Malaria and other vector-borne infection surveillance in the U.S. Department of Defense Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance program: review of 2009 accomplishments.

Abstract

Vector-borne infections (VBI) are defined as infectious diseases transmitted by the bite or mechanical transfer of arthropod vectors. They constitute a significant proportion of the global infectious disease burden. United States (U.S.) Department of Defense (DoD) personnel are especially vulnerable to VBIs due to occupational contact with arthropod vectors, immunological naiveté to previously unencountered pathogens, and limited diagnostic and treatment options available in the austere and unstable environments sometimes associated with military operations. In addition to the risk uniquely encountered by military populations, other factors have driven the worldwide emergence of VBIs. Unprecedented levels of global travel, tourism and trade, and blurred lines of demarcation between zoonotic VBI reservoirs and human populations increase vector exposure. Urban growth in previously undeveloped regions and perturbations in global weather patterns also contribute to the rise of VBIs. The Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) and its partners at DoD overseas laboratories form a network to better characterize the nature, emergence and growth of VBIs globally. In 2009 the network tested 19,730 specimens from 25 sites for Plasmodium species and malaria drug resistance phenotypes and nearly another 10,000 samples to determine the etiologies of non-Plasmodium species VBIs from regions spanning from Oceania to Africa, South America, and northeast, south and Southeast Asia. This review describes recent VBI-related epidemiological studies conducted by AFHSC-GEIS partner laboratories within the OCONUS DoD laboratory network emphasizing their impact on human populations.

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REVIEWOpen Access
Malaria and other vector-borne infection
surveillance in the U.S. Department of Defense
Armed Forces Health Surveillance Center-Global
Emerging Infections Surveillance program: review
of 2009 accomplishments
Mark M Fukuda1*, Terry A Klein2, Tadeusz Kochel3, Talia M Quandelacy1, Bryan L Smith, Jeff Villinski5, Delia Bethell4,
Stuart Tyner4, Youry Se4, Chanthap Lon4, David Saunders4, Jacob Johnson5, Eric Wagar6, Douglas Walsh6,
Matthew Kasper7, Jose L Sanchez1, Clara J Witt1, Qin Cheng8, Norman Waters8, Sanjaya K Shrestha4, Julie A Pavlin4,
Andres G Lescano3, Paul CF Graf3, Jason H Richardson4, Salomon Durand3, William O Rogers7, David L Blazes1,
Kevin L Russell1, the AFHSC-GEIS Malaria and Vector Borne Infections Writing Group1,4,5,6,7,8,9
Abstract
Vector-borne infections (VBI) are defined as infectious diseases transmitted by the bite or mechanical transfer of
arthropod vectors. They constitute a significant proportion of the global infectious disease burden. United States
(U.S.) Department of Defense (DoD) personnel are especially vulnerable to VBIs due to occupational contact with
arthropod vectors, immunological naiveté to previously unencountered pathogens, and limited diagnostic and
treatment options available in the austere and unstable environments sometimes associated with military operations.
In addition to the risk uniquely encountered by military populations, other factors have driven the worldwide
emergence of VBIs. Unprecedented levels of global travel, tourism and trade, and blurred lines of demarcation
between zoonotic VBI reservoirs and human populations increase vector exposure. Urban growth in previously
undeveloped regions and perturbations in global weather patterns also contribute to the rise of VBIs. The Armed
Forces Health Surveillance Center-Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) and its
partners at DoD overseas laboratories form a network to better characterize the nature, emergence and growth of
VBIs globally. In 2009 the network tested 19,730 specimens from 25 sites for Plasmodium species and malaria drug
resistance phenotypes and nearly another 10,000 samples to determine the etiologies of non-Plasmodium species
VBIs from regions spanning from Oceania to Africa, South America, and northeast, south and Southeast Asia. This
review describes recent VBI-related epidemiological studies conducted by AFHSC-GEIS partner laboratories within the
OCONUS DoD laboratory network emphasizing their impact on human populations.
Introduction
Vector borne infections (VBIs) such as malaria, dengue
fever, yellow fever, scrub typhus, and plague comprise a
significant proportion of the global infectious disease
burden. These diseases account for more than half of
the priority diseases in the Special Program for Research
and Training in Tropical Diseases, a scientific collabora-
tion of the World Health Organization (WHO), the
United Nations Children’s Fund (UNICEF), the United
Nations Development Program and the World Bank.
High priority VBIs include malaria, lymphatic filariasis,
leishmaniasis, African trypanosomiasis, onchocerciasis,
dengue and Chagas disease, many of which are also con-
sidered to be neglected diseases.
Typically defined as infections transmitted from the
bite or mechanical transfer of an arthropod vector [1],
* Correspondence: mark.m.fukuda@us.army.mil
1Armed Forces Health Surveillance Center, 2900 Linden Lane, Silver Spring,
MD 20910, USA
Full list of author information is available at the end of the article
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http://www.biomedcentral.com/1471-2458/11/S2/S9
© 2011 Fukuda 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.

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VBIs are of growing importance in an era of global tra-
vel. Increasingly blurred lines of demarcation between
human and zoonotic disease reservoirs and the unpre-
dictable effect of climate change on the distribution and
behavior of arthropod vectors also contribute to the rise
of VBIs. Disproportionately high VBI burdens fall in
areas with poor health infrastructure, underscoring the
need to develop and maintain responsive surveillance
systems capable of detecting VBI outbreaks in resource-
constrained environments.
The Defense Department has long operated a network
of medical research laboratories principally to conduct
research and development on diseases of military impact.
These laboratories commonly referred to as DoD OCO-
NUS laboratories, have emphasized VBIs in their infec-
tious disease research portfolios. The historical rationale
for this emphasis on VBIs is the need to conserve and
maintain the health and capacity of troops while operat-
ing in a variety of settings with increased exposure to dis-
ease-carrying arthropod vectors. The potential impact of
vector-borne disease on military populations is illustrated
by General Douglas MacArthur, who, referring to the
impact of VBI on World War II forces, famously lamen-
ted, “This will be a long war, if for every division I have
facing the enemy, I must count on a second division in
the hospital with malaria, and a third division convales-
cing from this debilitating disease.” [2].
The creation of DoD-GEIS was inspired by the 1992
Institute of Medicine (IOM) report on emerging infec-
tions and formally tasked through the June 1996 Presi-
dential Decision Directive (NSTC-7) on emerging
infections, which expanded on the original IOM report.
The merging of DoD-GEIS with the DoD OCONUS
laboratory research mission leveraged the laboratories’
strengths—capacity for high-quality hypothesis-driven
scientific rigor and established host-nation relationships
—and sought to incorporate the additional components
of global surveillance, training and response to infec-
tious disease threats. In addition, existing OCONUS
laboratory programs oriented toward the development
of new vaccines, drugs and diagnostics for diseases in
the developing world would benefit from the acquisition
of timely surveillance data to help guide their efforts.
The inception and subsequent execution of the pro-
gram coincides with a period when DoD’s public health
concerns, expressed by General MacArthur decades ago,
increasingly converged with those of the developing
world. Since the end of the Cold War, DoD personnel
increasingly have been deployed to to render humanitar-
ian assistance in regions of political and economic tur-
moil and natural disasters. The 2010 Haiti earthquake
relief effort, during which several DoD personnel con-
tracted Plasmodium falciparum malaria [3], exemplifies
this risk.
The AFHSC-GEIS network and its OCONUS labora-
tory partners conduct VBI surveillance of in arthropod
vectors, animals and humans, with emphasis on surveil-
lance of vector-borne diseases in humans, the primary
host of interest. The VBI program aims to characterize
present occurrences of VBI in humans as well as sup-
port the AFHSC-GEIS predictive surveillance program
[4] by validating the capability of satellite remote sen-
sing, ecological niche modeling, and arthropod vector
and zoonotic reservoir surveillance to predict the risk of
VBI transmission to humans. This report reviews the
2009 accomplishments of the AFHSC-GEIS and DoD
OCONUS laboratory VBI surveillance network.
Malaria surveillance
One of the world’s largest malaria drug resistance surveil-
lance networks is maintained by AFHSC-GEIS, with sites
in Africa, South America, the western Pacific islands, and
northeast, south and Southeast Asia. The emphasis on
malaria drug resistance is well justified. Since World War
II, an inexorable pattern of resistance has rendered once-
useful malaria treatments, such as chloroquine, sulfadox-
ine/pyrimethamine and mefloquine, ineffective in large
parts of the malaria-endemic world. Despite tremendous
progress, there is still no vaccine that prevents infection
or disease. This underscores the threat posed by emer-
ging drug resistance and the importance of effective sur-
veillance systems to detect the onset of resistance and
assure optimal treatments.
In 2009, the AFHSC-GEIS laboratory network ana-
lyzed 19,730 specimens from 25 sites spanning malaria-
endemic regions using techniques, such as molecular
characterization of resistance genes and in vitro drug
sensitivity assays to determine inhibitory concentrations
against a battery of common malaria drugs. Some sites
are also capable of conducting therapeutic efficacy and
complex pharmacokinetic in vivo studies to better
understand drug-parasite interactions.
Today, the most effective anti-malarial drugs are those
in the artemisinin class. The artemisinins, derived from
Artemisia annua, have been used in Chinese medicine
for centuries under the name Qinghaosu and eventually
incorporated as first-line treatment for P. falciparum
worldwide. Compared to other malaria drugs such as
mefloquine and chloroquine, artemisinin derivatives are
vastly superior in terms of safety, tolerability and effi-
cacy, and—until recently—unmarred by resistance.
Although the artemisinins have been used on their own
as a single-agent therapy, fears over the possible devel-
opment of resistance have given rise to the concept that
malaria treatments should follow the examples adopted
for tuberculosis and human immunodeficiency virus
(HIV)—that combining drugs with differing mechanisms
of action will both optimize patient outcomes and
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minimize the risk that resistance will develop. Such arte-
misinin combination therapies (ACTs) contain a short-
acting artemisinin component to quickly reduce parasite
burden and clinical symptoms and a longer-acting part-
ner drug to clear remaining parasites. This approach is
now recommended by WHO as the first-line treatment
for uncomplicated P. falciparum malaria in all endemic
countries.
The major global investment in ACTs has been threa-
tened recently by increasing ACT treatment failures on
the Thailand-Cambodia border, an area historically con-
sidered an epicenter of drug-resistant malaria. Between
2002 and 2004, increased parasite clearance times and
unusually high failure rates with the ACT regimens arte-
sunate-mefloquine and artemether-lumefantrine were
being reported on both sides of the border [5,6] and
begged the question of whether resistance to the artemi-
sinin component or its partner drug was the culprit. To
further explore this question, the Armed Forces Research
Institute of Medical Sciences (AFRIMS) in Bangkok,
Thailand, conducted a combined in vivo/in vitro artemi-
sinin-monotherapy efficacy study to isolate the specific
effect that artemisinin resistance may have played in the
ACT failures. Although the 28-day cure rate of the arte-
misinin monotherapy regimen was greater than 90 per-
cent, two subjects failed artemisinin therapy despite the
documentation of adequate plasma drug levels, direct
observation of medication doses and up to a 4.3-fold
higher IC50concentration than the overall mean. This
report, the first to document clinical artemisinin resis-
tance, raised serious concerns that resistance to the arte-
misinin component of ACTs had developed [7].
In 2009, AFRIMS continued to expand its drug-resistance
efforts to examine possible countermeasures to combat
the potential spread of resistant strains. No previous inves-
tigations had been conducted to determine the optimal
artemisinin dose regimens that most effectively clear
P. falciparum parasites. While current dosing regimens in
widespread use were effective for relatively sensitive para-
sites, the specter of artemisinin resistance raised the ques-
tion of whether higher doses might more effectively clear
resistant strains.
AFRIMS conducted a study exploring dose-effect rela-
tionships with particular attention to the safety and tol-
erability limitations imposed at doses higher than
previously tested in humans. Subjects with uncompli-
cated P. falciparum malaria were given a total of 14, 28
or 42 mg/kg of oral artesunate divided over a week and
followed for clinical and parasitological endpoints. Safety
and efficacy findings of the highest dose were particu-
larly critical since demonstration of improved cure rates
at higher doses might be critical in designing higher-
dose regimens for widespread deployment. Unfortu-
nately, enhanced efficacy was not noted at the high dose
arm, either in parasite clearance times or cure rates.
Furthermore, transient neutropenia was observed at the
42-mg/kg dose, suggesting toxicity to myeloid progeni-
tor cells. Together, these safety and efficacy findings
allowed AFRIMS to characterize an important dose-
limiting toxicity of the artemisinins—a valuable data set
in light of worldwide deployment of ACTs [8].
To further characterize the artemisinin resistance phe-
nomenon in 2009, Naval Medical Research Unit Number
2 (NAMRU-2) completed a P. falciparum therapeutic
efficacy study in the Chumkiri District of Kompot Pro-
vince, approximately 100 km south-southwest of Phnom
Penh, Cambodia. In contrast to the areas along the Thai-
Cambodian border, where AFRIMS had conducted its
drug resistance studies, the Chumkiri site was chosen in
part to determine whether ACT resistance had spread to
points farther east. The NAMRU-2 study documented an
18.8 percent treatment failure rate employing the
national standard regimen of artesunate-mefloquine
combination therapy. Treatment failure was associated
with increased pfmdr1 copy number, higher initial parasi-
temia, higher mefloquine IC50and longer parasite clear-
ance times [9]. This study demonstrated that resistance
to the artesunate-mefloquien regimen extended beyond
the highly suspected areas of drug resistance along the
Thailand-Cambodia border, highlighting the need to
expand containment efforts to include Kampot Province.
The increased failure rates of ACTs and the confirma-
tion of resistance to the artemisinin class documented by
AFRIMS and NAMRU-2 were regarded as a regional and
global emergency. If ACT treatment failures along the
Thai-Cambodian border follow the historical precedent
of chloroquine (CQ) and sulphadoxine/pyrimethamine
(SP) resistance, ACT regimens could be compromised
globally within a few years, leading to the frightening
possibility of compromising effective treatments for the
enormous biomass of P. falciparum parasites in sub-
Saharan Africa at immense cost to human life. In
response, the international malaria community is mount-
ing an aggressive campaign to contain these resistant
parasites [10].
This concern is well founded. Specifically, the phe-
nomena of CQ and S/P resistant P. falciparum are well
described in Africa and been demonstrated to have
spread from Southeast Asia to Africa in so-called “selec-
tive sweeps” [11,12], suggesting that history may repeat
itself with the newly discovered artemisinin resistance
phenomenon in Southeast Asia. The Malaria Drug
Resistance (MDR) laboratory of the U.S. Army Medical
Research Unit – Kenya (USAMRU-K), based in Kisumu,
in collaboration with the Kenya Medical Research Insti-
tute and Kenya Ministry of Health, has monitored in
vitro malaria drug sensitivity and molecular marker pro-
files across Kenya since 1995. In 2009, P. falciparum
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drug resistance surveillance efforts focused in western
Kenya at three district hospitals in Kisumu, Kericho,
and Kisii. A total of 213 P. falciparum specimens were
collected and frozen for later drug susceptibility profil-
ing against a panel of six to twelve antimalarial drugs.
Concurrently, 182 samples were examined for molecular
markers associated with P. falciparum drug resistance,
including Pfmdr1 copy number and select point muta-
tions in Pfmdr1, Pfcrt, and PfATPase6. Data analysis
indicates that decreasing but high levels of chloroquine-
resistant, low levels of mefloquine-resistant, and no arte-
misinin-resistant parasite profiles were present among
samples assessed. Reassuringly, in vitro drug sensitivity
patterns and mutation rates suggest that overall P. falci-
parum drug resistance was stable in Kenya from 2006
through 2009.
Future USAMRU-K drug resistance surveillance efforts
will emphasize monitoring artemisinin susceptibility of
Kenyan isolates with an integrated approach to correlate
in vitro drug sensitivity testing with clinical in vivo resis-
tance assessments. Artemisinin resistance monitoring is
particularly timely in light of the recent adoption of the
ACT artemether-lumefantrine as first-line therapy for
uncomplicated P. falciparum [13]. Timing is optimal to
now establish baseline laboratory and clinical resistance
data against which future assessments can be compared,
both within Kenya and globally.
Malaria surveillance efforts at the Australian Army
Malaria Institute (AMI) have focused primarily on the
prevalence of malaria infection and incidence of drug
resistance within the western Pacific region. Efforts in
2009 concentrated on the Vanuatu and the Solomon
Islands. In collaboration with the Pacific Malaria Initia-
tive Support Centre, village-based mass blood surveys
were conducted and malaria-positive samples were gen-
otyped to determine the prevalence of chloroquine
drug-resistance polymorphism within the Pfcrt gene.
Twelve codons of Pfcrt were evaluated and a consensus
polymorphic profile was established that allowed for
comparison between different countries. The establish-
ment of a consensus “genetic fingerprint” of Pfcrt poly-
morphisms and its correlation with microsatellite
markers, not under immune or drug selection, has pro-
vided information on the flow of malaria drug resistance
genotypes throughout the region. Current data demon-
strate the existence of a common consensus genotype in
Papua New Guinea, Vanuatu and the Solomon Islands—
distinct from genotypes arising in Indonesia and the
Philippines. These findings have implications for the
manner in which drug-resistant alleles originating in
Southeast Asia may spread throughout the western
Pacific.
The AFHSC-GEIS malaria program has also been
active in surveillance of Plasmodium vivax malaria
throughout Asia and South America. As opposed to
P. falciparum, P. vivax treatments are complicated by
the need to eradicate dormant hypnozoites. Because of
the difficulty in assessing which patients harbor unde-
tectable hypnozoites, it is critical to ensure that radical
curative regimens employing chloroquine (CQ) and pri-
maquine (PQ) are optimized. Although highly curative
when administered for a two-week course, most malaria
control programs acknowledge the real-world effective-
ness of PQ for hypnozoite eradication to be inadequate,
largely due to insufficient compliance with the pro-
tracted regimen. Concerns about G6PD-related hemoly-
sis also limit the incorporation of PQ into national
treatment guidelines.
In 2009, malaria scientists at the Naval Medical
Research Center Detachment (NMRCD) in Peru reported
the results of an efficacy study of abbreviated PQ regi-
mens for the prevention P.vivax relapses. Patients were
treated under direct supervision in three health centers
in Iquitos, the largest city of the Peruvian Amazon Basin,
with CQ, 25 mg/kg over three days, plus primaquine, in
one of three different randomly-assigned regimens:
0.25 mg/kg daily for 14 days, 0.5 mg/kg daily for seven
days or 0.5 mg/kg for five days. The regimens selected
represent the WHO-recommended regimen, the Pan
American Health Organization (PAHO)-recommended
regimen, and a shorter version of the PAHO regimen,
respectively. Of the evaluable 491 patients, 48 presented
with reappearance of parasitemia due to the same vivax
genotype after 35 days of initiating the therapy: 27 (16.0
percent) in the five-day arm, 9 (5.8 percent) in the seven-
day arm and 12 (7.4 percent) in the 14-day arm (unpub-
lished data). NMRCD concluded that the seven- and
14-day PQ regimens are similar to each other in efficacy
and superior to the shorter five-day regimen in prevent-
ing relapse of P.vivax malaria [14]. Despite the lower effi-
cacy of the five-day regimen, it likely offers some benefit
over regimens without a primaquine component.
Although resistance to malaria chemotherapy has tradi-
tionally been more problematic for P. falciparum, it is
also necessary to remain vigilant for resistant P.vivax
strains. Chloroquine is nearly universally used as the
first-line therapy for P. vivax malaria due to its high effi-
cacy and low cost, and PQ remains the only drug capable
of eradicating hypnozoites from the relapsing Plasmodia
species vivax and ovale. As part of the above-mentioned
treatment efficacy study, NMRCD investigators uncov-
ered new evidence of the transmission of CQ-resistant
P.vivax in the Peruvian Amazon Basin. Of the four
patients with reappearance of parasitemia, one was deter-
mined to be probably resistant to chloroquine when a
whole-blood CQ level at the time of reappearance of
parasitemia was measured to be 95 ng/mL and pvmdr1
gene sequencing and neutral microsatellite markers
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analysis revealed the same P. vivax genotype in the reap-
pearing and original parasites [15].
In the Republic of Korea, similar concerns that CQ-
resistant P.vivax may have caused an increased caseload
from 2005 to 2007 led GEIS partners to conduct a pro-
phylactic efficacy study in 2009. Enrolled into the study
were 142 vivax malaria patients, most of whom were
participants in the Korean Army hydroxychloroquine
(HCQ) chemoprophylaxis program. To rule out non-
compliance as a cause for prophylaxis failure, plasma
HCQ metabolite levels were determined on the day of
enrollment. Most soldiers with “breakthrough” vivax
malaria infections harbored undetectable HCQ levels.
Fourteen of 127 (11 percent) of subjects were deter-
mined to have HCQ levels >100 ng/mL, meeting estab-
lished criteria for biological resistance or suspected
biological resistance.
The study was the first to describe chloroquine-
resistant P.vivax prophylaxis failures on the peninsula
and raises concerns given the widespread use of HCQ
and chloroquine for both treatment and prophylaxis
of vivax malaria in Korea. Although noncompliance
may have contributed to the increased caseload, the
widespread use of unmonitored HCQ prophylaxis
raised concerns that chloroquine resistance, a phenom-
enon previously undocumented in Korea, may have
contributed [16].
Surveillance of other VBIs in human populations
Although malaria shares common clinical features with
other VBIs, the difficulty encountered by clinicians in
rendering accurate diagnoses of other VBIs is hampered
by the fact that they are not easily diagnosed at the
pathogen level. Many studies have corroborated the
need for laboratory-based diagnostics in order to distin-
guish one etiologic cause of undifferentiated fever from
another. This is particularly applicable to VBIs, which
generally present as undifferentiated fever [17-19].
Throughout the AFHSC-GEIS laboratory network,
efforts were made in 2009 to enhance or establish hospi-
tal-based febrile illness surveillance platforms in Azer-
baijan, Bolivia, Cambodia, Ecuador, Georgia, Kenya,
Nepal, Paraguay and Peru in an effort to guide clinical
treatments for undifferentiated febrile illness—many of
which were caused by VBIs. Working in collaboration
with local Ministries of Health and other institutions,
such as the U.S. Army Medical Research Institute of
Infectious Diseases, Walter Reed Army Institute of
Research, and the U.S. Centers for Disease Control and
Prevention, specimens collected from patients with
acute febrile illness at hospitals and clinics have allowed
AFRIMS, NMRCD, NAMRU-2, Naval Medical Research
Unit Number 3 (NAMRU-3), and U.S. Army Research
Unit-Kenya (USAMRU-K) laboratories to conduct
etiological agent identification, monitor the prevalence
of VBIs within the AFHSC-GEIS network regions, and
better understand VBI epidemiology and geographic
distribution.
In 2009, AFHSC-GEIS partner laboratories conducted
etiological agent identification of non-malaria VBIs on
more than 10,000 specimens from 43 sites in nine coun-
tries. The use of techniques such as viral culture, poly-
merase chain reaction (PCR) assays and enzyme-linked
immunosorbent assays (ELISA) led to the discovery of
new pathogens and serotypes new to regional areas. For
instance, Guaroa virus (GROV) infection, transmitted by
Anopheles neivai, was documented first in Colombia,
and later in Brazil and Panama. Through the febrile ill-
ness surveillance study by NMRCD researchers [20],
several GROV cases were documented in febrile illness
patients from Bolivia and Peru by ELISA detection of
IgM-specific antibodies. Prior to this study, GROV
infection had not been documented in Bolivia and Peru
but should now be considered in the differential diagno-
sis for febrile illness of unknown etiology in that region.
Recent reports of vector-borne diseases circulating in
Nepal have described the first documented case of den-
gue virus [21] and the spread of all dengue virus sero-
types circulating in 2008 [22]. To further expand on
these findings, AFRIMS initiated a hospital-based study
to determine etiologies of undifferentiated febrile ill-
nesses at four hospitals in Nepal (two in Kathmandu,
one in Pokhara and one in Bharatpur). Through fiscal
year 2009, 163 patients had been enrolled.
Although testing is still in progress, laboratory testing
has confirmed or suggested a diagnosis in over 75 per-
cent of cases enrolled to date. In addition to non-VBIs
detected (Pseudomonas aeruginosa (one), E. coli (one),
Salmonella typhi (three), Salmonella paratyphi A (four),
leptospirosis (37), hepatitis A virus (four), hepatitis C
virus (one), brucellosis (16), influenza A H3 (six), influ-
enza A H1Sw (two), influenza B (two) in the initially
enrolled patients, 28.2 percent had a VBI: scrub typhus
(19), murine typhus (three), Japanese encephalitis (JE)
(two), primary dengue infection (12), secondary dengue
infection (nine), and malaria (non-falciparum) (one).
Diagnostic analyses yet to be completed include testing
for Bartonella infection, which has not previously been
determined to be a cause of illness in Nepal, and patho-
gen discovery for unrecognized viruses. The study con-
tinues enrollment through 2010 to determine the
seasonal risk for VBI and other infections in Nepal.
Hospital-based surveillance conducted by the AFHSC-
GEIS partners provides practitioners with critical infor-
mation used to treat patients, and for implementing
disease prevention and control measures. An example is
provided by a 2009 seroprevalence study conducted by
NAMRU-3 researchers in Azerbaijan, which surveyed
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68 patients for West Nile virus (WNV), Rickettsia typhi,
hepatitis A, Q fever, leptospirosis and brucellosis serolo-
gies. Of 68 patients screened, 8.8 percent were positive
for leptospirosis, 7.3 percent were positive for Rickettsia
typhi IgG, 93 percent contained anti-hepatitis A virus
antibodies, 31 percent showed Q-fever IgG antibodies,
and 16 percent were reactive in brucellosis screening.
The data obtained from the study provided clinicians
with a better understanding of the risks and exposures
for regionally relevant infections, in turn supporting
improved treatments. Ancillary benefits of the study
included the training and laboratory infrastructure
enhancements that enabled the Azerbaijan Ministry of
Health to better meet public health needs.
Human seroprevalence of hantaviruses, arenaviruses,
brucellosis, WNV, Crimean Congo hemorrhagic fever
(CCHF), leptospirosis, rickettsias, and several other vec-
tor-borne and zoonotic diseases have also been con-
ducted throughout the network. For example, in 2005,
Nepal experienced an outbreak of JE, and an outbreak
response executed by WHO and the Nepal Ministry of
Health collected samples from acute encephalitis
patients. Serological testing, however, revealed that only
35 percent were positive for the disease. In 2009, using
randomized JE-negative samples, AFRIMS researchers
tested acute illness serum for the presence of IgM to
dengue virus, Chikungunya virus, WNV, Leptospira and
Brucella. Of 286 samples, AFRIMS found 75 patients
(26.2 percent) with antibodies against Leptospira, 18 (6.3
percent) with Brucella antibodies and five (1.7 percent)
with Chikungunya antibodies. No samples were positive
for exposure to dengue virus or WNV. Although VBIs
made up a small percentage of samples not positive for
JE, this was the first time Chikungunya infection had
been documented in Nepal.
Not only is characterization of pathogens responsible
for febrile diseases of considerable assistance to clini-
cians rendering care to individual patients, but it also
allows for temporal and spatial tracking of disease and
pathogen strains. In Cambodia, NAMRU-2 investigators
have tested specimens collected from 5,362 patients for
dengue virus, rickettsial infections, hantavirus infections
and other pathogens, and determined dengue-2 and
dengue-4 serotypes as the predominant circulating
strains by real-time PCR. Determination of circulating
dengue virus serotypes is particularly relevant in light of
the fact that heterotypic strain infection might increase
clinical disease severity through an antibody-dependent
enhancement mechanism [23].
Surveillance of VBIs in animals and vectors
While not a major focus of the review, vector and ani-
mal surveillance can play a role in mitigating the human
impact of emerging infections by triggering measures to
limit transmission of vector pathogens from vector and
animal reservoirs. In 2009, AFHSC-GEIS continued to
conduct arthropod surveillance in Afghanistan, Ethiopia,
Kenya, Libya, Peru and Thailand in collaboration with
host-nation organizations, including Afghani and Libyan
National Malaria and Leishmaniasis Control Programs,
Universidad Peruano Cayetano Heredia, Combined Joint
Task Force-Horn of Africa, Consortium for National
Health Research-Kenya, Cairo University, and several
other academic and public health agencies.
Efforts by AFRIMS, NAMRU-3, NMRCD, and
USAMRU-K focused on continuing entomology studies
for vectors such as mosquitoes, ticks, fleas and mites to
test for arboviruses, rickettsiae, and Leishmania species.
For example, USAMRU-K collected 50,718 ticks and
36,464 mosquitoes to screen for CCHF virus and dengue
virus, respectively, in five sites of Kenya: Busia, Kahawa,
Kakamega, Kisumu and Isiolo. After initial screening by
ELISA for CCHF, three of 16 positive samples were con-
firmed by PCR and sequenced. Pooled tick samples and
mosquito samples were also used for cell culture inocu-
lation for CCHF and dengue virus.
In 2009, AFHSC-GEIS-sponsored animal surveillance
activities continued to expand in Kenya, Korea, Peru
and Thailand. Tissue and sera from animals, such as
rodents and cattle, were collected and screened for the
presence of zoonotic pathogens, including arenaviruses,
brucellosis, anthrax, leptospirosis and hantaviruses using
assays such as Rose Bengal test, Microscopic Agglutina-
tion Test, hemaglutinin inhibition assay and ELISA.
A good example of the need for coordinated human-
animal surveillance is provided by a seroprevalence
study conducted by NMRCD researchers in the Peru-
vian Amazon region to characterize the epidemiology
of spotted fever group (SFGR) and typhus group rick-
ettsial (TGR) infections among humans and domestic
pets. From the 1,195 human sera analyzed for SFGR
and TGR using anti-SFGR and anti-TGR antibody ELI-
SAs, 521 (43.6 percent) and 123 (10.3 percent) were
positive, respectively [9]. Among the 71 canines sur-
veyed for SFGR and TGR, 42 (59.2 percent) were posi-
tive for SFGR antibodies and two (2.8 percent) were
positive for TGR antibodies. Using a nested PCR, one
active SFGR infection was detected among the canines.
Among the 17 felines screened, one (7.7 percent) con-
tained SFGR-specific antibodies while none had TGR
antibodies. The study demonstrated that prevalence of
these rickettsial infections was high within the study
population, providing clinicians with a greater aware-
ness of rickettsial infections as a cause of febrile illness
in the Iquitos area and that domestic pet owners may
be at higher risk [9].
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Discussion
The 1996 Presidential Decision Directive NSTC-7 for-
mally codified and expanded the role of DoD—already a
well established contributor in tropical infectious disease
research—to include the additional components of glo-
bal surveillance, training and response to infectious dis-
ease threats as part of the DoD-GEIS program.
Infectious disease surveillance data obtained from the
DoD OCONUS laboratory network are shared freely
and published in the peer-reviewed literature to inform
local, regional and global health program managers irre-
spective of national or geographical affiliation. This
mutual benefit between host-nation public health pro-
grams and DoD has arisen in part because of the
unique, communicable nature of infectious diseases. As
VBIs increase globally, the need to optimally manage
surveillance efforts for maximum impact becomes even
more critical.
The original DoD-GEIS Emerging Infections Preven-
tion Strategy [24] stipulated the need for “standardized
sentinel surveillance” to “strengthen and integrate pro-
grams to monitor, control and prevent emerging and
zoonotic diseases” among its strategic goals, emphasiz-
ing drug-resistant malaria, Rift Valley fever, rickettsial
infections and dengue fever. In 1998, following the
document’s publication, several reviews and panels cor-
roborated the necessity of VBI surveillance [25]. An
exhaustive review of global trends in emerging infectious
disease attributed 28.8 percent of all emerging infectious
disease events to VBIs in the decade following imple-
mentation of the original DoD-GEIS Strategy [26]. In
2009, the GEIS VBI surveillance program continued to
make significant contributions throughout its global net-
work (Figure 1). However its success, opportunities exist
for greater refinement of the program. Enumerated
below and in Table 1 are concepts to guide future
AFHSC-GEIS VBI surveillance efforts for maximum
impact.
Utility of organizing surveillance initiatives: VBIs
vs. non-VBIs
As a practical matter, managing AFHSC-GEIS surveil-
lance into a cohesive program under the familiar
nomenclature of “vector-borne infections” is desirable
since scientists, government public health structures and
medical research communities tend to be organized and
resourced accordingly. However, the necessity of con-
ducting surveillance of undifferentiated febrile illnesses
that do not fall into specific AFHSC-GEIS pillars (i.e.,
respiratory, enteric, sexually transmitted or antimicro-
bial-resistant) illustrates the inadequacy of constraining
surveillance efforts for “undifferentiated fever”—a clini-
cal description befitting many VBIs, but not necessarily
inclusive of all militarily relevant diseases. Hence, strict
adherence to the necessity for arthropod vector trans-
mission may not represent the best framework for the
comprehensive programmatic surveillance of diseases
that threaten DoD personnel and other military popula-
tions. For example, omitted from this review is a rather
substantial body of work conducted by AFHSC-GEIS
partners specializing in leptospirosis, a disease that does
not require an arthropod vector component for trans-
mission, but is transmitted through human contact with
infected animal urine.
A requirement for vector-borne transmission also
excludes another body of work by AFHSC-GEIS part-
ners in Korea who conducted an outbreak response
investigation of hemorrhagic fever with renal syndrome
[27]. The investigation localized transmission sites to be
near the demilitarized zone (where most U.S. and
Korean soldiers conducted field training) and led to the
characterization of three novel hantaviruses [28-30].
Although not technically VBIs, these leptospirosis and
hantavirus surveillance efforts were prospectively
supported by AFHSC-GEIS because of their perceived
relevance and potential impact on military and develop-
ing-world populations. The demonstrated value of these
efforts speaks to the need to judiciously support non-
VBI surveillance as conditions warrant rather than hew-
ing to a dogmatic requirement for vector transmission
as a condition for programmatic management.
Within in the U.S. military framework, prioritizing
disease surveillance for VBIs is consistent with the
Infectious Diseases Investment Decision Evaluation
Algorithm (ID-IDEAL) framework previously proposed
by DoD infectious disease officials [31]. The framework
was developed as an algorithmic model to prioritize
infectious diseases posing the most substantial threats to
deployed U.S. military forces and to guide research and
development. The model takes into account disease
severity and likelihood of infection on a spatial and tem-
poral basis and assigns a Global Severity Risk Index
(GSRI) for DoD personnel. Of the top 20 infectious dis-
ease threats prioritized by GSRI, half are VBIs (malaria,
dengue fever, Rift Valley fever, Chikungunya, CCHF,
sandfly fever, O’nyong-nyong, Sindbis virus, scrub
typhus and leishmaniasis).
More recently, a panel composed of DoD infectious
disease experts and policymakers issued a priority rank-
ing of infectious disease threats to the U.S. military [32],
listing many of the same VBIs identified by the ID-
IDEAL model. Taken together, the expert panel docu-
ment and ID-IDEAL’s GSRI scores may be considered
as doctrinal support for an “infectious disease military
impact rank” (Table 2) integrating these two reports to
guide future surveillance priorities. Incorporation of this
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Figure 1 Map inset: Major Accomplishments of the AFHSC-GEIS Vector-borne Illness Surveillance Program.
Table 1 Concepts for the AFHSC-GEIS Vector-Borne Infection (VBI) Surveillance Program
ConceptRationale
Programmatic organization of surveillance efforts as VBIs is a useful
principle to prioritize surveillance efforts
Strict adherence to a VBI-only surveillance program must be balanced
with an understanding of prevailing disease threats
VBI surveillance efforts should be closely coordinated with human
surveillance
Although disease burden in zoonotic or vector populations is of interest,
it is so primarily because of the potential impact on humans
Human VBI case definitions should require laboratory confirmation Clinical diagnoses of most VBI are of limited sensitivity and specificity;
pathogen level identification will guide effective treatment
Case definitions employed should be able to be applied consistently
across disparate geographies and longitudinally
If surveillance goal is to map disease in areas of sparse infrastructure,
simpler laboratory techniques may be preferable
Advancing technologies should be evaluated continually and
incorporated without jeopardizing capability for analysis of longitudinal
trends
Balance must be achieved between newer diagnostic technologies and
adherence to established laboratory case definitions. Substitution of more
sensitive methods may erroneously mimic disease emergence
Standardized laboratory and clinical approaches should be judiciously
applied and implemented based on proximal impact on human health
The imperative for a “standardized” surveillance system must be
tempered with consideration for the cost-benefit ratio of implementing
such standards
To properly power epidemiological studies over a broad geography,
laboratory case definitions may diverge from those typically used to
guide clinical diagnoses
Example: Studies intended to define the geospatial extent of
antimicrobial drug resistance might seek to characterize genotypes from
extracted DNA rather than rely on determination of minimum inhibitory
concentrations (MICs) from viable organisms, despite the fact that the
latter may be more predictive of clinical outcome
Patient samples and associated clinical data must be recorded and
maintained in a data and specimen repository in a consistent manner
over time
Longitudinal trends can be better assessed if specimens and associated
demographic data are catalogued in a manner to allow for retrospective
trend analysis
Full use must be made of existing, appropriately collected and
catalogued sample sets for retroactive analysis
As technology advances, capability to diagnose previously “undiscovered”
pathogens can be applied retroactively to banked specimens to better
determine the pace of emergence
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index to guide future AFHSC-GEIS endeavors would
emphasize surveillance priorities in terms of health
impact rather than by mode of transmission.
Need for “standardization” and requirement for
laboratory confirmation
Capitalizing on the expertise resident throughout the
OCONUS laboratory network, AFHSC-GEIS’s VBI sur-
veillance efforts have traditionally emphasized laboratory
characterization to the pathogen level. The non-specific
clinical presentation of most vector-borne diseases
makes pathogen-level diagnosis difficult even in the
hands of highly experienced clinicians. This emphasizes
the need for highly trained laboratory scientists and
technicians to use established diagnostic methods to
enable informed individual and community prevention
and treatment strategies.
The use of the adjective “emerging” as a prefix to
“infectious diseases” implies the necessity of determining
the temporal and geospatial distribution of any given
candidate infectious disease, and assumes consistent clin-
ical or laboratory case definitions are applied over time
or between surveillance locales for such comparisons to
be valid. Development and implementation of such stan-
dard methods, particularly in the realm of laboratory-
based diagnoses, are almost always easier said than done,
given their logistical and financial costs. In addition, once
any given standard approach is implemented, the pace of
technological development almost assuredly outdates it.
Thus, the imperative for a standardized surveillance
system must be tempered with consideration of the cost-
benefit ratio involved in implementing any given standar-
dization effort.
The single greatest factor contributing to the success of
AFHSC-GEIS has been the traditionally collaborative and
close relationship between DoD OCONUS laboratory
scientists, public health personnel and their host-nation
counterparts. Together, DoD personnel and host nations
work to identify, conceive and execute emerging infectious
disease surveillance activities based on regional DoD and
local Ministry of Health priorities. While this approach
has its merits, the emphasis on regional flexibility has
come at some expense to creating a standardized surveil-
lance system. The desire for standardization to enable the
generation of geographically and longitudinally generaliz-
able data must be balanced with the need to remain
responsive to host-nation capabilities and priorities.
A more appropriate approach calls for judicious applica-
tion of proscriptive standards to maximize the applicability
of the overarching surveillance product. Additionally, if
laboratory samples cannot be transported to centralized
reference laboratories (as may be the case due to human
Table 2 Military Infectious Disease Impact Rank: Top 20 febrile illnesses ranked by order of military significance
Rank DiseaseMedian GRSI Score Medical Force ICDT RankMilitary Impact Index (GRSI/ICDT Rank)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Malaria
Diarrhea, bacterial
Dengue
Norovirus and other viral diarrhea
Leptospirosis
Chikungunya
Rift Valley Fever
HIV/AIDS
Meningococcal meningitis
Diarrhea, protozoal
Crimean-Congo hemorrhagic fever
Leishmaniasis
Hepatitis E
Hemorrhagic fever with renal syndrome
Q fever (Coxiella burnetti)
Rickettsioses
Tick Borne encephalitis
Influenza
Plague
Lassa/other arenaviruses
4949
5236
3148
1964*
1745
2608
2519
728
698
411
430
12
402
252
92
155
134
35
89
63
1
3
2
7
4949
1745
1574
280
174
163
104
52
41
37
33
24
19
16
15
8
5
4
4
2
10
16
24
14
17
11
13
5
21
15
6
19
23
8
18
22
Index calculated as quotient of Infectious Diseases Investment Decision Evaluation Algorithm (ID-IDEAL) Global Risk Severity Index (GRSI)/Integrated Capabilities
Development Team (ICDT) rank for diseases listed in both documents. Adapted from refs 27 and 28.
*Mean of all GSRI scores for diarrheal diseases.
+Mean of cutaneous, visceral and mucosal leishmaniasis GSRI scores.
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use or regulatory considerations), laboratory approaches
that are implementable in both austere and well-developed
settings may be more desirable than technologically com-
plex methods if the former approach enables data compar-
isons between locales. As a corollary, laboratory case
definitions for epidemiological studies may diverge from
those typically used to guide clinical diagnoses.
Finally, longitudinal comparisons will be optimized if
the emphasis on harmonized laboratory approaches is
matched with the collation of clinical data and the use
of proper information systems to catalog both biological
samples and their associated clinical datasets.
Role of vector surveillance
Although this report has focused on surveillance of VBIs
in human hosts, entomological vector surveillance also
plays a critical role in estimating disease risk and guid-
ing interventions to control transmission. In the absence
of a vaccine or prophylactic drug for many VBIs, pre-
vention is reliant on vector control and reduction of
infective bites. Optimally, control efforts must be linked
with vector and human surveillance data to gauge their
effect and estimate disease risk.
A critical distinction between human and vector sur-
veillance is the complexity of vector collection when
considering the tremendous diversity of culprit arthro-
pods. In contrast with human surveillance, which gener-
ally focuses on disease incidence and/or prevalence in a
particular population, unique aspects of vector transmis-
sion complicate vector surveillance approaches. For
example, for diseases in areas where a specific vector
responsible for disease transmission may be unknown or
unconfirmed, approaches emphasizing vector identifica-
tion and transmission competence may need to be
prioritized. In other areas where the disease-transmitting
potential of arthropod species is well corroborated, tar-
geted characterization of infection rates and vector
population densities maximizes the predictive power of
field vector surveillance for human VBI cases [33], help-
ing decision makers prioritize vector control efforts and
public awareness campaigns [34].
Vector surveillance and control programs face fiscal
challenges; they are difficult to sustain because the pro-
portion of infected arthropods may be low and the pre-
dictive impact on the acquisition of human disease is
difficult to verify. Nonetheless, since surveillance of
VBIs in humans is by definition post factum, the VBI
surveillance approaches must not be neglected since
correctly executed vector control measures are uniquely
preventive in nature. These factors highlight the need
for close coordination between vector and human dis-
ease surveillance efforts.
Conclusion
The studies reviewed in this report highlight the prodi-
gious accomplishments of AFHSC-GEIS’s VBI surveil-
lance program and the potential impact on vector-borne
and other communicable diseases of well conceived, rele-
vant and timely surveillance. This review unequivocally
demonstrates the benefit provided to host-nation popula-
tions through surveillance activities that transcend tradi-
tional nation-state boundaries. The capacity of infectious
diseases to affect human beings in unforeseen ways, par-
ticularly with the advance of VBIs in an ever-shrinking
global community, endangers both military and the
developing world.
Future efforts of AFHSC-GEIS’s VBI program should
center on enhancing the integration of vector, zoonotic
and human surveillance activities, continuing to maxi-
mize the impact on human diseases of interest to both
military and civilian populations, and providing surveil-
lance data that genuinely empowers public health offi-
cials. It is essential that the AFHSC-GEIS VBI program
remains dedicated to the premise that in the fight
against infectious diseases, timely and actionable surveil-
lance data are critical.
Acknowledgements
#AFHSC-GEIS Malaria and Vector Borne Infections Writing Group*: Hoseah
Akala6, Joel C Gaydos1, Robert F. DeFraites1, Panita Gosi4, Ans Timmermans4,
Chad Yasuda7, Gary Brice7, Fred Eyase6, Karl Kronmann5, Peter Sebeny5,
Robert Gibbons4, Richard Jarman4, John Waitumbi6, David Schnabel6, Allen
Richards9, and Dennis Shanks8
The authors wish to thank the numerous individuals who perform
surveillance as part of the AFHSC-GEIS global network, including all
individuals in the Ministries of Health and Ministries of Defense of our
partner nations whose efforts have contributed to the success of the
network.
Disclaimer
The opinions stated in this paper are those of the authors and do not
represent the official position of the U.S. Department of Defense.
This article has been published as part of BMC Public Health Volume 11
Supplement 1, 2011: Department of Defense Global Emerging
Infections Surveillance and Response System (GEIS): an update for 2009.
The full contents of the supplement are available online at
http://www.biomedcentral.com/1471-2458/11?issue=S2.
Author details
1Armed Forces Health Surveillance Center, 2900 Linden Lane, Silver Spring,
MD 20910, USA.2Force Health Protection and Preventive Medicine, 65th
Medical Brigade, Unit 15281, APO AP 96205-5281 USA (Republic of Korea.
3US Naval Medical Research Center Detachment (NMRCD), Centro Medico
Naval “CMST,” Av. Venezuela CDRA 36, Callao 2, Lima, Peru.4US Army
Medical Component Armed Forces Research Institute of the Medical
Sciences, APO AP 96546, Bangkok, Thailand.5US Army Medical Research Unit
Kenya, United States Embassy, ATTN: MRU, United Nations Avenue, Post
Office Box 606, Village Market, 00621 Nairobi, Kenya.6US Naval Medical
Research Unit Number 3, Extension of Ramses Street, Adjacent to Abbassia
Fever Hospital, Postal Code 11517, Cairo, Egypt.7US Navy Medical Research
Unit-2, U.S. Embassy Unit 8166 Box P, APO AP 96546, Phnom Penh,
Cambodia.8Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli
Barracks, Enoggera, QLD 4051 Australia.9Naval Medical Research Center, 503
Robert Grant Ave. Silver Spring, MD 20910, USA.
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Competing interests
The authors declare that they have no competing interests.
Published: 4 March 2011
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doi:10.1186/1471-2458-11-S2-S9
Cite this article as: Fukuda et al.: Malaria and other vector-borne
infection surveillance in the U.S. Department of Defense Armed Forces
Health Surveillance Center-Global Emerging Infections Surveillance
program: review of 2009 accomplishments. BMC Public Health 2011 11
(Suppl 2):S9.
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