Journal of The Association of Physicians of India ■ Vol.

64 ■ July 2016 59

Review Article

Expanded Dengue
DB Kadam1, Sonali Salvi2, Ajay Chandanwale3

causal studies be done.

Abstract
Grades of Dengue fever
The World Health Organization (WHO) has coined the term expanded
dengue to describe cases which do not fall into either dengue shock Fever of 2-7 days with two or
syndrome or dengue hemorrhagic fever. This has incorporated several more of following – headache, retro-
atypical findings of dengue. Dengue virus has not been enlisted as orbital pain, myalgia, arthralgia
a common etiological agent in several conditions like encephalitis, with or without leucopenia,
Guillain Barre syndrome. Moreover it is a great mimic of co-existing thrombocytopenia and no evidence
epidemics like Malaria, Chikungunya and Zika virus disease, which are of plasma leakage is the classic
also mosquito-borne diseases. The atypical manifestations noted in presentation of dengue.
dengue can be mutisystemic and multifacetal. In clinical practice, the D H F I : A b o ve c r i t e r i a p l u s
occurrence of atypical presentation should prompt us to investigate for positive tourniquet test and
dengue. Knowledge of expanded dengue helps to clinch the diagnosis evidence of plasma leakage.
of dengue early, especially during ongoing epidemics, avoiding further Thrombocytopenia with platelet
battery of investigations. count less than100,000/cu mm and
Dengue has proved to be the epidemic with the ability to recur and has a hematocrit rise 20% over baseline.
diverse array of presentation as seen in large series from India, Srilanka, DHF II: Above plus some
Indonesia and Taiwan. WHO has given the case definition of dengue fever evidence of spontaneous bleeding
in their comprehensive guidelines. Accordingly, a probable case is defined in skin or other organs (black tarry
as acute febrile illness with two or more of any findings viz. headache, stool, epistaxis, gum bleeds) and
retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, abdominal pain. Thrombocytopenia
leucopenia and supportive serology. with platelet count less than 100,000
/cu mm and hematocrit rise 20%
There have been cases of patients admitted with fever, altered mentation over baseline.
with or without neck stiffness and pyramidal tract signs. Some had
DHF III (DSS): Above plus
seizures or status epilepticus as presentation. When they were tested
circulatory failure (weak rapid
for serology, dengue was positive. After ruling out other causes, dengue
pulse, narrow pulse pressure
remained the only culprit. We have come across varied presentations of <20 mm Hg. Hypotension, cold
dengue fever in clinical practice and the present article throws light on clammy skin, restlessness).
atypical manifestations of dengue. Thrombocytopenia with platelet
count less than 100,000 /cu mm and
hematocrit rise 20% over baseline.
Introduction be associated with co-infections, DHF IV (DSS): profound shock
co-morbidities or complications with undetectable blood pressure

E xpanded dengue is a
terminology developed in the
W H O g u i d e l i n e s o f ye a r 2 0 1 2
(Figure 1). 1 Unusual manifestations
o f p a t i e n t s w i t h s e ve r e o r g a n
involvement such as liver, kidneys,
brain or heart associated with
dengue infection have been
increasingly reported in dengue
hemorrhagic fever (DHF) and also
in dengue patients who do not
have evidence of plasma leakage.
These unusual manifestations may
of prolonged shock and can be
clubbed under the expanded
dengue syndrome (Figure 2). The
or pulse. Thrombocytopenia with
platelet count less than100,000 /cu
mm and hematocrit rise 20% over
unusual manifestations may be baseline. 2
underreported or unrecognized or
not related to dengue. However, End-Organ Damage
it is essential that proper clinical
assessment is carried out for Blood vessels and platelets are
appropriate management, and the two main end organs involved
in dengue.
1
Professor & Head, 2Associate Professor, Dept. of Medicine, 3Dean All B.J. Govt. Medical College, Pune, Maharashtra
Received: 01.12.2015; Accepted: 23.03.2016
60 Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016

occurs acutely within first two days

Asymptomatic
Undifferentiated
Fever (Viral Dengue Fever
syndrome)
Without
Hemorrhage
DSS = Dengue Shock Syndrome; DHF = Dengue Hemorrhagic Fever
Fig. 1: Classification of dengue
End-organ Damage
Coagulation
Disorder
Hemorrhage- Hyper-coagulable
related State
Fig. 2: Expanded dengue
Blood Vessels
Increased vascular permeability
is the hallmark pathophysiology
in dengue. 3 Intravascular volume
gets contracted and leads to
shock in severe cases. There is a
selective leakage of plasma in the
pleural and peritoneal cavities
over a short period (24–48 hours).
The underlying mechanism is
a functional change in vascular
i n t e g r i t y m e d i a t e d b y va r i o u s
cytokines. There is rapid recovery
of shock without sequelae in the
pleura and peritoneum.
Dengue Virus
Infection of acquiring the infection.
Intra-cerebral hemorrhage can
occur as a result of direct tissue
Symptomatic lesion caused by the virus, capillary
hemorrhage, disseminated
intravascular coagulation and in
Expanded
DHF Dengue cases of hepatic failure. Kumar
Syndrome e t a l h a ve r e p o r t e d 5 c a s e s o f
intra-cranial hemorrhage, two of
With unusual
which, succumbed to death. 5 Large
DHF Non-shock DHF with Shock data is not available regarding
Hemorrhage
the outcome of intra-cerebral
bleed; however, mortality remains
very high. Encephalitis, aseptic
meningitis and acute disseminated
encephalomyelitis are seen due to
Expanded Dengue
neuro-virulent effect of dengue
viruses and serotypes 2 and 3
have been isolated from the CSF
Other Organ
Co-infection
Dengue in High of these patients. Infiltration of
Damage Risk Group
virus laden macrophages seems to
be the possible mechanism. 6 Cam
Infants et al have reported a mortality of
Geriatric Group 22%. 7 Outcome in various other
Malaria
Pregnancy case reports, is favorable. In
Hypertension
Leptospirosis Jamaica, a study of 401 patients
IHD
Enteric Fever with suspected cases of viral
Hemoglobinopathies
Chikunguniya infection of the CNS showed
Immuno-
compromised that 54 (13.5%) were positive for
Patients dengue; Ischemic cerebral infarcts
are uncommon and arise out of
Cerebral Infarction
meningo-vasculitis. 8 There are two
Cortical Venous
Thrombosis case reports of dengue causing
Myocardial cortical venous sinus thrombosis
Infarction (CVST). Severe dehydration is the
plausible explanation for CVST and
requires anticoagulants in addition
to rehydration.9 Hypokalemic
periodic paralysis is a rare
manifestation and probably relates
Platelets to redistribution of potassium in the
Thrombocytopenia and hemo- cells. Paralysis responds promptly
concentration are constant findings to potassium supplementation. 10
in DHF. A drop in platelet count Guillain Barre syndrome (GBS)
to below 100,000 cells/mm3 is attributable to dengue is on the
u s u a l l y f o u n d b e t we e n t h e 3 r d rise. GBS presents in two forms
and 10 th days of illness. DENV-2 as axonal and demyelinating and
induces activation, mitochondrial responds to immunoglobulins
dysfunction and apoptosis in in a similar fashion as that of
platelets. 4 non-dengue GBS. 11,12 Opsoclonus-
myoclonus with normal imaging
Other Organ Damage has been noted and needs no special
t r e a t m e n t . 12 O p t i c n e u r o p a t h y
Central Nervous System is the most common posterior
Neurological involvement in segment ophthalmic involvement
dengue fever is heterogeneous. It and can either recover completely

Table 1: CNS manifestations
Intra-cerebral hemorrhage
Encephalitis
Aseptic meningitis
ADEM
Cerebral infarct
Cortical venous thrombosis
Myelitis
Hypokalemic periodic paralysis
G.B. syndrome
Opsoclonus myoclonus
Optic neuropathy
Myalgia cruris
Rhabdomyolysis
Dysarthria clumsy-hand syndrome
or progress to permanent visual
deficit.13 A rare muscle involvement
in dengue can take form of myalgia
cruris and is postulated to be due
to direct muscle fibre invasion
by dengue virus or release of
myogenic cytokines. Treatment is
symptomatic. 14 Dysarthria clumsy
hand syndrome is another rare
manifestation and is due to a lacunar
stroke as a thrombotic complication
of dengue.15 Thus, any unusual CNS
presentation occurring amidst a
dengue epidemic, should prompt
one to investigate for underlying
dengue infection.
Ta b l e 1 e n l i s t s v a r i o u s
neurological manifestations of
dengue.
Hepato-biliary System
Liver involvement in dengue
can range from asymptomatic
e l e va t i o n o f l i ve r e n z y m e s t o
fulminant hepatic failure (Table 2).
Transaminitis is seen in upto 30%
of patients in present epidemic. 16
In DHF and DSS, acute liver failure
occurs rapidly and jaundice can
be evident on first day of illness.
Laboratory-wise, AST elevation is
proportionately greater possibly
attributed to monocyte damage.
The levels of aminotransferases
(usually not more than 100 U)
generally reach maximum values
around the ninth day after the first
episode of fever and gradually
taper off toward normality within
two weeks. DSS is associated with
higher mortality than DHF.  Fatal
dengue hemorrhagic fever is
Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016
Table 2: Gastrointestinal
manifestations
Hepatic dysfunction (without ALF)
Acalculus cholecystitis
Fulminant hepatic failure
Acute pancreatitis
Diffuse peritonitis
Acute appendicitis
Acute parotitis
Spleen rupture
associated with acute, severe liver
damage due primarily to massive
direct infection of hepatocytes
and Kupffer cells with minimal
cytokine response. 17
Acalculous cholecystitis has
been documented in many case
reports. Asymptomatic gall
bladder edema as an ultrasound
examination finding can be a
surrogate marker of dengue before
arrival of laboratory investigations
report. Abnormal levels of alkaline
phosphatase, thickened gallbladder
wall, a positive Murphys’ sign,
peri-cholecystic fluid collection,
and no stone(s) in the gallbladder
are the features. Cholecystectomy
is not advised, however, a close
watch for impending gangrenous
gall bladder is a must. 18
Acute pancreatitis with raised
amylase and pancreatic edema is
also reported and usually runs a
benign course. 19 A very rare and
life-threatening complication of
dengue is splenic rupture and is
fatal. 20
An acute bilateral parotitis
mimicking mumps has also been
described in dengue. 21
Cardiovascular System
Myocarditis is the most common
cardiac involvement seen in
dengue. Myocardial endothelium
and cardio-myocytes are inflamed.
The myotubes are infected by
dengue virus and have increased
expression of the inflammatory
genes and protein IP-10 and a rise
in intracellular Ca2+ concentration.22
Incidence of asymptomatic
myocarditis can be as high as
24%. Significant mortality (23%)
has been reported in patients with
clinical evidence of myocarditis.
61
Table 3: Cardiovascular
manifestations
Asymptomatic myocarditis
Symptomatic myocarditis
Pericarditis
Myocardial infarction
S-A nodal block
A-V nodal block
Acute atrial fibrillation
Cardiomyopathy
Myocarditis can be asymptomatic
to start with and progress towards
palpitations, syncope. Resting
tachycardia and ECG showing
T inversions are suggestive of
myocarditis.
2-D echocardiographic evaluation
shows chamber dilatation, an
irregular jerky movement of the
ve n t r i c u l a r wa l l , a n d a m i n o r
degree of atrioventricular valvular
regurgitation. Right ventricle (RV)
dilation with associated tricuspid
regurgitation is more common than
left ventricular dilatation. Isolated
tricuspid regurgitation can also be
seen (Table 3).
Ejection fraction is preserved.
The findings simulate those in
Takotsubo cardiomyopathy. These
abnormalities are transient with no
residual deficit at the end of three
months. 23
C P K - M B c a n b e a va l u a b l e
tool to correlate, if ECG findings
and clinical picture suggestive
of myocarditis are present.
Corticosteroids have no role
in the management of dengue
myocarditis.
Tachycardia and volume loss
indicate poor prognosis. Such
patients should be hydrated till
they develop a relative bradycardia.
Continuous central venous
pressure monitoring during fluid
resuscitation is helpful.
Kidneys
Renal involvement in dengue is
uncommon (Table 4) as compared
to other organ involvement. The
commonest renal presentation is
that of a pre-renal acute kidney
injury (AKI) related to third space
fluid loss and dehydration. Lee et
al from Taiwan have reported an
62 Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016
Table 4: Renal manifestations
Myoglobinuric acute renal failure
Rhabdomyolysis
AKI associated with DHF
AKI with DSS/DHF
IgA nephropathy
Hemolytic-uremic syndrome
incidence of 3.3% (10/304). Patients
with renal failure associated with
DHF had high mortality than those
without renal failure. Amongst the
fatal DHF cases, an incidence rate
of 33.3% was reported. Pre-existing
renal disease (diabetic nephropathy
and hypertensive nephrosclerosis)
adversely affects the survival. 24
AKI can occur with or without
rhabdomyolysis. DHF and DSS
are associated with acute tubular
necrosis. Rhabdomyolysis leads
to pigment deposition and acute
tubular necrosis. IgA nephropathy
and hemolytic uremic syndrome
have also been described in
dengue. 25,26
AKI in dengue necessitates
appropriate fluid management.
Hemodialysis has been required
in variable number of patients
in different series reported.
Hyperkalemia that is unresponsive
to conventional treatment,
p r o g r e s s i ve l y d e c l i n i n g u r i n e
output despite intravenous
hydration and uremia are the
common indications for dialysis in
dengue related AKI. Low platelet
count can occur due to uremia or
the use of heparin, which further
complicates the clinical picture of
dengue.
Co-infections
Malaria
Malaria is by far the commonest
co-infection seen in malaria. Co-
infection rate has been documented
in the range of 8.3% in a Brazilian
series to 26% in an Indian series.
Pl. falciparum is most commonly
associated as per Indian studies;
h o we ve r , Pl . v i va x h a s b e e n
reported in foreign literature. 27,28
Typical fever paroxysms are
absent. Jaundice and bleeding
Table 5: Differentiating features
between dengue and zika
infection
Dengue Zika
High fever Mild fever
Severe myalgia/headache Mild bodyache
Rash well-defined Rash ill-defined
Hemorrhage ± No hemorrhage
manifestations are common
presentation along with headache,
myalgias and backache. Hypotension
and hepato-splenomegaly are
noted. Laboratory-wise, anemia,
leucopenia and thrombocytopenia
are more severe in co-infection.
Hematocrit may not be a useful
guide to treatment in the presence
of malaria. Malaria parasite index
is reportedly low in the presence
of dengue.
Chikungunya
Aedes aegypti is the common
vector for both Dengue and
Chikungunya. About 12% of
Dengue patients experience
arthralgias. So diagnosing
Chikungunya in the setting of
d e n g u e f e ve r i s a c h a l l e n g i n g
task. Evidence of serositis, shock
and thrombocytopenia point
towards dengue. 29 Arthralgia in
dengue is self-limiting, whereas;
Chikungunya leads to disabling
arthritis which may last for months.
Leptospirosis
Leptospirosis and dengue often
concurrently infect individuals as
both occur during rainy season.
C o - i n f e c t i o n r a t e va r i e s f r o m
1.3% to as high as 17.8%. Most
of the patients presented with
hepatorenal dysfunction and
thrombocytopenia. Thus, in cases
where hepato-renal impairment is
evident at presentation, concurrent
leptospirosis must be suspected
and antibiotic therapy needs to
be initiated. Mortality is due to
multiorgan system failure and
disseminated intravascular
coagulation. 30
Zika Virus Disease
The new emergent Zika virus
causes a syndrome of fever that
is often indistinguishable from
dengue virus. The occurrence
of arthralgia is common to both
infections. Zika virus diagnosis is
made only after the exclusion of
dengue infection with appropriate
serological tests.
Table 5 describes few features
that can be helpful in differentiating
between the two.
Dengue in High Risk
Groups
Diabetes Mellitus
Diabetes mellitus is the most
significant risk factor for dengue.
Apoptosis of microvascular
endothelial cells leads to increased
vascular permeability and
progression to DHF and DSS.
Also, in diabetes mellitus, rise
in cytokines potentiates vascular
leakage. 31
Hypertension
Hypertension is proposed to
have effect modification on the risk
of DHF outcome in dengue patients
with diabetes. Chinese who had
diabetes with hypertension had
2.1 (95% CI:1.07-4.12) times higher
risk of DHF compared with Chinese
who had no diabetes and no
hypertension. 31
Chronic Kidney Disease
CKD predisposes to acute kidney
injury in dengue as discussed
earlier. 24
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