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Blood Group AB Is Associated with Increased Risk for

Severe Dengue Disease in Secondary InfectionsX

Article in The Journal of Infectious Diseases ·

DOI: 10.1086/512244 · Source: PubMed

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BRIEF REPORT B
l
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 T
od Group AB Is Associated h
e
d
Received 28 September 2006; accepted 13 November 2006; e
with Increased Risk for Severe electronically published 23 February 2007.
n
g
Dengue Disease in Secondary Potential conflicts of interest: none reported.
u
Infections e
v
Presented in part: 55th meeting of the American Society of Tropical
Medical and Hygiene, Atlanta, Georgia, 11–16 November 2006 (abstract
ir
1010). u
Siripen Kalayanarooj,1,a Robert V. Gibbons,2,a David Vaughn,3 s
Sharone Green,5 Ananda Nisalak,2 Richard G. Jarman,2 Mammen P. e
Mammen, Jr.,2 and Guey-Chuen Perng2,4,6
s
Financial support: National Institutes of Health (grant P01
AI1034533).
a
r
1
Queen Sirikit National Institute of Child Health and 2Department of e
Virology, US Army Medical Corps–Armed Forces Research Institute of m
Medical Sciences, Bangkok, Thailand; 3Walter Reed Army Institute of
Research, Division
S.K. and R.V.G. contributed equally to this work. o
s
q
u
Reprints or correspondence: Dr. Guey-Chuen Perng, Dept. of
of Communicable Diseases and Immunology, Silver Spring, and 4Henry it
Virology, USAMC-AFRIMS, APO AP 96546 (pernggc@afrims.org).
M. Jackson Foundation, Rockville, Maryland; 5University of
Massachusetts Medical School, Center for Infectious Disease and o
Vaccine, Research, Worcester; -
b
The Journal of Infectious Diseases 2007; 195:1014–7 o
6
r
Department of Tropical Medicine, Medical Microbiology, and
Pharmacology, John A. Burns School of Medicine, University of Hawaii, n
Honolulu e
2007 by the Infectious Diseases Society of America. All rights v
reserved. 0022-1899/2007/19507-0015$15.00
ir
DOI: 10.1086/512244 u
s
e
s
o
Why certain individuals progress to severe dengue f
disease is unknown. In this study, blood groups t
associated with dengue disease were investigated. h
ABO phenotypes were identified by use of serum e
from 399 patients with dengue-virus infec-tion who F
participated in a cohort study. ABO blood-group l
frequencies were similar in primary versus a
secondary den-gue-virus infections. However, in -
secondary infection, indi-viduals with blood group v
AB were likely to have dengue hemorrhagic fever i
grade 3 than either grades 1 and 2 com-bined v
(corrected P value, !.0001; odds ratio, 0.097 [95% ir
i
con-fidence interval, 0.03–0.33]) or dengue fever
arthropod-borne human viral disease [1]. Globally, it has d
(corrected P value, !.0001; odds ratio, 0.119 [95%
been estimated that 50–100 million new dengue-virus a
confidence interval, 0.04–0.37]). To our knowledge,
infections oc-cur annually. Among these, there are e
this is the first report dem-onstrating an association f
200,000–500,000 cases of potentially life-threatening
between ABO blood group and the severity of a
dengue hemorrhagic fever (DHF)/ dengue-shock
dengue disease. m
syndrome (DSS), characterized by thrombocy-topenia
and increased vascular permeability [1]. The death rate il
associated with the more severe form of DHF/DSS y.
F
Infection with dengue virus is a serious emerging (DHF grades 3 [DHF3] or 4 [DHF4]) is ∼5%, mainly in
o
health threat and has commanded considerable medical children !15 years of age [1].
u
and public-health concern worldwide [1]. Today, r
dengue disease is considered to be, in terms of g
morbidity and mortality, the most important e
netically related but distinct serotypes, designated “DENV- The important role that host genetics plays in
1,” “-2,” “-3,” and “-4,” circulate worldwide determining the susceptibility to infectious pathogens in
humans has long been known. Although predisposition
to DHF or DSS deter-mined by human leukocyte
antigen (HLA) haplotype has been
Infection with any serotype can be either asymptomatic
or lead to 1 of the 4 clinical scenarios of increasing
severity: un-differentiated fever, dengue fever (DF),
DHF, and DSS [2]. Infection with one serotype leads to
lifelong immunity to that serotype but to only partial
and temporary immunity to the others; circulation of 11
serotype increases the risk of secondary infections and
of DHF and DSS [2].

DF results from the bite of a mosquito carrying

infectious dengue virus and is an acute self-limited
disease comprising 5– 7 days of fever, headache,
myalgia, bone/joint pain, and rash, often accompanied
by leukopenia. Occasionally variable degrees of
thrombocytopenia and cutaneous hemorrhage are
observed. Infrequently, DF may be accompanied by
unusual bleeding complications that may cause death
[1].

The clinical features of DHF are similar to those of DF

during the early febrile phase, but, at defervescence,
patients develop the pathophysiologic hallmarks of plasma
leakage, because of increased vascular permeability and
abnormal hemostasis [1]; studies of samples collected
during and after the acute disease suggest that immune and
inflammatory molecules play a role in increasing the
permeability of blood vessels [3]. The risk factors for DHF
are complex and poorly understood. Secondary infections,
which occur commonly in areas where dengue dis-ease is
endemic, have proven to be one of the main risk factors for
severe dengue disease [2, 4]; and this has led to the
antibody-dependent enhancement theory [2]. In addition,
other probable risk factors for DHF are the infecting
virus’s strain/serotype, the age of the patient, and the
genetic background of the patient [2]; however, none of
these factors alone accounts for the risk of DHF in patients
with dengue-virus infections.
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1014 • JID 2007:195 (1 April) • BRIEF REPORT

Table 1. Distribution of ABO blood groups in Dengue

patients with den-gue-virus infection.

ABO group
Dengue fever
hemorrhagic fever
Total

O
99
(42.3)
61 Material and methods. Serum samples were collected from
(37.0)
children with acute febrile illnesses who were enrolled in a
160
(40.1) prospective study that has been described elsewhere [9].
A The severity of DHF grading and diagnostic criteria
50 followed World Health Organization guidelines. Acute
(21.4) dengue-virus infections were confirmed both virologically
32 (by virus isolation and/or reverse-transcriptase polymerase
(19.4) chain reaction) and serologi-cally (by ELISA for IgM/IgG)
82 [9]. Standard hemagglutination assays were used to type
(20.5)
the blood groups [6]. The protocol was approved by the
B
71 Human Subjects Research Review Board, the Thai
(30.3) Ministry of Public Health, and the Institutional Review
58 Board of the University of Massachusetts Medical School.
(35.1) Writ-
129
(32.3)
AB
14 ten, informed consent was obtained from the parent or
(6.0)
guard-ian of each child.
14
(8.5)
28
(7.1)
Total All patients with confirmed dengue-virus infections were
234 in-cluded in these analyses. We compared ABO blood-
group fre-quencies in primary versus secondary infections,
as well as in the analysis of associations with disease
165 severity (DF vs. DHF), according to World Health
Organization criteria. The x2 test for ABO blood groups (2
3 2 contingency tables) was used. P ! .05 was considered to
399 be significant. We used Bonferroni’s method to correct for
multiple comparisons; this included cor-recting for blood
groups (n p 4), primary versus secondary in-fections (n p
2), and number of groups of patients (DF, DHF1, DHF2,
DHF3, all grades of DHF combined, and DF+DHF com-
bined [n p 6]). Corrected P values (Pc) !.05 were considered
to be highly significant. The odds ratio (OR) and 95%
confidence interval (CI) were used to assess the
predisposition risk of disease severity associated with a D
specific ABO blood group. o
w

Results. The frequencies of each blood group in the sample

population are presented in table 1 and were consistent with
those in the general Thai population [10]. The distribution
of each blood group among patients with DF was similar to
that among patients with DHF. Secondary infections are
known to be associated with a higher risk of development
of severe dis-ease, so each patient was assayed by IgM/IgG
NOTE. Data are no. (%) of patients.
ELISA to deter-mine whether he or she was presenting with
a primary or secondary infection. Table 2 shows the results
of these assays, stratified by ABO blood group. In primary
dengue-virus in-fections, all 4 blood groups had similar
proposed by several researchers, no clear, specific
susceptibility to severe disease—that is, to DHF3—and no
polymorphisms have been unequivocally described for
correlation between blood group and disease severity was
severe forms of dengue disease [5]. The ABO blood-group
seen. In contrast, among patients with secondary dengue-
system is part of the innate immune system [6], and it has
virus infection, blood group AB’s as-sociation with DHF3
been shown that individuals with different ABO blood
was similar to both its association with
groups differ in their susceptibility or re-sistance to viral
and bacterial infections and diseases [6, 7]. A relationship
between blood groups and disease was first hypoth-esized
by Kaipainen et al. during 1960 [8], and the gene involved
in ABO blood groups was discovered in 1990 [6].
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Table 2. Frequency of blood groups in patients with dengue fever (DF) and in patients with dengue O
hemorrhagic fever (DHF). A
B
A
B
T
o
t
a
l

Primary

Secondary

D
F
2
9
1
8
2
2
5
7
4

7
0
a

3
2
4
9
Disease severity
9
O b
A
B 1
AB 6
Total 0
DHF

4
a
,
c

2
8

7
b
,
d

2
1
D
H
F
s
u
b
t
o
t
a
l
5
2
6
Grade 1 1
2 1
1 4
1
0
4 5
6
3
0
5
c 2
18
1
8 3
13 1
d
2 5
41 1
Grade 2 T
3 o
1 t
4 a
1 l
9 (
D
F
+
D
c H
34 F
20 )
31 3
d
4 4
89 2
Grade 3 0
2
8
6
8
8
1

1
1 2
6
62
101
22
311

2
9,
2
0
1
5

NOTE. Data are no. of patients. OR, odds ratio; Pc, corrected P value.

Blood group O in DHF3 vs. in DF: x2 p4.7; P p.0304; Pc p 1.5 (not significant); OR, 3.306 (1.1 ! OR ! 10.3).

Blood group O in DHF3 vs. in DHF1 and DHF2 combined: x2 p3.4; P p .065; Pc not significant; OR, 2.8 (0.9 ! OR ! 8.9).

Blood group AB in DHF3 vs. in DF: x2 p 17.7; P ! .0001; Pc ! .0001; OR, 0.119 (0.04 ! OR ! 0.37).

Blood group AB in DHF3 vs. in DHF1 and DHF2 combined: x2 p18.95; P ! .0001; Pc ! .0001; OR, 0.097 (0.03 ! OR ! 0.33).

BRIEF REPORT • JID 2007:195 (1 April) • 1015

DF (Pc ! .0001; OR, 0.119 [95% CI, 0.04–0.37]) and its disease. The innate immune system—consisting of NK D
asso-ciation with DHF1 and DHF2 combined (Pc ! . cells, dendritic and mast cells, macrophages, natural H
0001; OR, 0.097 [95% CI, 0.03–0.33]). Also notable in antibody–producing B cells, the comple-ment system, and F
secondary dengue-virus infection was that blood group the host genetic factors—clearly plays a role in elimination /
O was associated less with DHF3 than with DF (P p . of viral infections [11]. Among these innate fac-tors, a D
0304); however, this difference was not statistically predisposition for an individual to be susceptible or re- S
significant after correction for multiple comparisons (Pc sistant to phenotypes of infectious diseases and their S
clinical manifestations resides in host genetic factors [6].
p 1.5). h
Two genetic factors—HLA and ABO blood groups—have,
a
to some extent, been demonstrated to play an important
s
role in resistance or susceptibility to infectious diseases [6].
b
Discussion. The results of the present study suggest that,
e
when associated with a secondary infection, blood group
e
AB may be a risk factor predisposing for severe dengue
n documented in infants during their first dengue-virus of natural IgM antibody circulating in individuals has an H
infection [1]. Presumably the enhancement of dengue effect on dengue disease remains to be seen. al
st
disease in infants is due to preexistent dengue antibody e
that is passively acquired, via cord blood, from mothers a
im-mune to dengue-virus infection [1]. One limitation d
Additionally, a correlation between HLA and dengue
of the pres-ent study is that no infants were included. S
disease has been reported; but no specific B
Whether ABO blood groups will play a similar role in
polymorphisms have been found to be unequivocally .
infants remains to be delin-eated. In the present cohort
associated with disease severity [5]. It therefore is of E
study, the incidence of DHF in children with primary pi
interest to see whether there is any correlation between a
dengue-virus infection was low (table 2). Factors d
polymorphism in the galactosyltransferase gene and
contributing to DHF in these children are unknown; e
dengue-disease severity. m
perhaps individual genetic background may play a
io
critical role in these children [2, 6].
lo
g
A previous study of HLA and dengue-virus infection y
found that the infecting viral serotype influenced the o
In ABO blood-group antigens, individuals who lack an f
an-tigen have natural antibodies with the ability to strength of the association between specific HLA alleles
d
agglutinate cells carrying that antigen [6]. The antigens and dengue-disease severity [15]. The potential e
are carbohydrate in nature; the immundominant sugar influence of dengue viral serotype in association with n
in the case of the A deter-minant is N-acetyl-D- disease severity and ABO group was ana-lyzed. All 4 g
serotypes were circulating during the periods of the u
galactosamine, and that in the case of the e
study, and the results suggest that, for blood groups O,
a
A, and B, no serotype was associated with disease n
severity. Interestingly, in the present study we found d
determinant is D-galactose. Galactosyltransferases are in- that, for blood group AB, more-severe dengue disease d
volved in the synthesis of these carbohydrates [6]. The seemed to be associated more with den-gue serotypes 2, e
antibody that recognizes these carbohydrates is primarily n
3, and 4 than with dengue serotype 1 (data not shown).
natural IgM. Interestingly, several dengue viral proteins g
Blood group AB’s association with DHF versus its u
have been shown to be glycosylated [12], and antibodies, association with DF was not significantly different from e
particularly IgM, produced in patients with dengue-virus that in the other blood groups. Because of the h
infection have been shown to cross-react with host cells limitations of the sample size in the present study, a
[3]. Two earlier studies found no association between e
further studies will be nec-essary to determine whether
blood group and disease severity in patients with dengue- m
dengue serotype, HLA, and ABO are independent o
virus infection [13, 14]; however, either the col-lected data
were incomplete [13] or not all patients in the study had
variables—and whether some blood subgroups are rr
laboratory-confirmed dengue-virus infection and a com- associated with a particularly high risk of dengue-virus h
infection. a
parison group with DF was not included [14]. Therefore,
gi
whether the combination of ABO blood group and the c
level fe
v
er
.
Acknowledgments I
n:
G
u
We thank Dr. Henry A. F. Stephens (Institute of Urology and bl
Nephrology, University College London), for his excellent technical er
support in the sta-tistical analysis and for helpful discussions, and Drs. D
Suchitra Nimmannitya (Queen Sirikit National Institute of Child
J,
Health, Bangkok) and Alan Roth-man (University of Massachusetts
K
Medical School, Boston), for their knowl-edgeable comments and
suggestions regarding the manuscript.
u
n
o
G
,
e
d
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