Journal of The Association of Physicians of India Vol. 64 July 2016 59

Expanded DengueDB Kadam1, Sonali Salvi2, Ajay Chandanwale3

R e v i e w A R t i c l e

1Professor & Head, 2Associate Professor, Dept. of Medicine, 3Dean All B.J. Govt. Medical College, Pune, MaharashtraReceived: 01.12.2015; Accepted: 23.03.2016

Introduction

Ex p a n d e d d e n g u e i s a terminology developed in the

WHO guidel ines of year 2012 (Figure 1).1 Unusual manifestations of pat ients with severe organ involvement such as liver, kidneys, brain or heart associated with d e n g u e i n f e c t i o n h a v e b e e n increasingly reported in dengue hemorrhagic fever (DHF) and also in dengue patients who do not have evidence of plasma leakage. These unusual manifestations may

causal studies be done.

Grades of Dengue fever

Fever of 2-7 days with two or more of following – headache, retro-orbital pain, myalgia, arthralgia w i t h o r w i t h o u t l e u c o p e n i a , thrombocytopenia and no evidence of plasma leakage is the classic presentation of dengue.

DHF I : Above cr i ter ia p lus p o s i t i ve t o u r n i q u e t t e s t a n d e v i d e n c e o f p l a s m a l e a k a g e . Thrombocytopenia with platelet count less than100,000/cu mm and hematocrit rise 20% over baseline.

D H F I I : A b o v e p l u s s o m e evidence of spontaneous bleeding in skin or other organs (black tarry stool, epistaxis, gum bleeds) and abdominal pain. Thrombocytopenia with platelet count less than 100,000 /cu mm and hematocrit rise 20% over baseline.

DHF I I I (DSS) : Above p lus circulatory failure (weak rapid pulse , narrow pulse pressure <20 mm Hg. Hypotension, cold c l a m m y s k i n , r e s t l e s s n e s s ) . Thrombocytopenia with platelet count less than 100,000 /cu mm and hematocrit rise 20% over baseline.

DHF IV (DSS): profound shock with undetectable blood pressure or pulse. Thrombocytopenia with platelet count less than100,000 /cu mm and hematocrit rise 20% over baseline.2

End-Organ Damage

Blood vessels and platelets are the two main end organs involved in dengue.

be associated with co-infections, co-morbidities or complications of prolonged shock and can be c l u b b e d u n d e r t h e e x p a n d e d dengue syndrome (Figure 2). The unusual manifestations may be underreported or unrecognized or not related to dengue. However, it is essential that proper clinical assessment i s carr ied out for appropriate management, and

AbstractThe World Health Organization (WHO) has coined the term expanded dengue to describe cases which do not fall into either dengue shock syndrome or dengue hemorrhagic fever. This has incorporated several atypical findings of dengue. Dengue virus has not been enlisted as a common etiological agent in several conditions like encephalitis, Guillain Barre syndrome. Moreover it is a great mimic of co-existing epidemics like Malaria, Chikungunya and Zika virus disease, which are also mosquito-borne diseases. The atypical manifestations noted in dengue can be mutisystemic and multifacetal. In clinical practice, the occurrence of atypical presentation should prompt us to investigate for dengue. Knowledge of expanded dengue helps to clinch the diagnosis of dengue early, especially during ongoing epidemics, avoiding further battery of investigations.

Dengue has proved to be the epidemic with the ability to recur and has a diverse array of presentation as seen in large series from India, Srilanka, Indonesia and Taiwan. WHO has given the case definition of dengue fever in their comprehensive guidelines. Accordingly, a probable case is defined as acute febrile illness with two or more of any findings viz. headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, leucopenia and supportive serology.

There have been cases of patients admitted with fever, altered mentation with or without neck stiffness and pyramidal tract signs. Some had seizures or status epilepticus as presentation. When they were tested for serology, dengue was positive. After ruling out other causes, dengue remained the only culprit. We have come across varied presentations of dengue fever in clinical practice and the present article throws light on atypical manifestations of dengue.

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Fig. 1: Classification of dengue

Fig. 2: Expanded dengue

Dengue Virus Infection

Asymptomatic Symptomatic

Undifferentiated Fever (Viral syndrome)

Dengue Fever

Without Hemorrhage

With unusual Hemorrhage

DHF

DHF Non-shock DHF with Shock

Expanded Dengue

Syndrome

DSS = Dengue Shock Syndrome; DHF = Dengue Hemorrhagic Fever

Expanded Dengue

End-organ Damage

Coagulation Disorder

Hemorrhage- related

Hyper-coagulable State

Cerebral InfarctionCortical Venous

ThrombosisMyocardial Infarction

Other OrganDamage Co-infection

MalariaLeptospirosisEnteric FeverChikunguniya

Dengue in High Risk Group

InfantsGeriatric Group

PregnancyHypertension

IHDHemoglobinopathies

Immuno-compromised

Patients

Blood Vessels

Increased vascular permeability is the hallmark pathophysiology in dengue.3 Intravascular volume g e t s c o n t r a c t e d a n d l e a d s t o 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 integrity mediated by various cytokines. There is rapid recovery of shock without sequelae in the pleura and peritoneum.

Platelets

Thrombocytopenia and hemo-concentration are constant findings in DHF. A drop in platelet count to below 100,000 ce l ls /mm 3 is usually found between the 3rd and 10th days of illness. DENV-2 induces activation, mitochondrial dysfunct ion and apoptos is in platelets.4

Other Organ DamageCentral Nervous System

Neurological involvement in dengue fever is heterogeneous. It

occurs acutely within first two days of acquiring the infection.

Intra-cerebral hemorrhage can occur as a result of direct tissue lesion caused by the virus, capillary h e m o r r h a g e , d i s s e m i n a t e d intravascular coagulation and in cases of hepatic failure. Kumar et al have reported 5 cases of intra-cranial hemorrhage, two of which, succumbed to death.5 Large data is not available regarding the outcome of intra-cerebral bleed; however, mortality remains very high. Encephalitis, aseptic meningitis and acute disseminated encephalomyelitis are seen due to neuro-virulent effect of dengue viruses and serotypes 2 and 3 have been isolated from the CSF of these patients. Infiltration of virus laden macrophages seems to be the possible mechanism.6 Cam et al have reported a mortality of 22%.7 Outcome in various other case repor ts , i s favorable . In Jamaica, a study of 401 patients wi th suspected cases of v i ra l in fec t ion o f the CNS showed that 54 (13.5%) were positive for dengue; Ischemic cerebral infarcts are uncommon and arise out of meningo-vasculitis.8 There are two case reports of dengue causing cortical venous sinus thrombosis (CVST). Severe dehydration is the plausible explanation for CVST and requires anticoagulants in addition to rehydrat ion . 9 Hypokalemic p e r i o d i c p a r a l y s i s i s a r a r e manifestation and probably relates to redistribution of potassium in the cells. Paralysis responds promptly to potassium supplementation.10

Guillain Barre syndrome (GBS) attributable to dengue is on the rise. GBS presents in two forms as axonal and demyelinating and responds to immunoglobul ins in a similar fashion as that of non-dengue GBS.11,12 Opsoclonus-myoclonus with normal imaging has been noted and needs no special t reatment . 12 Opt ic neuropathy is the most common posterior segment ophthalmic involvement and can either recover completely

Journal of The Association of Physicians of India Vol. 64 July 2016 61

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 levat ion of l iver enzymes to 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 deng ue hemorrhag ic f ever i s

associated with acute, severe liver damage due primarily to massive direct infection of hepatocytes and Kupffer cells with minimal cytokine response.17

Acalculous cholecystit is has been documented in many case r e p o r t s . A s y m p t o m a t i c g a l l bladder edema as an ultrasound examinat ion f inding 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 bi lateral parot i t is mimicking mumps has also been described in dengue.21

Cardiovascular System

Myocarditis is the most common c a r d i a c i n v o l ve m e n t s e e n i n 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

I n c i d e n c e o f a s y m p t o m a t i c myocardit is can be as high as 24%. Significant mortality (23%) has been reported in patients with clinical evidence of myocarditis.

Myocarditis can be asymptomatic to start with and progress towards palpitat ions, syncope. Resting tachycardia and ECG showing T inversions are suggestive of myocarditis.

2-D echocardiographic evaluation shows chamber di la tat ion, an irregular jerky movement of the ventr icular wal l , and a minor 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

CPK-MB can be a va luable tool to correlate, if ECG findings and clinical picture suggestive o f m y o c a r d i t i s a r e p r e s e n t . C o r t i c o s t e r o i d s h a ve n o r o l e in the management of dengue myocarditis.

Tachycardia and volume loss indicate poor prognosis . Such patients should be hydrated till they develop a relative bradycardia. C o n t i n u o u s c e n t r a l v e n o u s 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

Table 1: CNS manifestations

Intra-cerebral hemorrhageEncephalitisAseptic meningitisADEMCerebral infarctCortical venous thrombosisMyelitisHypokalemic periodic paralysisG.B. syndromeOpsoclonus myoclonusOptic neuropathyMyalgia crurisRhabdomyolysisDysarthria clumsy-hand syndrome

Table 2: Gastrointestinal manifestations

Hepatic dysfunction (without ALF)Acalculus cholecystitisFulminant hepatic failure Acute pancreatitisDiffuse peritonitisAcute appendicitisAcute parotitisSpleen rupture

Table 3: Cardiovascular manifestations

Asymptomatic myocarditisSymptomatic myocarditisPericarditisMyocardial infarctionS-A nodal blockA-V nodal blockAcute atrial fibrillationCardiomyopathy

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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 h a ve a l s o b e e n d e s c r i b e d i n dengue.25,26

AKI in dengue necess i tates appropriate fluid management. Hemodialysis has been required in variable number of patients i n d i f f e r e n t s e r i e s r e p o r t e d . Hyperkalemia that is unresponsive t o c o n v e n t i o n a l t r e a t m e n t , progress ively decl in ing ur ine o u t p u t d e s p i t e i n t r a v e n o u s hydrat ion 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-infectionsMalaria

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

m a n i f e s t a t i o n s a r e c o m m o n 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 ve c t o r f o r b o t h D e n g u e a n d C h i k u n g u n ya . A b o u t 1 2 % o f D e n g u e p a t i e n t s e x p e r i e n c e a r t h r a l g i a s . S o d i a g n o s i n g Chikungunya in the sett ing of dengue fever is a chal lenging task. Evidence of serositis, shock a n d t h r o m b o c y t o p e n i a p o i n t 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. Co- infec t ion ra te var ies f rom 1.3% to as high as 17.8%. Most of the patients presented with h e p a t o r e n a l d y s f u n c t i o n a n d 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 d i s s e m i n a t e d i n t r a v a s c u l a r 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 GroupsDiabetes Mellitus

Diabetes mellitus is the most significant risk factor for dengue. A p o p t o s i s o f m i c r o v a s c u l a r endothelial cells leads to increased v a s c u l a r p e r m e a b i l i t y a n d progress ion 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 d iabe tes and no hypertension.31

Chronic Kidney Disease

CKD predisposes to acute kidney injury in dengue as discussed earlier.24

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4. Hottz ED, Oliveira MF, Nunes PCG, et al. Dengue induces platelet activation, mitochondrial dysfunction and cell death

Table 4: Renal manifestations

Myoglobinuric acute renal failureRhabdomyolysisAKI associated with DHFAKI with DSS/DHFIgA nephropathyHemolytic-uremic syndrome

Table 5: Differentiating features between dengue and zika infection

Dengue Zika High fever Mild feverSevere myalgia/headache Mild bodyache Rash well-defined Rash ill-definedHemorrhage ± No hemorrhage

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