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Post by Prof. Henry Wilde   
ศุกร์, 30 มีนาคม 2007
Wichmann O, Gascon J, Schunk M, et al. Severe dengue virus infection in
travellers: risk factors and laboratory indicators. JID. 2007;
195:1089-1096.

Wilder-Smith A, Tambyah PA. Severe dengue virus infection in travelers.
JID. 2007; 195:1081-1083.

Jensenius M, Berild D, Ormaasen V, et al. Fatal subarachnoidal
haemorrhage in a Norwegian traveler with dengue virus infection. Scand J Infect
Dis. 2007; 39:272-4.


CONCLUSION: Dengue fever is common in travelers, and hemorrhagic
complications occur in the absence of the WHO criteria for dengue hemorrhagic
fever (DHF). High liver enzyme levels, severe thrombocytopenia, and
serological evidence of a second dengue infection may be better markers of
risk of bleeding in the individual patient than the WHO criteria for
DHF. The term dengue fever with hemorrhage may be useful for such
patients, but a new definition of severe dengue is needed. Travel health
advisors should stress the importance of daytime avoidance of mosquito bites
and learn to recognize clinical features of the infection.

ABSTRACT: Dengue fever is now the most commonly diagnosed cause of
fever in travelers returning from Asia (in contrast with malaria in
travelers returning from sub-Saharan Africa and Central America). The disease
is present in almost all tropical and sub-tropical countries and
incidence has risen 30-fold in the past 50 years. Health care providers need
to be aware of the clinical spectrum of the disease in returning
travelers. Most infections are asymptomatic (but may later be identified
serologically). The illness itself may be mild or severe and complicated by
bleeding and shock due to plasma leakage (dengue hemorrhagic fever).
(DHF is the main cause of death from dengue in children in endemic
areas.) It is not known why some infections are severe, but a second dengue
infection, perhaps caused by another of the 4 serotypes, is thought to
be the main factor. Infection with one serotype induces lifelong
immunity to that specific serotype and short-lived immunity to other sero
types. Travelers have died from fulminant hepatitis and subarachnoid
hemorrhage due to dengue, and encephalitis, blindness, and suicidal
depression are reported complications.

Between May 2003 and December 2005, members of the European Network on
Surveillance of Imported Infectious Diseases (TropNetEurop) from 14
sites used standard questionnaires and data collection sheets to
participate in a prospective study of imported dengue fever that was coordinated
by the center in Berlin. Patients were classified as per World Health
Organization (WHO) into 2 categories: those with confirmed dengue
infection (viral detection by reverse-transcriptase chain reaction [PRC] or
by significant changes in IgM or IgG antibody titres in paired samples)
and those with probable dengue infection (a single positive IgM
antibody test in a late acute- or convalescent-phase serum specimen). Second
dengue infections were detected through a secondary immune response
defined as a sample: calibrator absorbance ratio for IgG of greater than or
equal to 4 in the presence of an IgM ratio of greater than or equal to
1 (that is to say, the ratio of IgG units to IgM units was greate
r than 4). Other laboratory investigations included leukocyte and
platelet counts, and the liver enzymes aspartate aminotransferase (AST),
alanine aminotransferase (ALT), and lactate dehydrogenase (LDH).

WHO case definition for DHF was applied, requiring the presence of all
4 criteria: fever, platelet count <100,000 cells/cubic mm, hemorrhagic
tendency, and evidence of capillary leakage. Hemorrhagic tendency was
defined as spontaneous bleeding or signs of capillary fragility.
Spontaneous bleeding was evidenced by bleeding from nose, gums, or
gastrointestinal (GI) tract, or hypermenorrhea or ecchymosis. Petechiae and a
positive tourniquet test were considered to be signs of capillary
fragility. The term "severe clinical manifestations" was defined as internal
hemorrhage, plasma leakage, shock, and/or platelet count less than or
equal to 50,000 cells/cubic mm.

A total of 219 patients (109 male, 110 female) with dengue virus
infection were reported (median age 32 years, range 11-70 years). Most (90%)
were Europeans. All non-Europeans were born in dengue endemic
countries. Dengue was most commonly acquired in Southeast Asia (35%), the Indian
subcontinent (29%), or the Americas (28%). Of patients who visited only
one country, India, Thailand, and Sri Lanka topped the list of 39
countries. The median duration of travel was 24 days (range 4 days to 4
years). Sixty-one percent of patients had made previous visits to dengue
endemic countries, and 3% had documented previous dengue virus
infections. Dengue virus infection was confirmed in 133 patients (61%) and
considered probable in 86 (39%). Serology indicated a primary immune response
in 134 patients (77%) and a secondary response in 40 (23%). Thirteen
patients were excluded from analysis because of a history of immunization
against other flaviviruses (yellow fever or tick-borne encephal
itis). Thus 27 patients (17%) were regarded as having acquired a
second dengue virus infection, which was significantly more common in
non-Europeans than in Europeans (50% vs.14%; p=0.001).

Fever was the most common symptom (93% patients), followed by headache,
fatigue, rash, muscular pain, and orbital pain. Petechiae were present
in 28 patients (13%) and spontaneous bleeding, most commonly from the
nose or gums, in 17 (8%). One patient developed GI-tract bleeding
presenting as hematemesis. A tourniquet test was applied to 80 patients with
36 (44%) showing positive. A positive test was statistically associated
with the occurrence of petechiae (p<0.001) but not with spontaneous
bleeding (p=0.1). Nor was there an association between a positive
tourniquet test and the frequency of any of the severe clinical manifestations.
Most patients had a low leukocyte and/or platelet count in the acute
phase of the illness and 10% had marked thrombocytopenia (<50,000
cells/cubic mm). More than half the patients tested had raised liver enzyme
levels, being > 3 times normal in 29%. Cell counts fell early in the
disease (days 0-6 after the onset of symptoms) and persisted, while
liver enzyme values rose later (days 3-6) and persisted, or rose in
days 7-10.

Only 2 patients (0.9%) fulfilled the WHO criteria for DHF, one with a
primary infection and one with a second infection. Spontaneous bleeding
in 17 patients was associated with secondary immune response (odds
ratio [OR] 3.9), non-European origin (OR 6.4) and a > 3-fold increase in
ALT (OR 5.4). The median platelet count in these patients was 72,000
cells/cubic mm, compared with 110,000 cells/cubic mm in patients without
spontaneous bleeding (p=0.06). Severe dengue disease was manifest in 23
patients (11%) and was associated with a secondary immune response (OR
5.6) and > 3-fold rise in AST (OR 3.7). Eight patients with severe
clinical manifestations and 5 with spontaneous bleeding had visited dengue
endemic countries for the first time.

Jensenius et al. describe the case of a Norwegian traveler returned
with apparently mild dengue fever but with an extensive erythematous
exanthem that spread and darkened (perhaps indicative of bleeding), who died
of a subarachnoidal hemorrhage, for which at autopsy no local vascular
cause could be found. They refer to the term "dengue fever with
hemorrhage," which has been used for adults who bleed but do not fulfil the
criteria for DHF.

COMMENTARY: All flaviviruses have the potential to attack the liver
(notably yellow fever virus), the brain (notably Japanese and other
encephalitic viruses) or the capillaries, especially in the skin (notably
dengue virus). So the 3 disease syndromes may overlap to some extent. The
generalized erythema that is seen in the first day or 2 of early dengue
(and is listed in the table of clinical features in this article but
not discussed) may represent capillary dilatation in response to viral
invasion and may permit leakage of plasma and, rarely, of blood cells;
however, within a few days antibodies are produced that may damage the
capillary endothelium causing petechiae. Platelets and leukocytes are
probably consumed in both these processes. A tourniquet increases venous
pressure and encourages petechial bleeding and is thus a useful if
unstandardized and insensitive test (44% sensitive in this study) to further
suspicion of dengue fever in a febrile traveler returned from an
endemic area. The main danger to the patient with dengue fever is loss
of fluid through the leaky capillary bed threatening shock, which was
not a feature of the well-nourished European adults receiving good
clinical care in this series. Platelet counts in dengue rarely fall low
enough to be of concern in their own right, and as shown so clearly in this
study, spontaneous bleeding did not correlate with thrombocytopenia.
Cleary there must be an additional cause of bleeding in dengue, but its
nature is not known. A consumption coagulopathy (in which clotting
factors are exhausted through attempts to prevent capillary bleeding) has
been postulated. What this study makes clear is that a second dengue
infection or the secondary immune response it elicits seems to trigger this
mechanism in a large proportion of patients, but is not essential. The
other association with spontaneous bleeding is a high level of liver
enzymes. This might perhaps indicate a deficiency of clotting fact
ors, which were not measured in this study, or simply a heavier viral
infection and more persistent or severe disease.

The most important contribution of this study is to show, in travelers,
that dengue fever commonly causes bleeding in the absence of the
full-blown DHF syndrome. The original WHO definition was made when the
pathogenesis of the disease was less understood, and was useful for
statistical and epidemiological purposes. It related particularly to children in
developing countries. It is of no value in the clinical management of
the traveler with dengue fever. In endemic countries too, the DHF
classification has proved inadequate in clinical management (Deen JL, Harris
E, Wills B, et al. The WHO dengue classification and case definitions:
time for a reassessment. Lancet. 2006; 368 (9530):170-173). It lacks
both sensitivity and specificity when used an indicator of severe
complications (Rigau-Perez JG. Severe dengue: the need for new case
definitions. Lancet Infect Dis. 2006; 6 (5): 297-302). Dengue infection presents
a spectrum ranging from subclinical through mild and severe to on
e complicated by bleeding and/or shock. Clinicians need to focus on
the individual patient with dengue and look for the warning signs of
secondary immune response and high liver enzymes, especially in
non-Europeans, monitor blood pressure and hematocrit, and maintain an adequate
fluid intake.

In their Editorial Commentary, Wilder-Smith and Tambyah stress that
dengue fever is not necessarily mild in the absence of DHF with or without
shock, and that encephalitis, myocarditis, fulminant hepatitis, and
neuropathies may occur as well as hemorrhage, and may require medical
evacuation of a traveler sick with dengue. Dengue presents a clinical
spectrum rather than a series of defined identities. They plead for a better
definition of severe dengue in the hope that this may alert physicians
to the potentially fatal dangers of hemorrhage and shock. The challenge
of dengue is increasing, clinical diagnosis is difficult (but should be
suspected readily), all 4 serotypes are co-circulating and posing a
threat of serious disease, and vaccines are a long way off. They support
the plea of Deen et al. that "a large multicentre descriptive study is
needed to obtain the evidence to establish a robust dengue
classification scheme for use by clinicians, epidemiologists, public health
authorities, vaccine specialists, and scientists involved in dengue
pathogenesis research. Dengue case definitions derived in this way might
prove more useful for presumptive diagnosis, management, and final
diagnosis, than the existing scheme."

What can the travel health advisor do? First, stress the importance of
daytime measures to avoid mosquito bites. Second, point out that dengue
is increasingly becoming a rural infection, especially in India; third,
think of dengue as the most likely cause of fever in the returned
traveler once malaria has been ruled out. Last, watch for the telltale
physical signs and laboratory results that may warn of complications.

Prof. Henry Wilde
Division of Research Affairs
King Chulalongkorn Memorial Hospital
Rama IV Road, Bangkok, Thailand 10330
Last Updated ( พุธ, 25 เมษายน 2007 )
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