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Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Non-Vector Transmission of Dengue and Other
Mosquito-Borne Flaviviruses¶
Lin H. Chen*‚and Mary E. Wilson**
*Harvard Medical School, Travel Medicine Center, Mount Auburn Hospital,
Division of Infectious Diseases, Mount Auburn Hospital, 330 Mount Auburn Street, Cambridge,
MA 02238, USA
**Harvard Medical School, Division of Infectious Diseases, Mount Auburn Hospital,
330 Mount Auburn Street, Cambridge, MA 02238, USA
Abstract
A number of mosquito-borne viruses in the family Flaviviridae, genus Flavivirus, cause significant illnesses
in humans. These diseases include dengue, yellow fever, West Nile fever, Japanese encephalitis, St.
Louis encephalitis and Murray Valley encephalitis. The viruses cause syndromes that can be generally
classified as one of three types: haemorrhagic fever, fever with rash and arthralgia, and encephalitis.
Transmission of dengue virus following mucocutaneous exposure has recently been documented.
Transmission of West Nile virus (WNV) without a mosquito vector has also been reported. We review the
literature and summarize reported cases and routes of non-vector transmission of the six medically most
important mosquito-borne flaviviruses. We also compare the biological characteristics of the viruses in
humans and discuss how this could influence the probability of non-mosquito transmission.
Keywords: Dengue, flavivirus, West Nile virus, virus transmission.
Introduction:
Flavivirus Transmission
The genus Flavivirus, which belongs to the
family Flaviviridae, contains 73 RNA viruses[1].
Among these viruses, 34 are mosquito-borne,
17 are tick-borne and 22 are zoonotic agents;
22 of the 34 mosquito-borne and 13 of the 17
tick-borne flaviviruses are associated with
human disease[1]. There are three serological
groups – dengue serological group, Japanese
encephalitis serological group and yellow fever
virus group[1,2]. Non-vectored flaviviruses are
probably maintained in nature by animal-toanimal transmission via saliva and urinary
shedding.
Flavivirus infection in mosquito occurs
when the mosquito ingests a blood meal
containing the virus, which infects the midgut
epithelial cells and subsequently the salivary
gland[1]. Some days after the initial blood meal
(extrinsic incubation period), the virus is
¶
Although the non-mosquito route of transmission of dengue and other mosquito-borne viral infections is rare
and accidental but it has a lot of significance for physicians, who should keep this in mind and should aggressively
look for these possibilities while making differential diagnosis of mosquito-borne viral infections, particularly in
non-endemic areas. However, public health workers engaged in the prevention and control of dengue and other
vector-borne viral infections should essentially treat these as mosquito-borne infections - Editor.
[email protected]; 617 499 5026; Fax: 617 499 5453
18
Dengue Bulletin – Vol 29, 2005
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
secreted in the saliva and reaches a new host
when the mosquito takes another blood meal.
Infection of salivary gland leads to lifelong
infection in the mosquito[3]. Some enzyme
processing may occur in the mosquito’s midgut,
for example by trypsin, and may exert an
impact on the infectivity of the virus[4]. Following
a mosquito bite, which inoculates dengue virus
into skin, the virus appears to target skin
Langerhans cells, and replicates in local tissues
and regional lymph nodes, then disseminates
via lymphatics to the blood stream [1,5,6].
Similarly, after inoculation from an infected
mosquito, the West Nile virus (WNV) may
infect fibroblasts, vascular endothelial cells or
the reticuloendothelial system, leading to
viraemia, and then reach the central nervous
system to infect the host cells[2,3]. The recent
study that documents the infection of
uninfected mosquitoes co-feeding with WNVinfected mosquitoes on the same host (mouse)
shows that some local diffusion/dispersal of the
virus from bite site must occur as the mosquito
is feeding[7].
For a mosquito-borne infection, the
amount of virus in the mosquito saliva, the
frequency of bites and the duration of feeding
by infected mosquitoes would determine the
amount of virus inoculated. The amount of
WNV secreted in mosquito saliva has been
measured by real-time reverse transcriptasepolymerase chain reaction (RT-PCR) in Culex
pipiens quinquefasciatus, a vector of WNV;
mosquitoes infected with WNV could transmit
about 104.3 plaque-forming units of virus[8].
Furthermore, mosquitoes inoculate about 1%
of their total virus content when they take a
blood meal, thus each mosquito could transmit
at least 100 infective doses of virus[8].
The level of viraemia in humans depends
on the rate of clearance by macrophages, and
viraemia ceases with the production of humoral
antibodies in the host[1]. In vertebrate hosts,
dengue viraemia titers usually are >105/ml,
Dengue Bulletin – Vol 29, 2005
although virus can be below detectable levels
by conventional laboratory techniques[1]. The
time of onset, duration and level of viraemia
varies with different flaviviral infections and
may vary from one subtype or strain of a specific
virus to the other.
Analogous to mosquito-borne infection,
a non-vector transmission depends on the
amount of virus in the inoculum and volume
of material that reaches a receptive site.
Additional factors that may influence the
likelihood of direct transmission include
stability of shed virus in the environment, the
immune status of those potentially exposed,
the size of the inoculum and the route of virus
contact and entry[9]. Virus shedding may vary
among the flaviviruses, may be different in
humans as compared to experimental animals,
and may occur in irregular patterns. Many
reports of infection follow blood exposure,
but some flaviviral infections are associated
with virus in cerebrospinal fluid (CSF), urine,
or other fluids that clinicians and caretakers
could potentially be exposed to. A patient
who is critically ill and who has haemorrhage
is more likely to be a source of blood
exposures in the hospital setting or at home.
An important variable in the level of risk is
the time of viraemia relative to the presence
of severe illness and haemorrhage.
The viability of viruses in the environment
also may differ. For example, WN and yellow
fever viruses appeared to have prolonged
survival at room temperature in an experiment
where the viruses dried on filter paper were
tested for infectivity by culture, titration in Vero
cells and assessed by RT-PCR for viral RNA[10].
WNV was recovered up to 60 days after the
procedure and yellow fever up to 90 days[10].
The survival of Japanese encephalitis virus (JEV)
appeared to be inversely related to relative
humidity whereas the yellow fever virus
infectivity remained longer at higher relative
humidity[9].
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Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Dengue Virus
Dengue viruses can be associated with
haemorrhage, which can increase health care
workers’ exposure to blood, and presumably
lead to a greater risk for direct or nosocomial
transmission. Dengue virus transmission
without mosquito vector has been reported to
occur via different routes, including
needlestick, intrapartum, bone marrow
transplant and mucocutaneous exposure[11-21]
(Table 1).
Among the reported cases of dengue virus
infection from non-mosquito transmission,
most source patients did not have haemorrhagic
manifestations. Specifically, the reported health
care workers who acquired dengue infection
were not exposed to haemorrhagic source
patients. One case of intrapartum/vertical
transmission occurred in an infant born to a
mother who was diagnosed with dengue
haemorrhagic fever just before delivery[18].
There are no known animal models of
dengue virus transmission. Although serological
surveys have demonstrated dengue antibodies
in macaques in Sri Lanka, non-human primates
infected with dengue virus do not exhibit
symptoms of illness[22]. It is not clear whether
asymptomatic infections in non-human
primates contribute to maintenance of dengue
virus in nature.
Yellow Fever
Yellow fever is the prototype virus amongst
the flaviviruses. Because yellow fever virus is
associated with haemorrhage, there may be
a greater potential for transmission through
blood exposure in health care workers,
compared to flaviviruses that do not cause
haemorrhage. A review of literature identified
numerous cases of non-vector transmission in
the pre-vaccine era, where scientists and
20
laboratorians became infected with yellow
fever virus after contact with blood or tissues
of infected laboratory animals or handling
experimentally-infected animals[23,24]. One
case that occurred in 1930 in a hospital
technician who analysed the blood of a yellow
fever patient in London was described again
recently; the route of transmission was
unclear[25] (Table 1).
Experimentally, monkeys have become
infected with yellow fever virus that was
introduced through a gastric catheter[26].
Intranasal transmission and mucocutaneous
transmission via conjunctival sac has also been
documented in monkeys in the laboratory[27-29].
Furthermore, yellow fever virus rubbed on
intact abdominal skin of monkeys has led to
infection[30] (Table 2).
West Nile Virus
Human infections with WNV have been
reported to occur from needlestick,
breastfeeding, blood transfusion, organ
transplants, haemodialysis and intrauterine or
transplacental routes[31-38]. Two cases of West
Nile fever occurred in turkey breeders where
the route of transmission was unknown, but
was speculated to have been by aerosol, fecaloral or percutaneous exposure [37] . A
seroprevalence survey conducted on the
workers from six turkey farms showed that 18%
had recent infection with WNV; seroprevalence
was highest (55%) from the farm where the
two cases worked[37] (Table 1).
Among the reported cases of nonmosquito transmission, many source patients
were asymptomatic. In fact, asymptomatic
viraemic donors of blood products and organs
were the most likely contributors to nonmosquito transmission. This shows that
asymptomatically-infected individuals are
viraemic.
Dengue Bulletin – Vol 29, 2005
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Table 1. Reported routes of transmission in humans without vector
Dengue Bulletin – Vol 29, 2005
21
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Infected blood has, however, been the
most frequently documented source of nonmosquito transmission. WNV RNA has been
identified by reverse transcriptase-polymerase
chain reaction in the urine of a patient with
encephalitis on the 8th day of illness[39]. It is
not yet clear whether the WNV RNA in urine
is infectious, and whether viruria plays a
significant role in human WNV transmission.
Similarly, an experiment in hamsters found
WNV to persist in the brain and kidneys,
leading to chronic renal infection with persistent
viruria[40]. Although transmission from urine
exposure has not been documented in
literature, infectious WNV was cultured from
hamster urine for up to eight months and could
possibly spread to other animals by aerosol or
by ingestion[41]. WNV can also infect mice by
the oral route[42]. In hamsters, investigators
compared the pathogenesis of WNV following
infection by mosquito bite, needle inoculation
and ingestion; infection occurred by all three
routes, resulting in similar levels of viraemia,
duration of viraemia, clinical manifestations,
pathology and antibody response[43]. The onset
of viraemia was delayed following oral infection
and mortality was lower, but the importance
of oral route in the transmission of WNV in
nature remains unclear[43] (Table 2).
Flaviviruses are sensitive to acid pH and bile,
but their transmission via ingestion of infected
milk has been demonstrated with tick-borne
encephalitis, another flavivirus infection[1,44]. It is
conceivable that virus entry could occur at other
parts of oropharynx rather than in the stomach
or duodenum. With breastfeeding humans, one
could postulate that virus potentially could enter
via mucosa of oropharynx.
Japanese Encephalitis
No nosocomial cases in humans have been
reported. However, intrapartum, transplacental
22
or congenital infection has been
documented[45,46]. A study of five pregnant
women infected during an epidemic in Uttar
Pradesh, India, found that two women
delivered normal infants, two women
miscarried in the first or second trimesters, and
the virus was isolated from one aborted fetus[46]
(Table 1).
Experiments in animals have
demonstrated direct transmission of JEV. One
study showed that a bat that ingested infected
mosquitoes became infected [47]. Two
experiments showed possible aerosol
transmission [48,49]. Macaques inoculated
intranasally with JEV developed symptoms 1114 days later; viral antigen was identified by
immunofluorescent staining and histopathological changes were found in the
nervous system[48]. Investigators speculated
that JEV probably entered the blood stream
following aerosol infection and seeded the
central nervous system. A study in mice
infected with aerosolized JEV showed lesions
in olfactory bulb, frontal lobe and olfactory
portions of cerebrum initially, followed by
necrotic lesions in olfactory bulb, cerebrum,
brain stem and spinal cord; the suggested
spread was from nasopharynx across the
cribriform plate to the olfactory bulb[49]. Oral
infection in mice of JEV led to antibody
production and protection against intracerebral
challenge of JEV[50]. JEV has also been isolated
from mouse urine after infection; in addition,
JE viruria was shown to persist longer than
viraemia (days 5–9 versus days 1–2 after
infection)[51] (Table 2).
St. Louis Encephalitis
Direct, non-mosquito transmission of this virus
in humans has not been reported. However, a
study on mice exposed to aerosolized St. Louis
encephalitis virus in a closed chamber
demonstrated intranasal/aerosol transmission[52].
Dengue Bulletin – Vol 29, 2005
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Table 2. Potential routes of transmission in animals*
*WNV and St. Louis encephalitis virus have been isolated from urine of experimentally infected hamsters[40,41]
and JEV from urine of mice[51], but no reports documenting transmission from urine were found in the
published literature.
Patients with St. Louis encephalitis were found
to have viral antigen in urine by indirect
immunofluorescence, electron microscopy and
immune electron microscopy, although virus
Dengue Bulletin – Vol 29, 2005
was not isolated from urine[53]. Recent studies
show that hamsters experimentally infected by
subcutaneous injection of St. Louis virus can
shed the virus in urine for at least four months[41].
23
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Murray Valley Encephalitis
Direct, non-mosquito transmission of this virus
in humans has not been reported, which may
reflect the small number of human infections
as compared to the other flaviviruses.
Viraemia
The levels of viraemia among the flaviviruses
are difficult to compare because measurements
are described in different terms. These
measurements include median mosquito
infectious doses per millilitre (MID50/ml), copies
of RNA per millilitre, plaque-forming units per
millilitre (pfu/ml), and intracerebral median
lethal dose per millilitre (LD50/ml) (Table 3).
Yellow fever virus is readily isolated during
the first four days of illness, but may be
recovered from serum up to 17 days[54]. Yellow
fever viraemia in a human case showed that
virus titres were 104.6 LD50 at 5 days after the
onset of symptoms and 102.7 LD50 at 7 days
after the onset of illness[53]. Experience with
Japanese encephalitis also shows that viraemia
can persist following resolution of symptoms
and in recurrently symptomatic patients[55,56].
In natural infection with dengue virus, the
duration and level of viraemia varied among
different strains and serotypes[57]. The duration
of viraemia ranged from 1–7 days (2–12 days as
per Gubler, 1981), with a mean of 4.5 days,
median of 5 days[58]. The duration of viraemia is
underestimated in the study because some of
the children were still viraemic on the last blood
draw. The duration is longer in primary infection
(5.1 days), compared to secondary infection (4.4
days), and the peak virus titre was 108.2 MID50/
ml (median mosquito infectious doses per
millilitre)[58]. Patients with primary infections had
persistent viraemia until 1.6 days after
defervescence whereas those with secondary
infections cleared viraemia by 0.6 days after
24
defervescence[59]. Higher levels of viraemia
correlated with the severity of disease, and the
rate of virus clearance in the two days before
defervescence was greater in dengue
haemorrhagic fever than in dengue fever[59].
The measurement of plasma RNA by
quantitative competitor (RT-PCR) derived a
range of 10 5.5 to 10 9.3 copies/ml, which
correlated with MID50 by a geometric mean
number of 0.15 RNA copies per MID50[60].
These RNA levels peaked two days before
defervescence and declined to below
detection in two thirds of patients by
defervescence[60]. Therefore, one third of
patients had detectable dengue RNA at
defervescence and they were possibly
infectious after defervescence[60]. A study of
adult patients infected with DENV-3 in
southern Taiwan in 1998 using the quantitative
RT-PCR method showed that during
defervescence, viral RNA remained high in
DHF patients but was undetectable in DF
patients; viraemia in DHF patients persisted
for up to six days after defervescence[61].
Since the level and duration of viraemia
appear to correlate with the severity of the
disease, it is likely that asymptomatic dengue
infection would have lower levels and shorter
duration of viraemia than DF or DHF. Likewise,
other flavivirus infections are expected to have
lower levels of viraemia in asymptomatic
infections, compared to that in symptomatic
infections. Cases of WNV acquired through
transfusion demonstrate viraemia in
asymptomatic donors. Estimated viral loads in
blood donations that led to transfusionassociated transmission of WNV were 0.8–75
pfu/ml for 2002 and 0.06–0.5 pfu/ml in 2003[34].
Because RNA titres are higher than plaqueforming units by about 400[62], the RNA levels
would range from 24–30 000 copies/ml.
In West Nile infections, viraemia is present
during the two days before until about four
days after the onset of illness[63]. Rarely the
Dengue Bulletin – Vol 29, 2005
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
Table 3. Population at risk and viraemia
Dengue Bulletin – Vol 29, 2005
25
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
virus is isolated from the CSF in patients with
meningoencephalitis. The virus has also been
isolated from organs such as liver, spleen, lung
and pancreas, with a high concentration of
reticuloendothelial cells [64]. In immunocompromised patients intentionally infected
with West Nile virus as part of a study to
examine novel approaches to cancer
treatment, the virus could be recovered from
blood up to 28 days after inoculation.
In the case of percutaneous or
mucocutaneous exposure, the viral load would
depend on the amount of blood in contact.
Assuming a mean volume of blood inoculated
via needlestick to be 1 ul[65], the viral load after
a needlestick exposure would be in the range
of 103 to 107 RNA copies/ml for dengue virus
and up to 300 RNA copies/ml for West Nile
virus. Despite the minuscule amount of blood
transferred, needlestick transmission has been
documented for both dengue and West Nile.
Quantification of Risk
The risk of transfusion-associated transmission
of West Nile virus in Queens, New York, in
2002, was estimated to be 1.8/10 000
donations (mean) up to 2.7/10 000 donations
(peak) (or 1 in 3700 to 1 in 5555 donations)[66].
These estimates were based on the findings
that 80% of West Nile virus infections are
asymptomatic, that the incubation period lasts
2–6 days, and that the virus is detected in blood
1–2 days after mosquito inoculation; therefore
an asymptomatic donor may have a mean of
three viraemic days before the onset of
symptoms[66]. In comparison, the estimated
frequency of transfusion-associated hepatitis B
virus (HBV) infection in the United States with
currently available testing technologies is 1/
30 000–250 000 units, hepatitis C virus (HCV)
infection is 1/30 000–150 000 units, and
human immunodeficiency virus (HIV) infection
is 1/200 000 to 2 000 000 units[67].
26
A recent report of HCV transmission
associated with saline flushes (re-use of
disposable syringes and contamination of
shared saline bags) showed an attack rate of
27%, and the dose leading to infection of 50%
of exposed population for patients was three
flushes (30–60 ml of saline)[68,69]. Given the
relative rates, one could estimate that WNV
could be transmitted from up to 5% of viraemic
contacts if similar breaches in sterile techniques
occurred with saline flushes.
Health care workers (HCWs) regularly
encounter occupational exposure to blood and
body fluids, and the risk of injury is related to
precautions taken. A study in a community
hospital found that one-quarter of HCWs had
mucocutaneous blood exposure in the three
months prior to the survey, whereas one third
of HCWs had percutaneous injury in the same
period.[70] Another study that assessed the risk
of sharps injuries in nurses caring for diabetic
patients found nearly 80% of nurses
experienced at least one needlestick; the
American Nursing Association reported 600 000
to 1 000 000 sharps injuries in HCWs each
year[71]. The frequency of exposure in HCWs
illustrates the vulnerability to blood-borne
transmission of infections, including
flaviviruses. Health care workers in developing
countries face a substantially riskier
environment because of inadequate supplies
of sterile needles, masks, gloves and goggles
that could protect them from blood exposures,
though few studies are available to document
the magnitude of these risks[72].
Conclusion
Multiple routes of non-mosquito transmission
of flaviviruses in humans have been described
recently. Infections with dengue and West Nile
viruses have been the most commonly
documented. These two viruses can be
associated with asymptomatic infection, febrile
Dengue Bulletin – Vol 29, 2005
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
illness with rash and arthralgia, or more severe
illnesses such as dengue haemorrhagic fever/
dengue shock syndrome and West Nile
meningoencephalitis. The asymptomatically
infected persons appear to be particularly
important as sources in the transfusionassociated and transplant-associated
transmission of West Nile virus.
Syndromes with haemorrhage may increase
the risk of exposure to blood-borne pathogens,
possibly due to higher level of viraemia, greater
difficulty in avoiding accidental contact and more
intense contact needed to care for the severely
ill patients. In spite of the fulminant course and
haemorrhagic sequelae of yellow fever
infection, the only documented and published
cases of possible direct transmission of yellow
fever virus were reported before the availability
of the yellow fever vaccines. Vaccination
probably has provided significant protection to
health care workers and laboratorians. It is also
possible that health care workers take greater
personal protective measures in caring for
severely ill patients (for example, those with
haemorrhagic symptoms) and therefore
minimize their exposure.
Risks of non-mosquito transmission of
flaviviruses may differ among the viruses for
many reasons. These include the size of the
population exposed to the infection (which may
vary from year to year and change over time),
the availability and state of medical resources
(e.g. adequacy of infection control, testing of
donated blood, availability of organ
transplantation), biological characteristics of the
virus and immunity of the human population
because of prior infection or vaccination. As
discussed, the level of viraemia, the duration
of viraemia and peak viraemia differ among
the flaviviruses. The infective dose of virus may
also differ among the flaviviruses. Finally, the
period of clinical illness and the period of
viraemia may have different patterns of
overlap. Persistent shedders of virus would pose
a greater risk of transmission to their contacts.
Dengue Bulletin – Vol 29, 2005
Infection may not be detected in an
endemic population where the majority of
individuals have previously been infected or
vaccinated. For example, non-immune
youngsters are more likely to be infected by
dengue virus, but an association with nonmosquito transmission may not be apparent to
them. Furthermore, WNV is the only flavivirus
documented in the literature to be transmitted
by transfusion of blood products. One possible
explanation is that youngsters, in whom
flavivirus infections such as dengue occur at a
higher incidence, are less likely to donate blood.
Another explanation is that non-mosquito
transmission is unlikely to be recognized in an
area where an infection is endemic. In addition,
many flavivirus infections result in mild or
asymptomatic illness and may not prompt any
work-up, so could not be recognized as
transfusion-acquired infections.
Adequacy of infection control education
and materials will influence risks in the health
care setting. In many countries endemic for
JE, dengue and yellow fever, resources for
infection control are lacking and adherence to
precautions may be difficult or impossible.
Diagnostic laboratories and technologies to
document infections and their sources may be
unavailable in many endemic countries. It is
most difficult to differentiate between nonmosquito transmission and mosquito-borne
infection in endemic areas where the vector is
widespread. Hence, most cases of nonmosquito flavivirus transmission in humans
have been documented in developed countries.
Our review would suggest that nosocomial
transmission of these infections probably does
occur in endemic areas, and health care
workers should be aware of the these risks.
The authors searched Medline/Pubmed for
viraemia, nosocomial transmission and
mucocutaneous transmission of flaviviruses as
well as yellow fever, dengue, West Nile,
Japanese encephalitis, St. Louis encephalitis
and Murray Valley encephalitis for pertinent
information on the topic.
27
Non-Vector Transmission of Dengue and Other Mosquito-Borne Flaviviruses
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