268

Differential Diagnosis of Dengue Fever: Beware of Measles!

Lauren Pull, MD,∗ Ségolène Brichler, MD,† Olivier Bouchaud, PhD,‡ and
Jean-Yves Siriez, MD∗
∗
Service d’Accueil des Urgences Pédiatriques, Hôpital Robert Debré, Assistance Publique—Hôpitaux de Paris, Paris, France;
† Laboratoire de Virologie, Hôpital Avicenne, Assistance Publique—Hôpitaux de Paris, Bobigny, France; ‡ Service des Maladies
Infectieuses et Tropicales, Hôpital Avicenne, Assistance Publique—Hôpitaux de Paris, Bobigny, France

DOI: 10.1111/j.1708-8305.2012.00628.x

Febrile exanthema is a common symptom in returning travelers. In addition to cosmopolitan diseases, etiologies specific to the
visited country must be considered. As an accurate diagnosis is important, clinical suspicion should be confirmed by laboratory
tests. The case reports of three brothers returning from Indonesia highlight the possibility of misdiagnosis due to the clinical
similarity and serological cross reactivity of dengue fever and measles.

F ebrile exanthema in returning travelers may

be caused by a large spectrum of tropical or
cosmopolitan diseases. As treatment or isolation of
these patients may be necessary, it is important to
establish an accurate diagnosis when febrile exanthema
is present. Beyond febrile exanthema, other symptoms
within this spectrum of diseases overlap also, making
clinical diagnosis difficult; laboratory tests are often
required to confirm an etiology.
Case Reports
Case 1 (Index Case)
Seventeen days into a 3-week vacation in Bali with his
parents and two elder brothers (cases 2 and 3), a 7-year-
old French-born boy was hospitalized in Denpasar, Bali,
4 days after the onset of high fever, nausea, vomiting,
and redness in the face and chest. At the initial physical
examination, he was alert but unwell. He had an upper
respiratory tract infection and a skin rash diagnosed
by local doctors as urticaria and petechiae; no further
descriptions of the lesions were provided. Temperature
was subnormal (37.7 ◦ C). The parents reported that
their three sons had been exposed to mosquito bites
on the beaches of Bali. Initial laboratory results were
as follows: leukocyte count 2,360/mm3 (neutrophils
71%, lymphocytes 20%, monocytes 8%); platelet count
100,000/mm3 ; hemoglobin 13.4 g/dL; hematocrit 36%;
Corresponding Author: Lauren Pull, MD, Service d’Accueil
des Urgences Pédiatriques, Hôpital Robert Debré, Assistance
Publique—Hôpitaux de Paris, 48, boulevard Sérurier, F-75
935 Paris Cedex 19, France. E-mail: lauren.pull@rdb.aphp.fr
serum glutamic oxaloacetic transaminase (SGOT) 41
U/L, serum glutamic pyruvic transaminase (SGPT)
25 U/L; erythrocyte sedimentation rate 14 mm/h.
Urine and stool analyses were negative. Serological
tests were negative for typhoid and paratyphoid fever.
Two consecutive rapid diagnostic tests [Dengue Duo
immunoglobulin M (IgM) and immunoglobulin G (IgG)
Rapid Cassette Test] at a 48-hour interval were positive
for dengue fever (IgM positive, IgG negative). The
diagnosis of dengue hemorrhagic fever was based on the
presence of thrombocytopenia and petechiae, although
there were no signs of plasma leakage due to increased
capillary permeability. After a 4-day stay in the hospital,
the boy was discharged, stable and fever free. He
returned to France on the same day.
Case 2
On the day of his return to France, the second child
of the family, a 10-year-old boy, began experiencing
high fever, vomiting, and diarrhea. He was admitted
to our children’s hospital in Paris, France, 5 days later.
At admission he was weak and presented myalgia and
generalized maculopapular rash. His temperature was
38◦ C. Initial laboratory tests were unremarkable; a thin
blood smear for malaria was negative. Two consecutive
serologies for dengue fever [PANBIO IgM and IgG
Capture enzyme-linked immunosorbent assay (ELISA)]
as well as NS1 Ag detection were negative at 48-hour
intervals. Polymerase chain reaction (PCR) detection of
dengue virus was also negative, as was a third serology
10 days after the first.
Case 3
The eldest brother, aged 16 years, was the last of
the three siblings to have acute onset of fever, which

© 2012 International Society of Travel Medicine, 1195-1982

Journal of Travel Medicine 2012; Volume 19 (Issue 4): 268–271
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 Differential Diagnosis of Dengue Fever: Beware of Measles!
started 48 hours after his return to France. Admitted
to the hospital at the same time as his brother
(case 2), he presented with high fever (39.6 ◦ C),
diarrhea, conjunctival hyperemia, myalgia, sore throat,
and irritating cough. Initial laboratory tests were as
follows: leukocyte count 4,300/mm3 ; platelet count
132,000/mm3 ; hemoglobin 15.4 g/dL; SGOT 105 U/L
(normal 5–45 U/L), SGPT 77 U/L (normal 5–60 U/L);
C-reactive protein 40 mg/L (normal 0–10 mg/L). As
was the case for his brother, a thin blood smear for
malaria was negative. Three consecutive serologies for
dengue fever (PANBIO IgM and IgG Capture ELISA)
were negative, as were NS1 Ag and PCR detection.
Five days after onset of the first symptoms, the patient
developed a generalized maculopapular rash.
A Family Cluster of Measles
The three brothers recovered fully within 2 weeks of the
onset of symptoms. Initially, they presented with similar
clinical features, which quite naturally led us to suspect
a contagious disease. Although the first two serology
tests for dengue fever were positive in the index case in
Indonesia, a third one (PANBIO IgM and IgG Capture
ELISA), this time in France, came back negative for
both IgM and IgG. This led to the prescription of
serological tests for other infectious diseases, including
measles. For this latter, the tests for all three of the
boys were positive (Table 1). We note that none of
the siblings had been vaccinated for measles, despite
national recommendations.
Discussion
Measles should be included in the differential diagnoses
of patients presenting febrile exanthema after travel. A
few years ago, chikungunya was considered the most
likely cause of febrile exanthema in returning travelers.1
However, recent measles outbreaks throughout the
world have increased the risk for travelers to contract
this disease.
According to the GeoSentinel Surveillance Network,
febrile exanthema accounts for 12% of dermatological
Table 1 Serological and PCR results for dengue fever and measles
Dengue fever
Day after onset of first symptoms NS1 Ag IgM
Case 1 D4 (I) / +
D6 (I) / +
D25 (F) / −
Case 2 D5 (F) − −
D7 (F) − −
D15 (F) / −
Case 3 D3(F) − −
D5 (F) − −
D13 (F) / −
/: Not done; I: Dengue Duo IgM and IgG rapid cassette test (Indonesia); F: PANBIO IgM and IgG capture ELISA (France).
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269
conditions in returning travelers.2 In a study by Caumes
and colleagues in 1995, febrile exanthema was the main
symptom in 4.1% of returning travelers presenting with
skin diseases.3 Determining the etiology of febrile exan-
thema in travelers is important, as some of these patients
may require urgent treatment or isolation. Clinical
diagnosis is often difficult, as infectious exanthema-
tous diseases such as measles, rubella, human parvovirus
B19, dengue, human herpes virus (HHV)-6, roseola
infantum, and scarlet fever have overlapping clinical
symptoms. In Brazil, from 1994 to 1998, 327 patients
presenting with pathologies characterized by vari-
able combinations of exanthema, cough, conjunctivitis,
coryza, and fever were studied. A laboratory-confirmed
diagnosis was achieved in 71.3% of cases: 33% were
diagnosed with dengue fever, 20% with rubella, 9.2%
with human parvovirus B19, 6.7% with measles, and
2.1% with HHV-6.4 These results underline the impor-
tant proportion of cosmopolitan febrile exanthemas. In
France, Hochedez and colleagues screened 62 returning
travelers presenting with fever and exanthema for exotic
(if returning from endemic areas) and cosmopolitan
infections. They found a specific etiology in over 90%
of the patients. The three main diagnoses were chikun-
gunya, dengue, and African tick bite fever, followed
by infectious mononucleosis, human immunodeficiency
virus-1 primary infection, cytomegalovirus primary
infection, measles, rubella, chicken pox, streptococcal
infections, primary toxoplasmosis, acute schistosomia-
sis, and adverse drug reactions.1 Travelers presenting
with febrile exanthema should therefore be screened
not only for arboviral infections according to the area
visited but also for more common infections.
The diagnosis of dengue fever is based on the
detection of NS1 Ag, antibodies (IgM and IgG)
or reverse transcription (RT)-PCR (virus isolation is
used less often). For early diagnosis (onset < 5 days),
detection of NS1 Ag may be used, but its moderate
sensitivity requires the presence of both NS1 Ag and
IgM for a definite diagnosis.5 IgM are positive 4 to 5 days
after disease onset and remain so for up to 3 to 6 months.
IgG appear approximately 7–10 days after onset and are
detectable thereafter for life. RT-PCR detection of viral
Measles
IgG PCR (blood) IgM IgG PCR (saliva)
− / / / /
− / / / /
− / + + /
− − / / /
− / / / +
− / + + /
− − / / /
− / + − +
− / + + /
J Travel Med 2012; 19: 268–271
 270
RNA is a very reliable technique for patients presenting
within 5 to 7 days of the onset of symptoms, but this
method is more expensive, nonstandardized, and only a
few centers in France use it routinely.6
Consequently, serological tests are commonly
used to establish or confirm a diagnosis of dengue.
Currently available commercial rapid tests offer good
sensitivity, but they lack specificity, which may lead
to false-positive results as in our index case. Overall,
possible explanations for false-positive results include
cross-reactive flavivirus-specific antibodies, nonspecific
binding of antibodies secreted in the course of various
infections such as mononucleosis or hepatitis, and
rheumatoid factor.7 Cross-reactivity with measles
antibodies is not commonly assumed by biologists
and, to our knowledge, has only been reported once
in Belgium.8 Wichmann and colleagues analyzed 127
cases of dengue diagnosed on a single positive rapid
test. Each of the cases was further investigated via the
use of several IgM- and IgG-ELISAs, immunofluo-
rescence assays, and real-time reverse transcription
polymerase chain reaction assays. Overall, there was
a 42.5% false-positive rate; in 6.1% of false-positive
cases, both leukopenia and thrombocytopenia were
present. Therefore, positive rapid test results should
be confirmed by laboratory-based ELISA serology or
virus PCR detection for a reliable diagnosis of dengue
fever.7
Current outbreaks of measles in Europe are a
reminder of the risks of serious morbidity, and even
mortality, associated with this disease. Since 2008, more
than 22,000 cases of measles have been reported in
France, including 10 that resulted in death.9,10 Despite
several campaigns, sufficiently high vaccinal coverage
has not been achieved in many European countries.
This is especially the case in France, where national
coverage is only 85% in 2-year-old infants.11 This low
coverage may be the result of suboptimal effectiveness
of single dose measles vaccine and the lack of catch-up
of unprotected teenagers.12 Furthermore, migratory
movements and travel to areas with high prevalence of
measles have complicated existing control programs and
contributed to the spread of the disease.13 – 15 Given the
typical incubation period for measles, the date of onset
of symptoms in the index case raises the issue of the
location of contamination. Measles viruses are classified
into 8 clusters (A to H) and 23 genotypes. Genotyping
in our patients revealed the B3 genotype, which is not
the usual strain in Indonesia (genotype D9). It is also not
the usual strain in France, where the current outbreak
of measles is most frequently attributed to genotype D4
(98.8% of strains in 2010). Other genotypes in France
are either imported (B3, D8, D9, H1) or vaccine strains
(genotype A).16 Genotype B3 is predominant in Africa,
which reinforces the idea that the index case may have
been infected through contact with another traveler,
either in France or during his trip to Indonesia.
Efforts should be made to insure a full immunization
schedule in young children and travelers. WHO
J Travel Med 2012; 19: 268–271
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Pull et al.
recommends that the first dose of measles vaccine be
administered at the age of 9 months. However, countries
where the risk of measles is low often provide the first
dose at the age of 12–15 months.17 In the case of travel
to an endemic area, vaccination can be given at the age
of 6 months.9 The second dose should be administered
before the age of 2 years, with an interval of at least
1 month between the two doses. Young adults born
after 1980 should receive both doses and travelers born
before this date should receive at least one dose in the
absence of previous vaccination.18
Conclusion
Even though arboviral infections are one of the leading
causes of febrile exanthema in travelers, this symptom
is not synonymous with dengue fever. Cosmopolitan
infections such as measles must be considered, even
more so now that its incidence is increasing in several
parts of the world. Our cases provide a compelling
argument for the promotion of vaccination against
this disease, as recommended by the World Health
Organization.
Declaration of Interests
The authors state they have no conflicts of interest to
declare.
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