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virus infection: Epidemiology, pathogenesis,
presentation, diagnosis, and prevention
PhD, Z]/[aoc £ Robinson, MD, and Ursula Kuhnle, ~rD
Dengue virus infection is now the most com-
mon arthropod-borne disease worldwide
with an increasing incidence in the tropical
regions of Asia, Africa, and Central and
South America. It presents a spectrum of
disease, ranging from a harmless flulike ill-
ness to a severe hemorrhagic fever with high
morbidity and mortality, the latter almost
entirely in children. The virus is transmitted
by mosquitoes, AedeJ aegypti and Aedea albopic-
taJ. Cold-resistant strains of Aedes vectors
have been identified that may pose a threat
to children living in temperate zones. 1-4
It is estimated that 100 million cases of
infection occur worldwide per year.
Between 1986 and 1990 1.5 million cases
of dengue hemorrhagic fever or dengue
shock syndrome with 15,940 deaths were
report ed to the Worl d Health Organi-
zation. Deaths occurred primarily in chil-
dren between the ages of 5 and 15 years. It
is clear that dengue virus infection is the
most important arthropod-borne viral dis-
ease in human beings both in terms of mor-
bidity and mortality rates, s' 6
Dengue occurs in endemic and epidem-
ic forms. Recorded epidemics of a
From the Depart,zwnt of Microbiology, Faculty of Medicine,
University of Malaya, Kuala Lumpur, Malaysia; the
Department of Pediatrics, University of Melbourne, R~al
Children's Hospital, Melbourne, Australia; and the
Department of Pediatrics, National University of Malaysia,
Kuala Lumpu~:
Reprint requests: Ursula Kuhnle, MD, Universit~ts-
kinderldinik, Abteilung Endokrinologie, Lindwurm-
str. 4, 80337 Munich, Germany.
J Pediatr 1997;131:516-24.
Copyright © 1997 by Mosby-Year Book, Inc.
0022-3476/97/$5.00 + 0 9/19/82209
denguel i ke disease date to 1779, when
outbreaks were reported in Batavia (pre-
sent-day Jakart a) and Cairo. Since then
epidemics have been report ed in Phila-
del phi a (1780), Zanzi bar (1825 and
1870), Calcutta (1824, 1853, 1871, and
1905), the West Indies (1827), Hong
Kong (1901), Greece (1927-1928),
Australia (1925-1926; 1942), the United
States (1922), and Japan (1942-1945). 7-9
See rel ated article, p. 525.
The earlier outbreaks were uncompli-
cated cases of dengue fever characterized
by high-grade fever and severe bone and
back pains. Hemorrhagi c complications
have been i ncreasi ngl y document ed in
outbreaks since 1944. Between 1956 and
1989 more than 2.5 million cases of DHF
were report ed to the Wor l d Heal t h
Organi zat i on wi t h 42,751 deaths. 5
Sout heast Asia, part i cul arl y Thailand,
/V[yanmar, and Vietnam, are the most af-
fected areas, where large DHF epidemics
occur each 3 to 4 years. 10-13 For example,
between 1982 and 1987 Thailand record-
ed more than 403,000 cases of DHF with
approximately 2400 fatalities. Dengue he-
morrhagic fever is among the 10 leading
causes of illness and death in hospitalized
children in these areas. 11
In recent years several countries with
long-standing dengue virus activity report-
ed epidemics of DHF for the first time
(Fig. 1). China experienced its first epi-
demic of DHF on Hai nan Island in
1985-1986 with a morbidity of 1915 per
100,000 residents. 14 India (where DF has
been endemic and with numerous epi-
demics reported in the past 200 years) ex-
perienced the first outbreak of DHF/ DSS
in New Delhi in 1988, with 24 patients
hospitalized within 2 mouths and a case fa-
tality rate of 33%. 15 In 1989 DHF/ DSS
was reported for the first time in Tahiti and
New Caledonia. 16'17 In 1990 Sri Lanka re-
ported 935 cases with 54 deaths. 18
In the Americas there is an increasing
incidence of DF and DHF. The first large
epidemic of DHF occurred in Cuba in
1981 wi t h 24,000 cases of DHF and
10,000 cases of DSS report ed with 158
deaths during a 3-month period. 19'20 In
1986 and 1987 massive outbreaks of DF
were reported in Brazil. 21'22 Subsequent
serologic investigations estimated almost
4 million cases of DF compared with the
clinically estimated 1 million. 21 In 1988 an
outbreak of DF was reported at 1700 m
above sea level in Guerrero State,
Mexico. 23 In 1990 almost one fourth of
the 300,000 people living in Iquitos, Peru,
cont ract ed DF 24 and in the same year
3108 cases of DHF with 78 deaths were
reported in Venezuela. 25
The increasingly wi despread distribu-
tion and the rising incidence of dengue
virus infections is related to increased dis-
tribution ofA. aegypti and to the increase
in urban population in the "mega-cities" of
Sout heast Asia. Lack of effective pro-
grams to contain the vector, development,
and deterioration of the urban environ-
ment are responsible. However, the rea-
son for the change from simple DF epi-
demics to a severe hemorrhagic disease,
Vol ume 13 I, Number 4
often associated with shock, DHF/DSS, . . . . .
is not well understood. , a ~ ~ t~ 3~ ~
Furthermore, increased air travel and c=,,,
hence the spread ofthe mosquito vector al- t3o ~ t " .
most certainly facilitates the spread of ~ ~ ~' f f e : ~ ~ ~ ' ~
DF'26 A linlited number °f "imP°fred" a~, ~ ~ ~ ( f l
cases of DF and DHF have been reported
from New Zealand, 27 the Netherlands, 28 ~, 4 . . 1.4
England, 29 Germany, and Switzerland. a°'al ' ~" ,.,, 1.2 " ~ ' ~, ) ~
Int he United States 22 of24 confirmed ~ ~ ~a ~J ~r t
~BL . af "
cases in 1990 were imported from Oceania, . . ~7. ~ ~:~ " ~' 1" ~. . . ; 2"
theCarribean'Asia'lVie~de°'andPeru'32 ~ ~ J ~ j ~
TRANSMI SSI ON 0,o0 ..... o.~
The known natural hosts for dengue
viruses are man, lower primates, and mos-
quitoes. The arthropod vectors are mem-
bers of the genus Aedea that thrive both in
urban and rural areas. 3a-as The predomi-
nant species implicated in disease trans-
mission are A. aegypti and A. albopictu~. 56-a8
Aedea aegypt£ considered the most effi-
cient vector, originated in the forests of
Africa and has now spread throughout
most of the world and is found between
50 degrees north latitude and 20 degrees
south latitutde. 3942 The female mosquito
feeds during the daytime, with peak activ-
ity in the morning and late afternoon. 43'44
After feeding on a viremic individual, the
mosquito may transmit the virus directly
by change of host, or after 8 to 10 days
during the time the virus multiplies in the
salivary glands. 45 The infected mosquito
then remains capable of transmission for
its entire life. 43 Transovarian transmission
of dengue viruses has been document-
ed, 35'46'47 anclA, aeyyptf eggs are highly re-
sistant to desiccation and can survive for
extended periods. 48 These facts may ex-
plain the occurrence of spontaneous out-
breaks of DF.
Aedes a/bapictua is indigenous to
Southeast Asia, feeds during the day, and
has been shown to have a higher biting
frequency than A. azgypH. 49 Recently it
has been introduced into Nigeria, Europe,
and the United States, apparently by
shipments of used automobile tires. In the
United States, A. albopicl~ has spread as
far north as Chicago. 50"52 With the spread
of the adaptable, cold-resistant strains of
A. albopict~o to Europe, it has been sug-
gested that conditions might arise, which
F~. 1. World map demonstrating the,global distribution of the various clinical forms of dengue virus in-
fections and of the various subtypes of dengue viruses, Adapted from Halstead SB.The XXth century pan-
demic: need for surveillance and research.World Health Stat Q 1992;45:292-8. Reprinted with permission.
are suitable for a major European out-
break of dengue virus infection .4
Dengue viruses are members of the
family Flaviviridae, which include human
pathogens, such as the Japanese en-
cephalitis virus and yellow fever virus. 53
Four dengue virus serotypes and various
"biotypes" can be differentiated.
All members of the family Flaviviridae
share common morphologie characteris-
tics, genome structure, and replication
and translation strategies. 2Vrtature dengue
virus particles consist of a single-stranded
ribonucleic acid genome surrounded by
an approximately icosahedral nucleocap-
sid with a diameter of 30 nm. The nucleo-
capsid is covered by a lipid envelope of 10
nm thickness derived from host cell mem-
branes and contains the envelope and
membrane proteins. 53
The viral genome of approximately 11
kb is infectious, has a messenger-like pos-
itive polarity, and can be translated in
vitro. The 5" end of the RNA has a type I
cap structure but lacks a poly A tail at the
5" end. 54-56 It contains a si@e open read-
ing frame of about 10,000 nucleotides en-
coding three structural and seven non-
structural proteins. The gene order is
5"- C- pr M( M) - E- NS 1-NSYA-NSYB-
NS5-NS4A-NSdB-NS5. The proteins
are synthesized as a polyprotein of about
5000 aminoacids that is processed co-
translationally and posttranslationally by
viral and host proteases. 57-66
The structural proteins include a capsid
protein rich in arginine and lysine residues
and a nonglycosylated prYi protein pro-
duced from a glycosylated precursor in a
late step of virus maturation. 54'55,67'68 The
major structural envelope protein is in-
volved in the main biologic functions of the
virus particle such as cell tropism, acid-
catalyzed membrane fusion, and the in-
duction of hemagglutination-inhibiting,
neutralizing, and protective antibodies. 69
The first nonstructural protein is NS1,
a glycoprotein with a function in the virus
life cycle that is unknown. 7° NS1 proteins
are detected in high titers in patients with
secondary dengue infections, but are
rarely found in primary infectlons. 71 The
NS2 region codes for two proteins
(NSYA and NSYB) that are thought to be
implicated in polyprotein processing;
whereas NS5 is probably the viral pro-
teinase that functions in the cytosol. 65'66'72
The NS4 region codes for two small hy-
drophobic proteins that seem to be in-
volved in the establishment of the mem-
branebound RNA replication complex.
The protein encoded by the NS5 gene has
a molecular weight of 105,000 and is the
most conserved flavivirus protein. On the
F~. 2. Typical bright red rash of a dengue virus infection with clear areas scattered in between, the so-
called "islands of white in a sea of red."
basis of the amino acid sequence, this pro-
tein is believed to be the virus-encoded
RNA-dependent RNA polymerase. 7a
The clinical features of dengue virus in-
fection vary from an asymptomatic infec-
tion to a febrile "flulike" infection (DF) to
the more severe DHF, which can lead to
DSS. 74'76 This clinical variability is poor-
ly understood and seems to be related to
the age and sex of the individual but also
to the immunologic and nutritional status.
Dengue hemorrhagic fever is most likely
to develop in immune-competent, well-
nourished girls between the ages of 7 and
12 years. 76 Dengue viruses tend to cause
a mild illness in the yew young infant, but
DHF/ DSS can develop in infants born to
immune mothers as a result of waning
passive maternal antibodies. 77 Dengue
hemorrhagic fever is rare after the age of
lb years.
The incubation period of DF after the
mosquito bite (as well as the febrile peri-
od) averages 4 days. Dengue fever may
manifest with fever and a discrete macular
or maculopapular rash. In this situation
the clinical differentiation from other viral
illnesses may not be possible, recovery is
rapid, and need for supportive treatment
is minimal) In more severe DF, the tem-
perature rises rapidly (frequendy reach-
ing a9 ° c or higher) and persists for 5 to
6 days. Fever is characteristically biphasic
and returns to almost normal in the mid-
die of the febrile period giving rise to the
saddleback temperature chart. It reaches
its highest level during the last 24 hours
before abatement. The patient is general-
ly ill. Symptoms include headache and
retroorbital pain, particularly when pres-
sure is applied to the eyes ("Fire is coming
out of my eyes"). Arthralgia, myalgia, and
a macular or maculopapular rash may ap-
pear at the onset. Some patients report se-
vere backache (back-break fever), sore
throat, or abdominal pain, which can be
severe enough to be confused with appen-
dicitis. The febrile period usually lasts up
to 6 days during which time the rash may
become diffusely erythematous with clear
areas scattered in between, the so-called
"islands of white in a sea of red" (Fig. 2).
These patients are lethargic with accom-
panying anorexia and nausea. Hepato-
megaly can be present, although spleno-
megaly is uncommon. Laborat ory
parameters are generally normal but
platelets can be decreased and serum he-
patic enzyme levels (alanine aminotrans-
ferase in particular) may be moderately
elevated (rarely exceeding 100 IU/L).
Differentiation from viral, certain bacteri-
al infections, and Kawasaki disease can be
difficult. Recovery from DF is usually
complete in 7 to 10 days.
The incubation period for DHF is un-
known but is probably similar to that of
DE Dengue hemorrhagic fever com-
mences acutely with high fever and many
of the symptoms of DE However, drowsi-
ness and lethargy tend to be more
marked. In addition, there is increased
vascular permeability and abnormal he-
mostasis that can lead to hypovolemia and
hypotension, and in severe cases, result in
hypovolemic shock often complicated by
severe internal bleeding.
The hemorrhagic manifestations appear
usually by the third day and consist of
scattered petechiae over the trunk, limbs,
and axillae. These petechiae are associat-
ed with, or may be preceded by a positive
tourniquet test result. Bleeding at veni-
puncture sites is the rule, and there may
be hemorrhage from the gastrointestinal
tract, nose, and gums. After 2 to 7 days,
and as the fever begins to subside, signs of
circulatory insufficiency can appear; the
patient becomes restless and sweaty with
cold extremities. Pleural effusion, charac-
teristically on the right side, and abdomi-
nal ascites may be noted. These features
are almost diagnostic of DHF. With ap-
propriate treatment this phase usually re-
solves within 24 to 48 hours. 78'79
Dengue shock syndrome results from
leakage of plasma into the extravascular
compartment. Rapid and poor volume
pulse, hypotension, cold extremities, and
restlessness occur. In addition to the plas-
ma leakage, which is the result of general-
ized vasculitis, disseminated intravascular
coagulation is present. Dengue shock syn-
drome is usually a progression of DHE
but there are patients who have circulato-
ry insufficiency when first seen after a
febrile illness of only short duration. 80
Increasingly neurologic manifestations
are recognized as a separate entity and not
as sequelae of hemorrhage, acidosis, or
shock. Direct isolation of virus in the
cerebrospinal fluid and brain tissue ap-
pears to indicate infectious encephalitis.
However, further clinical, pathologic, and
Volume 13 I, Number 4
aut opsy studies are necessary t o det er-
mine the clinical relevance. 81-83
Laborat ory investigations in DHF con-
sistently r eveal t hr ombocyt openi a t hat
may reach levels of 20,000 platelets/mm a
or less. Dependi ng on the hemoconcen-
tration and severity of shock the hemat-
ocrit can be increased by 20% or more.
Commonl y hypoal bumi nemi a, hypo-
volemia, and moderat el y elevated serum
aminotransferase and blood urea nitrogen
levels can be documented. Partial t hrom-
boplastin time and the t hrombi n time may
be prolonged. 79 Hypofibrinogenemia and
complement depletion correlate wi t h the
severity of the disease.
The pat hol ogi c findings in DHF are
vasculifis of small vessels in soft tissues
and viscera. Lymph gland hyperplasia and
areas of necrosis in spleen, liver, and bone
mar r ow are also noted as is maturation ar-
rest of megakaryocytes. /Vlacroscopically
there are petechial hemorrhages, ecchy-
moses, and effusions into pleural cavities
and into the peritoneal cavity. 84
The pathogenesis of DHF is not clear;
DHF is rare in early infancy and uncom-
mon in adul t hood. Infect i on wi t h one
dengue serotype provides lifelong homol-
ogous i mmuni t y gut limited heterologous
immunity. Almost aH patients with DHF
have had previous experience with at least
one of the four seroWpes of dengue virus-
es, leading t o t he hypot hesi s t hat het-
erot ypi c antibodies from a previ ous
dengue virus infection promot e increased
viral replication wi t hi n mononucl ear
l eukocyt es - - t he phenomenon of anti-
body-dependent enhancement. 85 Furt her-
more, i mmunol ogi c processes ai med at
eliminating dengue vi rusMnfect ed cells
can result in the release of cytokines wi t h
vasoactive or procoagul ant properties, the
release of interferon-7, and the activation
of complement. 86-88
Ot her hypotheses suggest t hat DHF re-
sults from infection by a more vi rul ent
biotype of the virus or even from unfavor-
able host factors such as concomitant bac-
terial infection. Thus duri ng the last Vene-
zuelan hemorrhagic epidemic a dengue 2
subtype could be genetically identified as
a Southeast Asian biotype, a9
Whet her certain ethnic groups are more
susceptible or resistant to the hemorrhag-
ic manifestations of dengue is suggested
from epidemiologic studies. As shown in
Fig. 1, severe hemorrhagi c disease is more
common in Sout heast Asi a compar ed
wi t h Afri ca and America. I n t he 1981
dengue out break in Cuba it was observed
t hat black individuals are relatively resis-
t ant to DHF/ DSS and a "resistance gene"
present in t he Afri can popul at i on has
been speculated. 89
Regardless of t he inciting cause, in-
creased vascul ar permeabi l i t y results in
hemoconcent rat i on, r educed bl ood vol-
ume, poor tissue perfusion, tissue hypox-
ia, and shock. The cause of bleeding in
DHF appears to be complex and may in-
volve one or more of the following: t hrom-
bocyt openi a, mi crovascul ar inju W,
platelet dysfunction, and disseminated in-
t ravascul ar coagulation. The mor t al i t y
rate for DHF ranges from 1% to 30% de-
pending on availability of supportive care.
The diagnosis of dengue relies in most
cases on clinical j udgment because only a
few major centers have the facilities and
means t o perform and verify the clinical
impression. Diagnostic criteria for DHS
based on clinical observations have been
pr oposed by t he Wor l d Heal t h Or gan-
izafion and should be used to avoid over-
diagnosis. 90
The c[&ical cr#eria for diagnosis are as
follows: (1) fever; (2) hemorrhagic mani-
festations, i ncl udi ng at least a positive
t our ni quet t est result and a maj or or
minor bleeding phenomenon; (3) hepatic
enlargement; (4) shock (high pulse rate
and narrowi ng of the pulse pressure to 20
mm Hg or less, or hypotension). The/ ab-
oratory criteria include (5) t hrombocyt ope-
ni a (_<100,000/mm3), and (6) hemoeon-
cent rat i on (hemat ocri t increase ->20%).
Thrombocyt openi a wi t h concurrent high
hemat ocri t levels differentiates DHF
from classic DE
CurrenCy routine laborato W diagnosis
of dengue infections depends on virus iso-
lation or t he det ect i on of dengue
virus-specific antibodies. The isolation of
viruses f r om clinical speci mens can be
carri ed out in cul t ured mosqui t o cells,
such as AP-61 or C6/56 cell cultures. 91-94
Whe n dengue vi rus serotype-specifie
monocl onal antibodies are used, virus
identification by indirect immunofluores-
cence can be achieved within 2 weeks. 95'%
The development of mosquito inoculation
techniques has not onl y i mproved the sen-
sitivity but also reduced the time required
for vi rus isolation and identification.
Parenteral inoculation of adult A. albapic-
tua yields results in 7 days. 97"98 Virus iso-
lation by i nt racerebral i nocul at i on of
Toxorbyncbitis spZendens mosqui t o or its
fourth instar larvae can even be achieved
within 2 to 5 days. 99'1°°
The serologic identification of the vari-
ous types of dengue virus infection is com-
plicated by the occurrence of cross-reac-
tive antibodies to antigenic determinants
shared by all four dengue viruses and
other members of the flavivirus family. 1°1
The commonl y used serologic test is the
hemagglutination inhibition t est ) °2 I n a
pri ma W infection dengue hemagglutina-
tion inhibition ant i body titer is generally
less t han 1:20 in a sample collected within
t he first 4 days after the onset of symp-
toms. I n t he conval escent phase sample
(collected 1 t o 4 weeks after the onset of
sympt oms) a fourfol d or great er rise in
ant i body fiter is detected, with ant i body
titer _<1:1280.103
A seconda W dengue infection is charac-
terized by the rapid appearance of broad-
ly cross-react i ve antibodies. Hemag-
glutinafion inhibition fiters of 1:20 in the
acute-phase sample rise t o _>1:2560 in the
convalescent phase sample. An ant i body
fiter of >1:1280 in the acute-phase sample
wi t hout a fourfold or greater increase in
the second sample also is considered pre-
sumptive of recent infection. An i mproved
and less time-consuming met hod is a cap-
ture enzyme-linked i mmunosorbent assay
t hat can detect specific anti-dengue I gM
in a single acute-phase sample. 104
Recently commercial kits for the detec-
tion of specific I gG as well as I gM anti-
bodies have become available. They are
based on a dot enzyme assay or a nitro-
cellulose membr ane- bas ed capt ure for-
mat, respectively, and should be suitable
for field research. 105-107
An alternative t o virus isolation is the
detection of viral RNA by reverse t ran-
scri pt i on pol ymer ase chai n react i on.
Ther e are vari ous pr ot ocol s available
using different primers and template iso-
lation. 67'108113 Reverse t r anscr i pt i on
polymerase chain reaction coupl ed wi t h
hybridization wi t h labeled serotype-spe-
cific pr obes can det ect as few as 4
pl aque-formi ng units per 100 btl serum
and gives t he best resul t s ear l y in t he
acute phase of the disease when dengue
antibodies are still low. 112 Less t han 1 ~tl
of serum can be sufficient for the detec-
tion of viral RNA. 114 Reverse transcrip-
tion pol ymerase chain reaction is a high-
ly sensitive t echni que of particular value
in t he earl y di agnosi s of dengue infec-
tion, but at present is onl y available in re-
search settings.
The management of DF is supportive
wi t h bed rest, adequate fluid intake, and
control of fever and pain wi t h antipyretics
and analgesics (e.g., paracetamol). Use of
aspirin is contraindicated because of the
increased bleeding tendency. Patients can
be treated as outpatients if close monitor-
hag is possible.
Differentiation between DF and DHF
is difficult in the early stages and frequent
measurement s of t he platelet count and
hemat ocri t are necessary. A fall in t he
platelet count and a rising hemot ocri t
level indicate devel opment of t he shock
syndrome. Nar r owi ng of the pulse pres-
sure and hypot ensi on indicate shock,
whi ch must be treated as a medical emer-
gency. The major problem in DHF/ DSS
is fluid loss rat her t han bl ood loss, and
management must be di rect ed t owar d
maintenance of blood volume and blood
pressure. Mild cases respond after 1 or 2
days of plasma expansion with isotonic or
hal f isotonic saline solution.
Decreased levels of coagulation factors
indicate disseminated intravascular coag-
ulation; infusion of heparin and replace-
ment of c o @a t i o n factors may be re-
quired. Severe hemorrhage may require
blood transfusion, preferably with fresh
whole blood; concentrated platelet infu-
sions may be required. Regular clinical and
l aborat ory monitoring is mandatory. Re-
versal of plasma leakage can be expected
within 12 t o 24 hours; intravenous infu-
sion must be reduced because hypervo-
lemia can lead to acute heart failure, 115-118
I n some centers corticosteroids (methyl-
prednisoloue) or carbazochrome sodium
sulfonate (acona [AC-17]) are used to sta-
bilize capillary permeability and reduce
plasma leakage. A relatively large, placebo-
controlled; double-blind st udy has not
shown a positive effect from steroids in
DSS, whereas a somewhat smaller and
less stringent st udy claimed a beneficial ef-
fect of AC-17 in DHE Whet her this dif-
ference is a direct drug effect or reflection
of the different patient populations studied
cannot be decided with the available data.
Furt her studies t hat take into account the
varyi ng degrees of severity of DHF and
DSS are indicated before a fmal conclu-
sion can be drawn. 119'120
Mosquito control measures
As long as there is no vaccine available,
the spread of DF and DHF can onl y be
curt ai l ed by cont rol l i ng vect or popul a-
tions. This appr oach was successfully
started in the Americas at the beginning of
this century, and eradi cat i on pr ogr ams
were st art ed in 1947. The mosqui t oes
reemerged when specific programs aimed
at their eradication were given lower pri-
ority. I n addition, insecticide resistance
has been a problem in some areas. I21
I n addition to insecticide application t o
cont rol adul t mosqui t o popul at i ons,
breeding sites of Ae de s mosquitoes should
be r educed vigorously. St agnant wat er
and wat er containers should be avoided.
Educat i on programs must be implement-
ed and legislation pr ovi di ng fines for
those allowing Aedes breeding sites might
be helpful. 122'1% Insect repellents are use-
ful t o prevent mosquito bites. However, it
must not be forgot t en t hat programs t o
eradicate mosquito vectors impose a great
financial burden on developing countries
and are ineffective in situations of open
conflict, lawlessness, and large-scale
refugee migrations.
Vaccine Development
Current l y no vaccine is available to pro-
tect against dengue infections. The major
concern in the development of a dengue
vaccine is an immunologic response in the
vaccinee t hat could lead to antlbody-de-
pendent enhancement of infection and
thus produce DHF/ DSS. Candidate vac-
cines based on live at t enuat ed viruses
should therefore contain all four serotypes
to give comprehensive protection wi t hout
adverse side effects.
I n 1944 a serially attenuated, dengue 1
vi rus candi dat e vacci ne pr epar ed in
mouse brain was tested in human volun-
teers, but abandoned because t he sub-
strate was t hought t o be unsafe. 124-127
Recent l y live at t enuat ed vacci nes have
been devel oped by multiple passages in
pri mary clog ki dney cells by researchers at
the Mahi dol University in Bangkok and
candidate monovalent, bivalent, trivalent,
and t et raval ent vacci nes are cur r ent l y
being tested in phase I and I I trials with
favorable results in Thailand. 128"131
Efforts to create a subunit vaccine by
use of r ecombi nant DNA t echnol ogy
have been initiated because of the concern
of possible reversion of a live attenuated
vaccine to a virulent strain. Recombi nant
prot ei ns have beerl expressed in
Es c be r i c bi a c ol ~ a s well as vaccinia viruses
and insect cells ( S p o d o # e r a f r u g i p e r d a )
using engi neered baculoviruses. 132-I43
Both the structural and the NS1 proteins
have been shown t o elicit protective im-
muni t y in monkeys and mice and thus the
development of safe vaccines appears to
be f e a s i b l e . 133-135'157'159'141
1. Halstead SB. Dengue. In Warren KS,
Mahmoud AAE editors. Tropical and geo-
graphical medicine. New York: McGraw-
Hill; 1990. p. 675-85.
2. Hanson SM. Field overwinter survivorship
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50 Years Ago in The J ournal of Pediatrics
Jackson RL, Kelly HG, Ro/~ret CH, Duane JM. J Pediatr 1947,'31:390-402
Fi ft y year s ago in rural Iowa, j ust as in ur ban Amer i can settings, rheumat i c fever ( RF) was a t hr eat for indivt~-
ual pat i ent s and a maj or public health pr obl em for schoolchildren. Hospi t al s wer e fdl ed wi t h pat i ent s wi t h RF and
rheumat i c hear t disease, and t her e wer e numerous report s descri bi ng t he hi gh i nci dence of RF and preval ence of
rheumat i c hear t disease. I n contrast, hal f a cent ur y later, t he r educt i on in RF i nci dence in i ndust ri al i zed count ri es
is striking. Yet in most of t he devel opi ng worl d, t he disease remai ns at a level comparabl e to t hat al l uded to by
J a c ks on and colleagues. The percept i ve article by J acks on et al. descr i bed t he rel at i onshi p bet ween recurrences
of RF and subopt i mal social, economic, and nut ri t i onal status. The decline in i nci dence of RF in i ndust ri al i zed
count ri es began before t he clinical i nt roduct i on of antibiotics; this reduct i on has hi st ori cal l y been associ at ed wi t h
i mpr ovi ng social and economi c factors. Yet dur i ng t he past decade, a "resurgence" of RF has been descr i bed in
Nor t h Amer i can mi ddl e class subur ban chi l dren wi t h r eady access to medi cal care and in mi l i t ary recrui t s. These
publ i s hed obser vat i ons suggest t hat f act or s ot her t han soci al and economi c st at us ar e equal l y i mpor t ant .
"Rheumat ogeni c" pot ent i al and t he vi rul ence of specific strains of gr oup A st rept ococci cannot be i gnored. I t was
not possi bl e to st udy such vari abl es in t he l abor at or y 50 year s ago. Thus t he rel at i onshi p bet ween social, econom-
ic, and nut ri t i onal status and mi crobi ol ogi c and i mmunol ogi c factors coul d not be compar ed at t he t i me when t he
disease was so common. Maybe t he fact t hat t he pat hogenesi s of this uni que disease remai ns i ncompl et el y defi ned
is a consequence.
Ant i bi ot i cs and bet t er living conditions are cl earl y not t he compl et e sol ut i on to cont rol l i ng gr oup A st rept ococ-
cal infections and t hei r complications. One at t ract i ve t heoret i cal appr oach to conqueri ng this maj or cardi ovascu-
l ar disease woul d be devel opment of a cost-effective vaccine. Per haps this can be real i zed in t he not t oo di st ant fu-
ture. Then it is possi bl e t hat t he i nci dence of RF and t he preval ence of r heumat i c hear t disease, sometimes r ef er r ed
to as t he most prevent abl e of all cardi ovascul ar diseases, coul d be significantly reduced. Despi t e a need to i mprove
social and economi c status of at - r i sk pedi at ri c popul at i ons for many heal t h-rel at ed reasons, t i me-t est ed t echni ques
of accurat e diagnosis and appr opr i at e ant i bi ot i c t her apy for t he pr ecedi ng st rept ococcal infection wi l l continue to
be t he most pract i cal and effective met hods of control.
Ed,~ard L. Kaplan, ~ID, and James H. Ztloller, ~/ID
Department of Pediatrics
University of Minnesota
Minneapolis, M N 55455