Article

Dual Infection of Novel Influenza Viruses A/H1N1 and A/H3N2 in a Cluster of Cambodian Patients

Naval Health Research Center, San Diego, California, USA.
The American journal of tropical medicine and hygiene (Impact Factor: 2.7). 11/2011; 85(5):961-3. DOI: 10.4269/ajtmh.2011.11-0098
Source: PubMed

ABSTRACT

During the early months of 2009, a novel influenza A/H1N1 virus (pH1N1) emerged in Mexico and quickly spread across the globe. In October 2009, a 23-year-old male residing in central Cambodia was diagnosed with pH1N1. Subsequently, a cluster of four influenza-like illness cases developed involving three children who resided in his home and the children's school teacher. Base composition analysis of internal genes using reverse transcriptase polymerase chain reaction and electrospray ionization mass spectrometry revealed that specimens from two of the secondary victims were coinfected with influenza A/H3N2 and pH1N1. Phylogenetic analysis of the hemagglutinin genes from these isolated viruses showed that they were closely related to existing pH1N1 and A/H3N2 viruses circulating in the region. Genetic recombination was not evident within plaque-purified viral isolates on full genome sequencing. This incident confirms dual influenza virus infections and highlights the risk of zoonotic and seasonal influenza viruses to coinfect and possibly, reassort where they cocirculate.

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Am. J. Trop. Med. Hyg., 85(5), 2011, pp. 961–963
doi:10.4269/ajtmh.2011.11-0098
Copyright © 2011 by The American Society of Tropical Medicine and Hygiene
Globally, influenza remains a leading cause of human mor-
bidity and mortality, largely as a result of the virus’s inher-
ent evasiveness from the immune response.
1
Coinfection
of viruses in birds or mammals, such as swine, increases the
chance for the emergence of new variants.
2,
3
Novel viruses
can emerge within a population, evade immunity, and result
in local epidemics or in some instances, pandemics. However,
recombination among subtypes remains rare.
4
In early 2009, a
novel influenza A/H1N1 virus (pH1N1) emerged in Mexico.
By October 2009, pH1N1 had become the predominant influ-
enza subtype infecting populations in most areas of the world.
5
Notwithstanding, in Southeast Asia, seasonal influenza viruses
as well as the avian influenza virus A/H5N1 continued to cir-
culate [World Health Organization (WHO) Pandemic (H1N1)
2009–Update 82; http://www.who.int/csr/don/2010_01_08/en/
index.html ). In the Southeast Asian nation of Cambodia, we
and others have shown that cases of influenza peak with the
monsoon between the months of July and December.
6,
7
In early October 2009, a 23-year-old man from central
Cambodia presented to the Ta Khmau health clinic with
influenza-like symptoms ( Table 1 ). Real-time reverse tran-
scriptase polymerase chain reaction (rRT-PCR) assays to
detect influenza A and B viruses were used to diagnose pH1N1
infection.
8
The patient received treatment to alleviate symp-
toms and recovered at his residence.
On October 14, 2009, three male (M) children, ages 13, 8,
and 4 years, who lived in the same home as the suspected index
case presented at the health clinic with fever (39°C), cough,
sore throat, headache, and symptoms of either nausea or vom-
iting ( Table 1 ). The students attended classes in a single-room
school. They reported neither recent extended contact with ani-
mals nor travel. A day after their illness, their teacher reported
febrile illness, and samples were obtained. Specimens from
one of three school children and the teacher indicated dual
infection with both seasonal A/H3N2 and pH1N1 viruses.
Virus isolation from collected clinical specimens was per-
formed in Madin-Darby canine kidney (MDCK) cells and
shell vials. Isolated viruses were analyzed on the Ibis T5000
by ESI-MS (Ibis Biosciences, Inc., Carlsbad, CA) analysis to
generate a specific mass measurement for each amplified PCR
product. Primer sequences and other PCR components were as
previously described.
9
The base composition signature for the
product was then compared with known sequences in a data-
base to generate an internally verified identification. Analyses
from six regions of the influenza genome confirmed pH1N1
infection in the 23-year-old man and dual A/H3N2 and pH1N1
infection in specimens from one of three children (8/M) and
the teacher (24/female [F]). Only A/H3N2 viruses were evi-
dent in samples from the 4/M and 13/M victims. Analysis did
not discern recombined signatures in gene segments within
the isolated viruses ( Table 2 ).
To fully characterize the gene segments of dual-infected
individuals, single-passaged viruses from two of the patients
and six of corresponding purified virus plaques were processed
for pyrosequencing using a specialized multisegment RT-PCR
procedure to amplify the genome of all subtypes of the influ-
enza A virus through degenerate primers. Sequencing, genome
assembly, and closure reactions were performed as previously
described.
10
Complete genomes (> 99% open reading frame
[ORF]) were obtained for all eight segments of each virus
isolate. A complete ORF region (100% genome length) was
obtained for all isolates. Sequences for the hemagglutinin
(HA) segment from the isolates were compared with known
sequences (data not shown). Relative to A/Perth/16/2009
(H3N2), the H3N2 vaccine component for 2010 and 2011, a
total of 3 aa substitutions were seen in the area sequenced,
I25V, P162T, and S214I, with an overall similarity of 99%. The
latter mutation corresponds to a previously identified anti-
body combining site.
11
More complete datasets for recent
swine strains allowed for a fuller comparison of pH1N1 HA
sequences. Comparison between the pH1N1 reference strain,
A/California/04/2009, and the full genome sequence of iso-
late material from 4/M revealed 4 aa changes from the vaccine
strain (P100S, S220T, I338V, and Y528H), with an overall sim-
ilarity of 99.3% over 566 aa. Phylogenetic analysis of the
HA genes of all analyzed plaques revealed a single genetic
sequence for both the A/H3N2 and pH1N1 strains. None of the
isolated plaques showed evidence of recombination between
Short Report : Dual Infection of Novel Influenza Viruses A/H1N1 and
A/H3N2 in a Cluster of Cambodian Patients
Christopher A. Myers , Matthew R. Kasper , Chadwick Y. Yasuda , Chin Savuth , David J. Spiro , Rebecca Halpin , Dennis J. Faix ,
Robert Coon , Shannon D. Putnam , Thomas F. Wierzba , and Patrick J. Blair *
Naval Health Research Center, San Diego, California; US Naval Medical Research Unit No. 2, Phnom Penh, Kingdom of Cambodia;
National Institute of Public Health, Ministry of Health, Phnom Penh, Kingdom of Cambodia; J. Craig Venter Institute, Rockville, Maryland
Abstract. During the early months of 2009, a novel influenza A/H1N1 virus (pH1N1) emerged in Mexico and quickly
spread across the globe. In October 2009, a 23-year-old male residing in central Cambodia was diagnosed with pH1N1.
Subsequently, a cluster of four influenza-like illness cases developed involving three children who resided in his home and
the children’s school teacher. Base composition analysis of internal genes using reverse transcriptase polymerase chain
reaction and electrospray ionization mass spectrometry revealed that specimens from two of the secondary victims were
coinfected with influenza A/H3N2 and pH1N1. Phylogenetic analysis of the hemagglutinin genes from these isolated
viruses showed that they were closely related to existing pH1N1 and A/H3N2 viruses circulating in the region. Genetic
recombination was not evident within plaque-purified viral isolates on full genome sequencing. This incident confirms
dual influenza virus infections and highlights the risk of zoonotic and seasonal influenza viruses to coinfect and possibly,
reassort where they cocirculate.
* Address correspondence to Patrick J. Blair, Department of Respi-
ratory Diseases, Naval Health Research Center, 140 Sylvester Road,
San Diego, CA 92106. E-mail: patrick.blair@med.navy.mil
Page 1
962
MYERS AND OTHERS
pH1N1 and A/H3N2, and all had full sequences for the eight
influenza segments from both strains.
Herein, we describe a cluster of influenza-like illness (ILI)
cases at a school in central Cambodia. Among the afflicted,
two were coinfected with A/H3N2 and pH1N1 influenza
viruses. The finding of coinfections has rarely been reported.
A recently study of over 2,000 clinical samples found no dual
infection.
12
However, coinfection of pH1N1 and A/H3N2 has
been reported in a 38-year-old woman from Singapore,
13
and
mixed infection was also evident in six individuals after an out-
break of influenza at a college campus near Beijing, China.
14
A
more recent New Zealand study collected and screened 1,044
clinical samples during the pandemic and found 11 coinfec-
tions with A/H1N1 seasonal viruses.
15
Transmission of pH1N1 at a time when seasonal influenza
viruses were circulating in Cambodia resulted in coinfection
and raised the possibility of reassortment. The generation of
novel influenza viruses through reassortment has occurred
when zoonotic viruses mix in birds, swine, and humans, and
gene segments are reshuffled. Pandemic strains often are the
result of emerging viruses from reservoirs to which humans
have little or no immunity. The A/H2N2 1957 and A/H3N2 1968
pandemics occurred after reassortment between human and
avian strains.
16,
17
The 1957 virus was generated when A/H1N1
1918 reassorted with avian viruses to pick up new PB1, HA,
and neuraminidase (NA) segments. Similarly, the novel virus
isolated from ILI cases in southern California in April 2009
contained genetic elements from four different sources, includ-
ing North American swine influenza viruses, North American
avian influenza viruses, human influenza viruses, and a Eurasian
swine influenza virus.
18
In our analysis , recombination was not
detected in viruses isolated from the Cambodian patients.
The clinical disease within the dual A/H3N2 and A/H1N1
Cambodian patients did not result in hospitalization nor did
these patients’ disease seem more severe than the disease
in the other patients with influenza.
19
Clinical findings were
broad, including upper respiratory and gastrointestinal symp-
toms. None of five patients in this outbreak had been vacci-
nated against either seasonal or pH1N1 influenza infections.
Indeed, in rural Cambodia, little seasonal influenza vaccination
is conducted, and use of therapeutics such as neuraminidase
inhibitors is rare
20
; thus community-wide immunity is lacking.
Southeast Asia has proven to be a critical region for the
adaptation and emergence of variants of seasonal influenza
viruses
21
as well as an area of zoonotic virus transmission in
humans. Cases of A/H5N1 have largely been restricted to
the Near East and southeast Asia, with Cambodia suffering
15 confirmed human cases and 13 fatalities since 2005. The
endemicity of A/H5N1 in poultry in many areas of south-
east Asia provides increased opportunity for human expo-
sure and adaptation of a lethal virus suitable for sustained
human transmission. Our findings emphasize the importance
Table 1
Demographics of Cambodian cases involved in influenza cluster
FSS08728 FSS08731 FSS08732 FSS08733 FSS09305
Age (years)/sex 23/M 13/M 8/M 4/M 24/F
Disease onset 10/08/09 10/12/09 10/12/09 10/13/09 10/12/09
Date sampled 10/09/09 10/14/09 10/14/09 10/14/09 10/15/09
Occupation Lawyer Student Student Student Teacher
Clinical findings *
Fever (°C) 39°C 39°C 39°C 39°C 39°C
Malaise Y N N N Y
Headache Y Y Y Y Y
Sore throat Y Y Y Y N
Cough Y Y Y Y Y
Nausea N Y N N N
Vomiting N N Y Y N
Rhinorrhea N N N N Y
Medication Amoxicillin and
paracetamol
Amoxicillin and
paracetamol
Amoxicillin and
paracetamol
Amoxicillin and
paracetamol
N
Epidemiology
Recent travel Within country N N N N
Animal exposure N N N N N
Disposition Recovered Recovered Recovered Recovered Recovered
* Recorded on date of sample collection.
Table 2
Base composition data from clinical samples
Patient Detection *
Target segment
PB1 NP M1 PA NS1 NS2
23/M 1:pH1n1 A39 G32C24 T33 A35 G21 C20 T25 A24 G28 C24 T29 A36 G25 C27 T24 A36 G36 C20 T28 ND
13/M 1:H3N2 A41 G30C23 T34 A32 G24 C20 T25 A25 G29 C21 T30 A31 G25 C25 T31 A40 G30 C20 T29 A37 G25 C16 T27
8/M 1:pH1N1 A41 G30 C22 T35 A35 G21 C20 T25 A25 G27 C24 T29 A37 G24 C26 T25 A37 G34 C19 T29 A35 G28 C15 T27
8/M 2:H3N2 A41 G20 C23 T34 ND A25 G29 C21 T30 ND A41 G29 C19 T30 A37 G25 C16 T27
4/M 1:H3N2 A41 G30 C23 T34 A32 G24 C20 T25 A25 G29 C21 T30 A41 G22 C26 T23 A40 G30 C20 T29 A37 G25 C16 T27
24/F 1:pH1Ni ND A35 G21 C20 T25 A25 G27 C23 T30 ND A37 G34 C19 T29 A34 G29 C16 T26
24/F 2:pH3N2 A40 G31 C23 T34 ND A25 G29 C21 T30 A40 G23 C27 T22 ND A37 G25 C16 T27
ND = not determined.
* The listing of strain determinations made by the PlexID instrument based on the base compositions detected in the sample.
The more recent version of the influenza surveillance plate that was used for sample 2 3/ M does not include an NS2 primer pair.
Page 2
963
DUAL INFLUENZA INFECTIONS, CAMBODIA 2009
of national and international cooperation to survey for the
emergence of novel and/or reassorted influenza viruses.
Received February 16, 2011. Accepted for publication June 6, 2011.
Acknowledgments: This work would not be possible without the sub-
stantial daily efforts of the staff at the clinical sites in Kandal Province.
The authors thank the laboratories at Naval Health Research Center
and J. Craig Venter Institute and the US Naval Medical Research Unit
No. 2 and National Institute of Public Health, Kingdom of Cambodia,
for their contributions in diagnosing and characterizing resulting
viruses. This research has been conducted in compliance with all appli-
cable federal regulations governing the protection of human subjects
in research (Protocols NAMRU2.2005.0004 and NHRC.2010.0007).
Financial support: This work was funded in part by grants from the
US Department of Defense Armed Forces Health Surveillance
Center division of the Global Emerging Infections Surveillance and
Response System (AFHSC/GEIS) and the US Defense Advanced
Research Projects Agency, (DARPA) under work unit number
60941. A portion of this project was funded by the National Institute
of Allergy and Infectious Diseases, National Institute of Health,
Department of Health and Human Services under contract number
HHSN272200900007C.
Disclaimer: The views expressed in this article are of the authors and
do not reflect the official policy or position of the Department of the
Navy, the Department of Defense, or the US Government.
Authors’ addresses: Christopher A. Myers, Dennis J. Faix, and Robert
Coon, Naval Health Research Center, San Diego, CA, E-mails: Chris
.Myers2@med.navy.mil , dennis.faix@med.navy.mil , and robert.coon@
med.navy.mil . Matthew R. Kasper, Chadwick Y. Yasuda, Shannon D.
Putnam, and Thomas F. Wierzba, US Naval Medical Research Unit
No. 2, Phnom Penh, Kingdom of Cambodia, E-mails: Matthew.Kasper@
med.navy.mil , Chad@namru2.org.kh , shan.putnam@med.navy.mil ,
and twierzba@IVI.int . Chin Savuth, National Institute of Public
Health, Ministry of Health, Phnom Penh, Kingdom of Cambodia,
E-mail: savuth_chin@yahoo.com . David J. Spiro and Rebecca Halpin,
J. Craig Venter Institute, Rockville, MD, E-mails: david.spiro@nih.gov
and rhalpin@jcvi.org . Patrick J. Blair, Naval Health Research Center,
San Diego, CA and US Naval Medical Research Unit No. 2, Phnom
Penh, Kingdom of Cambodia, E-mail: patrick.blair@med.navy.mil .
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    • "For baseline values of model parameters we assume that among the contacts between co-infected people with the susceptible, 80% generate single infections equally with strain 1 or strain 2, and 20% to dual infections (soˇd = 0.20 × ˇ 1 = 0.075). Because co-infections were rarely reported (Peacey et al., 2010; Myers et al., 2011), data for their epidemiological and dynamics characteristics are lacking. Here we assume that the infectious period of co-infection is longer than either single infection with 1/ d = 6 days and its severity is double that of the single infection. "
    [Show abstract] [Hide abstract] ABSTRACT: Reassortment is an important evolutionary route for influenza A viruses to generate pandemic strains. The pre-requisite for reassortment to occur is co-infection of different influenza virus strains in the same host population. Empirical evidence suggests that co-circulation of influenza A virus strains is common and co-infection in patients has been reported. Whether a novel virus can successfully spread among a host population is determined by its life-history (infectivity and infectious period). It is also well known that different influenza A strains interfere through the immune response of human body cells. The reassortant virus strain generated from co-infections deviates dramatically in antigenic and genetic properties from its parental strains such that human populations have limited immunity against it. We consider a mathematical model which includes two strains of influenza virus within a standard SIR model and integrate life history and cross-immunity into the evolutionary dynamics of influenza virus. We assume that, following primary infection by one strain and recovery, individuals are susceptible to secondary infection by the other strain only but with reduced probability due to cross-immunity. Co-infection is included to examine how life-history and cross-immunity interplay to regulate the co-circulation and co-infection of different influenza A virus strains in human populations. Further, we introduce novel strains via reassortment and investigate how the opportunities of a reassortant strain developing into a pandemic are constrained by its life-history and the residual immunity within human populations. We find that though the probability of pandemic emergence via reassortment increases with transmissibility of reassortant strains and the rate of reassortment, the existence of cross-immunity acquired through previous infections or vaccination can greatly constrain pandemic emergence.
    Full-text · Article · Mar 2013
  • Source
    • "For baseline values of model parameters we assume that among the contacts between co-infected people with the susceptible, 80% generate single infections equally with strain 1 or strain 2, and 20% to dual infections (soˇd = 0.20 × ˇ 1 = 0.075). Because co-infections were rarely reported (Peacey et al., 2010; Myers et al., 2011), data for their epidemiological and dynamics characteristics are lacking. Here we assume that the infectious period of co-infection is longer than either single infection with 1/ d = 6 days and its severity is double that of the single infection. "
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  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Population-based febrile respiratory illness surveillance conducted by the Department of Defense contributes to an estimate of vaccine effectiveness. Between January and March 2011, 64 cases of 2009 A/H1N1 (pH1N1), including one fatality, were confirmed in immunized recruits at Fort Jackson, South Carolina, suggesting insufficient efficacy for the pH1N1 component of the live attenuated influenza vaccine (LAIV). To test serologic protection, serum samples were collected at least 30 days post-vaccination from recruits at Fort Jackson (LAIV), Parris Island (LAIV and trivalent inactivated vaccine [TIV]) at Cape May, New Jersey (TIV) and responses measured against pre-vaccination sera. A subset of 78 LAIV and 64 TIV sera pairs from recruits who reported neither influenza vaccination in the prior year nor fever during training were tested by microneutralization (MN) and hemagglutination inhibition (HI) assays. MN results demonstrated that seroconversion in paired sera was greater in those who received TIV versus LAIV (74% and 37%). Additionally, the fold change associated with TIV vaccination was significantly different between circulating (2011) versus the vaccine strain (2009) of pH1N1 viruses (ANOVA p value = 0.0006). HI analyses revealed similar trends. Surface plasmon resonance (SPR) analysis revealed that the quantity, IgG/IgM ratios, and affinity of anti-HA antibodies were significantly greater in TIV vaccinees. Finally, sequence analysis of the HA1 gene in concurrent circulating 2011 pH1N1 isolates from Fort Jackson exhibited modest amino acid divergence from the vaccine strain. Among military recruits in 2011, serum antibody response differed by vaccine type (LAIV vs. TIV) and pH1N1 virus year (2009 vs. 2011). We hypothesize that antigen drift in circulating pH1N1 viruses contributed to reduce vaccine effectiveness at Fort Jackson. Our findings have wider implications regarding vaccine protection from circulating pH1N1 viruses in 2011-2012.
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