
Mild (0.5–1.0 3 109/L), n 5 13,118 48 (0.4) 53 (0.4) 1.74 (1.26–2.40) 0.0008
Severe (1.0 3 109/L), n 5 1,288 14 (1.1) 18 (1.4) 5.43 (3.04–9.74) <0.0001
HL
No 227 (0.1) 74 (0.0) 1.00 0.014a
Mild 10 (0.1) 5 (0.0) 1.71 (0.68–4.27) 0.25
Severe 0 (0.0) 3 (0.2) 9.09 (2.77–29.84) 0.0003
Non-HL
No 584 (0.2) 524 (0.2) 1.00 0.44a
Mild 15 (0.1) 28 (0.2) 1.29 (0.88–1.90) 0.17
Severe 6 (0.5) 3 (0.2) 1.23 (0.39–3.86) 0.72
Multiple myeloma
No 84 (0.0) 168 (0.1) 1.00 0.95a
Mild 3 (0.0) 8 (0.1) 1.10 (0.53–2.27) 0.80
Severe 4 (0.3) 1 (0.1) 1.21 (0.17–8.81) 0.85
Acute lymphatic leukemia
No 51 (0.0) 12 (0.0) 1.00
Mild 1 (0.0) 0 (0) –
Severe 0 (0.0) 0 (0) –
CLL
No 198 (0.1) 145 (0.0) 1.00 0.0012a
Mild 16 (0.1) 15 (0.1) 2.57 (1.50–4.43) 0.0006
Severe 6 (0.5) 3 (0.2) 5.00 (1.57–15.94) 0.0065
Acute myelogenous leukemia
No 65 (0.0) 77 (0.0) 1.00 0.26a
Mild 3 (0.0) 1 (0.0) 0.33 (0.05–2.39) 0.27
Severe 0 (0.0) 1 (0.1) 3.00 (0.41–21.73) 0.28
cMPNs
No 195 (0.1) 255 (0.1) 1.00 0.0058a
Mild 12 (0.1) 23 (0.2) 1.65 (1.04–2.61) 0.032
Severe 4 (0.3) 6 (0.5) 3.87 (1.67–8.96) 0.0016
Monocytic leukemia
No 2 (0.0) 6 (0.0) 1.00
Mild 0 (0.0) 0 (0) –
Severe 0 (0.0) 0 (0) –
All-cause death
No 23,353 (6.8) 1.00 <0.0001a
Mild 1,249 (9.5) 1.16 (1.09–1.24) <0.0001
Severe 201 (15.6) 1.60 (1.35–1.91) <0.0001

Values are numbers (%) of the eosinophilia group in question and odds ratios (95%) and P-values for the defined outcomes from multivariable logistic regression
analysis adjusted for sex, age (quadratic), year, month, C-reactive protein, previous eosinophilia, and comorbidities (Charlson’s comorbidity index). Individuals with pre-
vious cancer were omitted from the analyses (n 5 1,234).
a
P-value for the likelihood-ratio test of all categories of eosinophilia simultaneously.

associated with CLL with ORs of 2.57 (1.50–4.43, contribute to this discussion with our data. However, the fact
P 5 0.0006) and 5.00 (1.57–15.94, P 5 0.0065) for mild and that only patients demonstrating severe eosinophilia are at
severe eosinophilia, respectively. In the 18 patients with risk, indicates the existence of a specific reaction where pro-
eosinophilia who were later diagnosed with CLL we ana- nounced eosinophilia is produced by signaling during the
lyzed their differential counts in more detail in order to scru- development of HL. This observation may be in accordance
tinize the relationship between the observed eosinophilia with a previous, large study of eosinophilia in HL, where less
and the diagnosis of CLL. In 16/18 patients (89%), lympho- than 2% of patients had eosinophil counts above 1 3 109/L
cytosis was present in addition to eosinophilia at the time [9]. Eosinophil infiltration is found in the lymphoma tissue
of the blood sampling (median lymphocyte count 5 16.3 3 [21] and blood eosinophilia has been associated with a sur-
109/L, range 5 7–131). Finally, eosinophilia was associated vival benefit [9]. However, the impact of both tissue infiltration
with all-cause death with ORs of 1.16 (1.09–1.24, and blood eosinophilia in HL remains controversial, and pre-
P < 0.0001) and 1.60 (1.35–1.91, P < 0.0001), for mild and viously eosinophil granulocytes were assumed to play a role
severe eosinophilia, respectively (Table II and figure 2). in the development and deregulation of interactive signaling
between Reed-Sternberg cells and adjacent, reactive cells
[22]. Recently, eosinophilic cationic protein was reported to
Discussion exert a cytotoxic effect on HL cell lines [23]. Therefore, the
In this large prospective epidemiological study blood finding of blood eosinophilia preceding the diagnosis of HL
eosinophilia may be considered a marker for development may represent an immunological defense mechanism
of HL and cMPNs. Interestingly, we also demonstrate that against HL or its subclasses. Similarly, tissue infiltration by
mild and severe eosinophilia may both precede the diagno- eosinophils has been associated with a favorable prognosis
sis of CLL and increase the risk of death. in some solid tumors [24] and proposed to represent
Various mechanisms have been suggested for the reactive an immunological antitumor mechanism in prostate
eosinophilia in HL, including GM-CSF [20] and interleukin-5 cancer [25].
mediated eosinophilia [21]. It has been reported that only Interestingly, our data also showed a significant associa-
mixed cellularity and nodular sclerosis histology subclasses tion between eosinophilia and CLL. This link to CLL has
of HL are associated with eosinophilia [9,11], but we cannot not been reported earlier. The concomitant lymphocytosis

American Journal of Hematology 845

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research article
as it provides the justification for further examination of
patients with unexplained blood eosinophilia.
The CopDiff database has several strengths. First, all
malignant diagnoses in this study were derived from the
DCR which was established in 1942 and to which reporting
is mandatory. Validity of the DCR is secured through quality
control routines applied in the daily production and in com-
pleting annual reports. Quality of the DCR is secured by
manual coding and validation of data. Furthermore, compu-
terized checks for internal consistency, item validity, and
inter-record consistency in the DCR are performed annu-
ally. This includes checks for rare or unlikely combinations
of sex and site, date of death and date of diagnosis, mor-
phology, topography and ICD-10 diagnosis, and, for some
cancers, combinations of grade, stage, and laterality [16].
Second, The CopDiff database comes from a population
which can be assumed to exhibit pleocytosis and general
disease to a greater extent than the general population.
The use of logistic regression analysis on the 3-year inci-
dence ensures that the measures of excess risk (OR) can
be interpreted independently of the frequency of the out-
comes in the study, and the OR is, therefore, a valid esti-
mate for excess risk in the general population as well. Is it
important to stress, however, that absolute risks of hemato-
Figure 2. Odds ratios for the 3-year incidence of hematological malignan- logical malignancies among these individuals are low; the
cies, according to level of eosinophilia. Black, no eosinophilia (<0.5 3 109/L);
blue, mild eosinophilia (0.5–1.0 3 109/L); red, severe eosinophilia (1.0 3 109/
majority of cases of eosinophilia will be reactive to
L). Bars indicate 95% confidence intervals. [Color figure can be viewed in the benign conditions. Third, we observed an incidence of
online issue, which is available at wileyonlinelibrary.com.] hematological malignancies of 89/100,000 person-years
which is compatible with the reported national incidence of
80 per 100,000 person-years [27] suggesting that the Cop-
in the majority of these patients indicates that the malig- Diff database does not differ much from the general popu-
nancy was probably already present at the time of the lation with respect to cancer incidence. Fourth, the CopDiff
blood sampling, and, therefore, the eosinophilia should population was sampled continuously without any restric-
most likely be regarded as an indicator of disease. How- tions as to why the differential count was requested by the
ever, since moderate to severe lymphocytosis correlates general practitioner. This study, therefore, avoids surveil-
well with the presence of CLL, this blood cell is a better lance bias [28] to a large extent as the patients are not
candidate for early warning for this specific disease entity sampled at the time of any diagnosis, but patients are
than the eosinophil despite of the association found in the nevertheless all under some degree of surveillance in pri-
present analyses. Nevertheless, it is an interesting hypoth- mary care since they were referred to the CGPL for blood
esis that eosinophilia correlates with improved outcomes sampling.
for CLL patients, which has been proposed in cases of This study also has important limitations. First, sub-
eosinophilia in HL [9,10]. Unfortunately, the CopDiff diagnoses based on common classifications, as in HL and
database does not permit an approach to determine the in NHL, are not included separately in the statistical analy-
prognostic impact of this new observation due to the long sis. The main implication for the interpretation of the find-
natural course of CLL. At a later stage in the course of ings, however, is to consider the eosinophilia-associated
CLL, few patients treated by fludarabine-containing regi- lymphoma diagnosis earlier in the investigation of patients
mens may show eosinophilia [26]. However, it is unlikely with unexplained eosinophilia. Second, we did not have
that such patients have had blood collected in primary access to information on body mass index, smoking, alco-
care. In addition, patients who had experienced a hemato- hol consumption, exercise patterns or family history of dis-
logical cancer prior to the study were excluded from the ease which for the majority are associated with several
analyses. types of solid cancer, but, on the other hand, not convinc-
The signaling in T-cell disorders from interleukins and ingly with hematological cancers [29]. Third, the follow-up
other cytokines causes eosinophilia in adult T-cell lym- period of 3 years is relatively short. The period was chosen
phoma, angioimmunoblastic T-cell lymphoma and some in order to link the eosinophil count to the specified out-
other non-Hodgkin T-cell diseases [11]. However, the rarity comes with a reasonable certainty, which would have been
of these patients in the overall NHL disease entity, may more difficult with longer follow-up. Even so, we cannot rule
explain why these correlations did not appear in this study. out that some eosinophilia-related cancers appeared after
Likewise, some acute leukemias may be associated with the 3-year time window due to the latency period for cancer
(a clonal) eosinophilia [4]. These patients are also rare and development. Fourth, it is not possible by our methods to
it is not likely that more than but a few of these patients describe or characterize the patients with severe eosino-
have consulted a general practitioner and have had blood philia, since we did not have access to the medical records.
samples performed, considering that these patients usually The fact that the incidence of cMPNs increased in a step-
are hospitalized with acute infections and bleedings. wise manner with the severity of eosinophilia indicates that
Eosinophilia was also associated with an increased risk these patients in general exhibit a steadily progressive
of death, but the exact mechanisms behind this causality course when left untreated.
remain unknown. The associations demonstrated in this In conclusion, in this large cohort from primary care we
study cannot readily explain all causes (Table II) and fur- confirm that there is an association between blood eosino-
ther studies are, therefore, needed. The link between philia and HL as well as cMPNs. In addition, we demon-
eosinophilia and death is important in clinical daily practice strate for the first time that eosinophilia per se is a definite

846 American Journal of Hematology

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research article
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