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<title>Molecular identification of adenovirus causing respiratory tract infection in pediatric patients at the University of Malaya Medical Center</title>
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Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
Open Access
RESEARCH ARTICLE
Molecular identification of adenovirus causing
respiratory tract infection in pediatric patients at
the University of Malaya Medical Center
Research article
Juraina Abd-Jamil†, Boon-Teong Teoh†, Eddy H Hassan†, Nuruliza Roslan† and Sazaly AbuBakar*†
Abstract
Background: There are at least 51 adenovirus serotypes (AdV) known to cause human infections. The prevalence of
the different human AdV (HAdV) serotypes varies among different regions. Presently, there are no reports of the
prevalent HAdV types found in Malaysia. The present study was undertaken to identify the HAdV types associated
primarily with respiratory tract infections (RTI) of young children in Malaysia.
Methods: Archived HAdV isolates from pediatric patients with RTI seen at the University of Malaya Medical Center
(UMMC), Kuala Lumpur, Malaysia from 1999 to 2005 were used. Virus isolates were inoculated into cell culture and DNA
was extracted when cells showed significant cytopathic effects. AdV partial hexon gene was amplified and the
sequences together with other known HAdV hexon gene sequences were used to build phylogenetic trees.
Identification of HAdV types found among young children in Malaysia was inferred from the phylograms.
Results: At least 2,583 pediatric patients with RTI sought consultation and treatment at the UMMC from 1999 to 2005.
Among these patients, 48 (< 2%) were positive for HAdV infections. Twenty-seven isolates were recovered and used for
the present study. Nineteen of the 27 (~70%) isolates belonged to HAdV species C (HAdV-C) and six (~22%) were of
HAdV species B (HAdV-B). Among the HAdV-C species, 14 (~74%) of them were identified as HAdV type 1 (HAdV-1) and
HAdV type 2 (HAdV-2), and among the HAdV-B species, HAdV type 3 (HAdV-3) was the most common serotype
identified. HAdV-C species also was isolated from throat and rectal swabs of children with hand, foot, and mouth
disease (HFMD). Two isolates were identified as corresponding to HAdV-F species from a child with HFMD and a patient
with intestinal obstruction.
Conclusions: HAdV-1 and HAdV-2 were the most common HAdV isolated from pediatric patients who sought
treatment for RTI at the UMMC from 1999 to 2005. HAdV-B, mainly HAdV-3, was recovered from ~22% of the patients.
These findings provide a benchmark for future studies on the prevalence and epidemiology of HAdV types in Malaysia
and in the region.
Background
Respiratory tract infections (RTI) are common in adults
and children worldwide. The disease varies in severity,
presenting as uncomplicated, subacute, acute and chronic
infection. RTIs can be life threatening depending on the
causative agent and host condition. In children, a high
incidence of RTI is caused either by: 1) heightened expo* Correspondence: sazaly@um.edu.my
1
Tropical Infectious Diseases Research and Education Center (TIDREC),
Department of Medical Microbiology, Faculty of Medicine, University of
Malaya, 50603 Kuala Lumpur, Malaysia
† Contributed equally
sure of young children to RTI infectious agents from siblings, friends, and child care; 2) environmental factors;
and 3) inherited disorders of the immune system [1]. In
industrialized and developed countries, nearly 50% of
pediatric consultations are RTI related [2,3], and at least
1.9 million children died from acute RTI with 70% of
them in Africa and Asia in 2000 [4].
There are a number of infectious agents that cause RTI.
Bacteria, such as Haemophilus influenzae, Streptococcus
pneumoniae, Escherichia coli, Klebsiella pneumoniae,
Mycoplasma pneumonia, and Chlamydia trachomatis are
among the most common. However, 80%-90% RTI are
Full list of author information is available at the end of the article
© 2010 Abd-Jamil et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
caused by viruses, such as respiratory syncytial virus
(RSV), influenza virus, parainfluenza virus, and adenovirus (AdV) [1,5]. RSV is one of the most common agents
of RTI in infants and young children in many countries. It
is estimated to cause ~39% of all pneumonia cases and up
to 6% of pneumonia-associated deaths [6]. Parainfluenza
virus and influenza virus also are commonly isolated
viruses from children with viral RTI.
HAdV-associated RTI is reportedly low. It accounts for
4%-10% cases of pneumonia, 2%-10% cases of bronchiolitis, and 3%-9% cases of croup [7]. Severity of infection
associated with HAdV varies with the different HAdV
serotypes [7-9]. There are at least 51 immunologically
distinct HAdV types classified into six species, designated A to F [10]. Viruses causing RTI are usually isolated
in the laboratory from patients' nasal secretions and serotyped by immunological typing methods [11-13]. In
recent years, molecular identification of the virus has
become more common, where distinction of the virus
types can be made through specific genomic sequence
amplification by polymerase chain reaction (PCR) and
determination of the partial hexon gene sequence [14,15].
Presently, there is no report of the prevalent HAdV types
causing infections among Malaysians. This could be due
to the low infection and fatality rates of the infection
resulting in limited interest in typing the virus. The present study was undertaken to type HAdV of pediatric
patients younger than 5 years seen at the University of
Malaya Medical Center (UMMC), Kuala Lumpur, Malaysia.
Methods
Virus
Twenty-seven archived HAdV isolates were recovered
from the UMMC virology repository and used for the
study. The isolates were derived mainly from the
nasopharyngeal secretions (NPS) of children younger
than 5 years diagnosed with RTI (Table 1). Virus isolation
and propagation were performed using African green
monkey kidney cells (Vero), human lung carcinoma cells
(A549), and dog kidney cells (MDCK). The presence of
HAdV was detected by immunofluorescence staining
using specific antibodies (Cat. No. 5000; Light Diagnostics Inc., Salt Lake City, UT, USA) following manifestation of cytopathic effects. Virus inoculum was prepared
and kept at -70°C until needed for genomic typing. Further maintenance and propagation of the HAdV isolates
were performed in A549 cells.
PCR amplification and genome sequencing
Viral genomic DNA was extracted using Tri Reagent®
(Molecular Research Center Inc., Cincinnati, OH, USA)
following the manufacturer's protocol. The partial hexon
gene was amplified using the primer pair, AdTU7 (5'-
Page 2 of 7
GCCACCTTCTTCCCCATGGC-3') and AdTU4 (5'GTAGCGTTGCCGGCCGAGAA-3') to amplify a 1,001
bp fragment of the partial hexon gene (position 20,733 21,734; Accession # NC_001405). A nested polymerase
chain reaction (PCR) also was performed on the amplified fragment using the primers, AdU-S (5'-TTCCCCATGGCNCACAACAC-3')
and
AdU-A
(5'-GCCT
CGATGACGCCGCGGTG-3') which resulted in a 956 bp
fragment. Amplification was performed for 36 cycles
consisting of a denaturation step at 94°C for 1 min, an
annealing step at 50°C for 1 min, and an extension step at
72°C for 2 min. The extension was continued at 72°C for 7
min. The amplified DNA fragment was separated in 1.5%
agarose gel (Promega, Madison, WI, USA), and purified
using QIA Quick gel extraction system (Qiagen GmbH,
Hilden, Germany) according to the manufacturer's protocol. The DNA fragments were sequenced at Macrogen
Inc. (Seoul, Korea).
Sequence and phylogenetic analysis
The partial hexon gene sequences were aligned and phylogenetic trees were drawn as previously described [16].
Briefly, the HAdV partial hexon gene sequences were
analyzed using Sequencher 4.6 (Gene Codes Corporation, Ann Arbor, MI) and aligned against other available
AdV sequences using ClustalX [17]. Phylogenetic trees
were drawn using the maximum-likelihood method as
implemented in PHYLIP 3.67 [18] and the maximumparsimony method using MEGA4 [19]. Bootstrap values
were obtained from a random sampling of 100 replicates.
Reference HAdV sequences used to build the phylogenetic trees were obtained from the GenBank. Details on
the reference sequences are shown in Table 2.
The study was approved by the University Malaya Medical Centre Ethics Committee (Approval #794.6).
Results
A total of 2,583 pediatric patients with RTI were treated
at the UMMC from 1999 to 2005. Of these patients, 48
(<2%) were positive for HAdV by either direct immunofluorescence staining of the patient's NPS, PCR amplification, or virus isolation. HAdV also was isolated from
the throats of patients with HFMD. These HFMD
patients usually did not present with RTI symptoms, but
throat swabs were routinely collected in addition to rectal
swabs.
In the present study, the partial hexon gene sequences
(nucleotide 20,734-21,737) of 27 HAdV isolates from
UMMC were determined. The sequences were aligned
and phylogenetic trees were drawn using the maximumlikelihood and maximum-parsimony methods. Only
results from the maximum-likelihood method were presented, as trees drawn from both the methods were similar. The nucleotide sequence alignment clustered the
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
Page 3 of 7
Table 1: Human adenoviruses isolated at the University of Malaya Medical Centre from 1999 to 2005.
Sample
Year
AD01MY99
1999
AD02MY99
Isolation sitea
Age
Diagnosis
Serotype
NPS
NAb
Pneumonia
B3
1999
NPS
3 mth
Chronic lung diseases
B7
AD04MY00
2000
RS
7 mth
HFMD
F40
AD05MY00
2000
TS
1 yr
HFMD
C2
AD06MY00
2000
TS
8 mth
HFMD
C1
AD07MY01
2001
RS
6 mth
Intestinal obstruction
F41
AD08MY00
2000
RS
NA
HFMD
C5
AD09MY01
2001
NPS
I yr
Acute bronchiolitis
C1
AD10MY01
2001
NPA
1 yr
Bronchiolitis
C2
AD11MY02
2002
NPS
1 yr
Bronchopnuemonia, hypochronic anemia
C1
AD12MY02
2002
NPS
1 yr
Bronchiolitis
C1
AD13MY03
2003
NPS
10 mth
Acute gastroenteritis
C2
AD14MY03
2003
NPS
1 yr
Viral fever
C5
AD15MY03
2003
NPS
8 mth
Acute bronchiolitis
C2
AD16MY03
2003
NPS
NA
Bronchopneumonia
C2
AD17MY04
2004
NPS
2 yr
Acute bronchiolitis
C1
AD18MY04
2004
NPS
9 mth
Pneumonia
C5
AD19MY04
2004
NPS
5 mth
Bronchiolitis
B3
AD20MY04
2004
NPS
2 yr
Pneumonia
C2
AD21MY04
2004
NPS
3 yr
Pneumonia
C1
AD22MY04
2004
NPS
1 yr
Bronchopneumonia
C2
AD23MY04
2004
NPS
5 mth
Bronchiolitis
C6
AD24MY04
2004
NPS
3 yr
Viral fever
B3
AD25MY04
2004
NPS
8 mth
Pulmonary collapse
C5
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
Page 4 of 7
Table 1: Human adenoviruses isolated at the University of Malaya Medical Centre from 1999 to 2005. (Continued)
AD26MY04
2004
NPS
1 yr
AD27MY04
2004
NPS
AD28MY05
2005
NPS
aNPS
bNot
Pneumonia
B3
3 mth
Acute bronchiolitis
C2
2 yr
Bronchopneumonia
B3
is nasopharyngeal secretion; RS is rectal swab; TS is throat swab
available
UMMC isolates into HAdV-C species (n = 19), HAdV-B
species (n = 6), and HAdV-F species (n = 2) with high
bootstrap values. Within the HAdV-C species, eight isolates were HAdV-2 (42%); six isolates, HAdV-1 (32%);
four isolates, HAdV-5 (21%);, and one isolate, HAdV-6
(5%; Figure 1a). When compared with other HAdV from
the GenBank, most of the UMMC HAdV-5 and HAdV-2
isolates formed a separate subcluster of their own (Figure
1a). Within HAdV-B species, five isolates grouped into
HAdV-3, and one was HAdV-7 (Figure 1b). HAdV-3 isolates from the study formed a separate subcluster
together with an isolate from Guangzhou, China (Accession # AY878716) distinct from other known HAdV-3.
This raised the possibility that the viruses may share a
common ancestral lineage with the Malaysian isolate that
was isolated in 1999. The HAdV-7 clustered together
with isolates from the East Asian countries suggesting a
possible widespread presence of the virus in the East
Asian region. Four of the HAdV isolates sequenced in the
study were from HFMD patients, and three of them clustered together with the HAdV-C species. One isolate
clustered with known HAdV-40, whereas an isolate from
the rectal swab of a patient diagnosed with intestinal
obstruction clustered with known HAdV-41. No HAdVB genotype previously associated with fatal cases of
HFMD [20,21] was detected in any of the HFMD patient
samples. Isolates from HFMD patients were included in
the study initially because no effort was made to discriminate the samples from those strictly with RTI. Patients
with HFMD normally would not present with RTI symptoms.
Discussion
Human adenovirus is most commonly associated with
respiratory illnesses. However, depending on the infecting serotype, the virus also causes various other illnesses,
including gastroenteritis, conjunctivitis, cystitis, and
non- specific exanthemas [13,22]. Symptoms of the respiratory illness associated with HAdV range from mild
infection to severe pneumonia [8,23]. Young children and
immunocompromised patients are especially vulnerable
to severe complications of HAdV infection [24,25]. The
findings that less that 2% of UMMC pediatric RTI is asso-
ciated with HAdV respiratory infection is consistent with
other reports that HAdV-associated respiratory infection
is usually low in comparison to other viruses, such as RSV
and parainfluenza virus. The infection also is generally
milder and rarely leads to severe complications and
deaths [8,26]. The low number of HAdV isolation among
pediatric patients seen at the UMMC also suggests that
the virus is not associated with any major RTI outbreaks
during the period from 1999 to 2005. This is perhaps
among the reasons why there have not been many efforts
to identify the HAdV species and types in children with
RTI in many countries, including Malaysia. In addition,
the low incidence of RTI caused by HAdV in the community hampered the effort to get enough representative
isolates.
In our study, HAdV partial hexon gene sequences were
used to type the different HAdV isolates. This gene
region contains the hypervariable region that confers
HAdV serotype specificity. Using this molecular typing
method, HAdV-C species, specifically type 1 and 2, were
the most common HAdV isolated from the pediatric
patients seen at UMMC from 1999 to 2005. In contrast,
studies done in the United States of America, United
Kingdom, Korea, and China, showed HAdV-B species as
the most commonly isolated HAdV [27-30]. The reasons
for the marked differences are not known. It could be that
HAdV-C is more common in the region in comparison to
the more developed countries. However, the prevalence
of HAdV-C species in the neighboring countries could
not be compared because information from these countries are lacking.
Overrepresentation of HAdV-C in UMMC pediatric
patients could suggest a high prevalence of the virus in
the community. There are reports that the virus could
persist and cause asymptomatic latent infection in rabbits
for as long as one year [31]. HAdV-C serotypes 1, 2, and 5
are the most common serotype of HAdV associated in
latent infection of tonsils and adenoids of humans, which
at times cause RTI in young children [32]. The prolonged
presence of the virus in infected children increases its
transmissibility, and this could contribute to the persistence of the virus of young children in Malaysia. The
ubiquitous presence of the virus also could help explain
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
Table 2: Reference adenovirus (AdV) strains from the
Genbank used for the typing of human AdV isolated at the
University of Malaya Medical Centre.
Page 5 of 7
Table 2: Reference adenovirus (AdV) strains from the
Genbank used for the typing of human AdV isolated at the
University of Malaya Medical Centre. (Continued)
Country/Strain
HAdV_34_AY737797
B34
Compton/ATCC VR716
A12
ATCC
HAdV_34_AB052911
B34
NA
HAdV_B_NC_004001
B11
Slobitski
HAdV_35_AC_000019
B35
Old world monkey strain
HAdV_C_NC_001405
C2
NAa
HAdV_35_AY128640
B35
Holden/ATCC VR718
HAdV_D_NC_002067
D17
NA
HAdV_35_AY271307
B35
35p
HAdV_E_NC_003266
E4
Vaccine CL68578
HAdV_35_AB052912
B35
Japan
HAdV_F_NC_001454
F40
Dugan
HAdV_50_DQ149643
B50
NA
HAdV_F_L19443
F40
Dugan
HAdV_50_AY737798
B50
Wan/ATCC VR1502
HAdV_3_AY878716
B3
Guangzhou, China
HAdV_1_AC_000017
C1
P1 C124G1
HAdV_3_AF542108
B3
Korea
HAdV_1_Y17244
C1
Ad71
HAdV_3_AF542129
B3
Korea
HAdV_2_AC_000007
C2
NA
HAdV_3_DQ086466
B3
NA
HAdV_2_AY224392
C2
Korea
HAdV_7_AF053085
B7
S-1058; Japan
HAdV_2_AF542118
C2
Korea
HAdV_7_AY769945
B7
95-81; Korea
HAdV_2_AJ293905
C2
Germany
HAdV_7_AF515814
B7
China
HAdV_2_AJ293901
C2
United Kingdom
HAdV_7_AC_000018
B7
NA
HAdV_5_AF542130
C5
Korea
HAdV_7_AY769946
B7
Strain 99-95; Korea
HAdV_5_AF542128
C5
Korea
HAdV_7_AB243009
B7
Kyoto, Japan
HAdV_5_AF542124
C5
Korea
HAdV_11_AC_000015
B11
NA
HAdV_5_AC_000008
C5
NA
HAdV_11_AF532578
B11
Slobitski
HAdV_5_AF542109
C5
Korea
HAdV_11_AY163756
B11
Ad11p Slobitski
HAdV_6_DQ149613
C6
NA
HAdV_14_AY803294
B14
De Wit/ATCC VR1091
HAdV_6_Y17245
C6
Ton66
HAdV_14_DQ149612
B14
NA
HAdV_40_X51782
F40
Dugan
HAdV_16_X74662
B16
ATCC CH.79
HAdV_41_X51783
F41
Tak
HAdV_21_AB053166
B21
AV-1645
HAdV_41_D13781
F41
Tak
Accession Number
Serotype
HAdV_A_NC_001460
aNot
Available
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
Page 6 of 7
Figure 1 Molecular typing of human adenoviruses (HAdV) isolated at the University of Malaya Medical Center (UMMC) from 1999 to 2005.
HAdV-1 and HAdV-2 comprised most of the HAdV-C species isolated at the UMMC (a). HAdV-B species consisted of HAdV-3 and HAdV-7. HAdV-3
formed its own distinct cluster separate from the rest of the group (b). Two isolates from the study were grouped as HAdV-F serotype 40 and 41 (c),
commonly implicated in gastroenteritis.
isolation of the virus from patients with HFMD and nonspecific viral fever. On the other hand, the results also
could reflect the higher tendency of children with HAdVC species infection to seek medical attention, hence suggesting that the virus could cause more severe manifestations of RTI. Further studies, however, will be needed to
verify this.
Conclusions
The present study is the first to report the prevalent and
circulating HAdV types in Malaysia. It showed that
HAdV-C species especially HAdV-1 and HAdV-2 were
the most commonly isolated HAdV among pediatric
patients seen at UMMC from 1999 to 2005, followed by
HAdV-B species type 3. These viruses are common sero-
Abd-Jamil et al. BMC Pediatrics 2010, 10:46
http://www.biomedcentral.com/1471-2431/10/46
types of HAdV causing acute RTI in pediatric patients.
Because no such study has ever been reported in Malaysia, the present study provides a benchmark for future
studies of HAdV infection in the country.
Abbreviations
HAdV: human adenovirus; HFMD: hand, foot and mouth disease; NPS:
nasopharyngeal secretion; RTI: respiratory tract infection; UMMC: University of
Malaya Medical Center.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
SAB is the principal investigator of the study. SAB and JAJ designed the study
and drafted and wrote the manuscript. NR and EHH propagated and maintained the virus isolates and performed the initial genomic sequence amplification. BTT performed the sequence alignment, sequence analysis, and treedrawing. All authors have read and approved the final manuscript.
Acknowledgements
We thank the Department of Medical Microbiology, University of Malaya for
allowing the study to be undertaken using virus isolates from the UMMC Virology repository. None of the authors received specific funding for this study.
Author Details
Tropical Infectious Diseases Research and Education Center (TIDREC),
Department of Medical Microbiology, Faculty of Medicine, University of
Malaya, 50603 Kuala Lumpur, Malaysia
Received: 17 November 2009 Accepted: 2 July 2010
Published: 2 July 2010
© 2010 Abd-Jamil et 10:46 distributedCentralthe terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open2010, al;from: http://www.biomedcentral.com/1471-2431/10/46
BMC article is available article BioMed under Ltd.
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