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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
serum glutamic oxaloacetic transaminase (SGOT) 41
U/L, serum glutamic pyruvic transaminase (SGPT)
25 U/L; erythrocyte sedimentation rate 14 mm/h.
these patients may be necessary, it is important to Urine and stool analyses were negative. Serological
establish an accurate diagnosis when febrile exanthema tests were negative for typhoid and paratyphoid fever.
is present. Beyond febrile exanthema, other symptoms Two consecutive rapid diagnostic tests [Dengue Duo
within this spectrum of diseases overlap also, making immunoglobulin M (IgM) and immunoglobulin G (IgG)
clinical diagnosis difficult; laboratory tests are often Rapid Cassette Test] at a 48-hour interval were positive
required to confirm an etiology. for dengue fever (IgM positive, IgG negative). The
diagnosis of dengue hemorrhagic fever was based on the
presence of thrombocytopenia and petechiae, although
Case Reports there were no signs of plasma leakage due to increased
capillary permeability. After a 4-day stay in the hospital,
Case 1 (Index Case) the boy was discharged, stable and fever free. He
Seventeen days into a 3-week vacation in Bali with his returned to France on the same day.
parents and two elder brothers (cases 2 and 3), a 7-year-
old French-born boy was hospitalized in Denpasar, Bali, Case 2
4 days after the onset of high fever, nausea, vomiting, On the day of his return to France, the second child
and redness in the face and chest. At the initial physical of the family, a 10-year-old boy, began experiencing
examination, he was alert but unwell. He had an upper high fever, vomiting, and diarrhea. He was admitted
respiratory tract infection and a skin rash diagnosed to our children’s hospital in Paris, France, 5 days later.
by local doctors as urticaria and petechiae; no further At admission he was weak and presented myalgia and
descriptions of the lesions were provided. Temperature generalized maculopapular rash. His temperature was
was subnormal (37.7 ◦ C). The parents reported that 38◦ C. Initial laboratory tests were unremarkable; a thin
their three sons had been exposed to mosquito bites blood smear for malaria was negative. Two consecutive
on the beaches of Bali. Initial laboratory results were serologies for dengue fever [PANBIO IgM and IgG
as follows: leukocyte count 2,360/mm3 (neutrophils Capture enzyme-linked immunosorbent assay (ELISA)]
71%, lymphocytes 20%, monocytes 8%); platelet count as well as NS1 Ag detection were negative at 48-hour
100,000/mm3 ; hemoglobin 13.4 g/dL; hematocrit 36%; intervals. Polymerase chain reaction (PCR) detection of
dengue virus was also negative, as was a third serology
10 days after the first.
Corresponding Author: Lauren Pull, MD, Service d’Accueil
des Urgences Pédiatriques, Hôpital Robert Debré, Assistance Case 3
Publique—Hôpitaux de Paris, 48, boulevard Sérurier, F-75 The eldest brother, aged 16 years, was the last of
935 Paris Cedex 19, France. E-mail: lauren.pull@rdb.aphp.fr 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! 269

started 48 hours after his return to France. Admitted conditions in returning travelers.2 In a study by Caumes
to the hospital at the same time as his brother and colleagues in 1995, febrile exanthema was the main
(case 2), he presented with high fever (39.6 ◦ C), symptom in 4.1% of returning travelers presenting with
diarrhea, conjunctival hyperemia, myalgia, sore throat, skin diseases.3 Determining the etiology of febrile exan-
and irritating cough. Initial laboratory tests were as thema in travelers is important, as some of these patients
follows: leukocyte count 4,300/mm3 ; platelet count may require urgent treatment or isolation. Clinical
132,000/mm3 ; hemoglobin 15.4 g/dL; SGOT 105 U/L diagnosis is often difficult, as infectious exanthema-
(normal 5–45 U/L), SGPT 77 U/L (normal 5–60 U/L); tous diseases such as measles, rubella, human parvovirus
C-reactive protein 40 mg/L (normal 0–10 mg/L). As B19, dengue, human herpes virus (HHV)-6, roseola
was the case for his brother, a thin blood smear for infantum, and scarlet fever have overlapping clinical
malaria was negative. Three consecutive serologies for symptoms. In Brazil, from 1994 to 1998, 327 patients
dengue fever (PANBIO IgM and IgG Capture ELISA) presenting with pathologies characterized by vari-
were negative, as were NS1 Ag and PCR detection. able combinations of exanthema, cough, conjunctivitis,
Five days after onset of the first symptoms, the patient coryza, and fever were studied. A laboratory-confirmed
developed a generalized maculopapular rash. diagnosis was achieved in 71.3% of cases: 33% were
diagnosed with dengue fever, 20% with rubella, 9.2%
A Family Cluster of Measles with human parvovirus B19, 6.7% with measles, and
The three brothers recovered fully within 2 weeks of the 2.1% with HHV-6.4 These results underline the impor-
onset of symptoms. Initially, they presented with similar tant proportion of cosmopolitan febrile exanthemas. In
clinical features, which quite naturally led us to suspect France, Hochedez and colleagues screened 62 returning
a contagious disease. Although the first two serology travelers presenting with fever and exanthema for exotic
tests for dengue fever were positive in the index case in (if returning from endemic areas) and cosmopolitan
Indonesia, a third one (PANBIO IgM and IgG Capture infections. They found a specific etiology in over 90%
ELISA), this time in France, came back negative for of the patients. The three main diagnoses were chikun-
both IgM and IgG. This led to the prescription of gunya, dengue, and African tick bite fever, followed
serological tests for other infectious diseases, including by infectious mononucleosis, human immunodeficiency
measles. For this latter, the tests for all three of the virus-1 primary infection, cytomegalovirus primary
boys were positive (Table 1). We note that none of infection, measles, rubella, chicken pox, streptococcal
the siblings had been vaccinated for measles, despite infections, primary toxoplasmosis, acute schistosomia-
national recommendations. sis, and adverse drug reactions.1 Travelers presenting
with febrile exanthema should therefore be screened
not only for arboviral infections according to the area
Discussion visited but also for more common infections.
The diagnosis of dengue fever is based on the
Measles should be included in the differential diagnoses detection of NS1 Ag, antibodies (IgM and IgG)
of patients presenting febrile exanthema after travel. A or reverse transcription (RT)-PCR (virus isolation is
few years ago, chikungunya was considered the most used less often). For early diagnosis (onset < 5 days),
likely cause of febrile exanthema in returning travelers.1 detection of NS1 Ag may be used, but its moderate
However, recent measles outbreaks throughout the sensitivity requires the presence of both NS1 Ag and
world have increased the risk for travelers to contract IgM for a definite diagnosis.5 IgM are positive 4 to 5 days
this disease. after disease onset and remain so for up to 3 to 6 months.
According to the GeoSentinel Surveillance Network, IgG appear approximately 7–10 days after onset and are
febrile exanthema accounts for 12% of dermatological detectable thereafter for life. RT-PCR detection of viral

Table 1 Serological and PCR results for dengue fever and measles

Dengue fever Measles


Day after onset of first symptoms NS1 Ag IgM IgG PCR (blood) IgM IgG PCR (saliva)

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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270 Pull et al.

RNA is a very reliable technique for patients presenting recommends that the first dose of measles vaccine be
within 5 to 7 days of the onset of symptoms, but this administered at the age of 9 months. However, countries
method is more expensive, nonstandardized, and only a where the risk of measles is low often provide the first
few centers in France use it routinely.6 dose at the age of 12–15 months.17 In the case of travel
Consequently, serological tests are commonly to an endemic area, vaccination can be given at the age
used to establish or confirm a diagnosis of dengue. of 6 months.9 The second dose should be administered
Currently available commercial rapid tests offer good before the age of 2 years, with an interval of at least
sensitivity, but they lack specificity, which may lead 1 month between the two doses. Young adults born
to false-positive results as in our index case. Overall, after 1980 should receive both doses and travelers born
possible explanations for false-positive results include before this date should receive at least one dose in the
cross-reactive flavivirus-specific antibodies, nonspecific absence of previous vaccination.18
binding of antibodies secreted in the course of various
infections such as mononucleosis or hepatitis, and
rheumatoid factor.7 Cross-reactivity with measles Conclusion
antibodies is not commonly assumed by biologists Even though arboviral infections are one of the leading
and, to our knowledge, has only been reported once causes of febrile exanthema in travelers, this symptom
in Belgium.8 Wichmann and colleagues analyzed 127 is not synonymous with dengue fever. Cosmopolitan
cases of dengue diagnosed on a single positive rapid infections such as measles must be considered, even
test. Each of the cases was further investigated via the more so now that its incidence is increasing in several
use of several IgM- and IgG-ELISAs, immunofluo- parts of the world. Our cases provide a compelling
rescence assays, and real-time reverse transcription argument for the promotion of vaccination against
polymerase chain reaction assays. Overall, there was this disease, as recommended by the World Health
a 42.5% false-positive rate; in 6.1% of false-positive Organization.
cases, both leukopenia and thrombocytopenia were
present. Therefore, positive rapid test results should
be confirmed by laboratory-based ELISA serology or Declaration of Interests
virus PCR detection for a reliable diagnosis of dengue
fever.7 The authors state they have no conflicts of interest to
Current outbreaks of measles in Europe are a declare.
reminder of the risks of serious morbidity, and even
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