20 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 9, NO. I, 1996

Review Article

Dengue haemorrhagic fever and the dengue shocksyndrome in India

R. LALL, V. DHANDA

ABSTRACTThe clinical spectrum of dengue fever ranges fromasymptomatic infection through severe haemorrhage andsudden fatal shock. Increased capillary permeability is thediagnostic feature of dengue haemorrhagic fever (DHF). Thepathophysiology of DHF/dengue shock syndrome (DSS) isrelated to sequential infection with different serotypes of thevirus, variations in virus virulence, interaction of the virus withenvironmental or hostfactors and a combination ofvarious riskfactors. Infection due to low virulence strains is assumed to bethe reason for the infrequent incidence of serious denguedisease in India. Since all four serotypes of the dengue virushave been implicated in various outbreaks in this country andseveral outbreaks of DHF/DSS have been recorded since thefirst report in 1963, further epidemics of the disease are likely.The situation is aggravated by the recent emergence of DHFIDSS in Sri Lanka. In view of the potential of this disease tospread, effective preventive and control measures should bea priority.Natl Med J India 1996;9:20-23

INTRODUCTIONDengue haemorrhagic fever (DHF) is clinically defined as anillness that worsens two days or more after its onset, and ischaracterized by a haemorrhagic diathesis, hypoproteinaemia anda tendency to develop a shock syndrome that may be fatal. I TheWorld Health Organization (WHO) case parameters for DHFinclude: (i) fever; (ii) haemorrhagic manifestations, including atleast a positive tourniquet test (except in patients in shock), andeither major or minor bleeding phenomena; (iii) thrombocytopenia(platelet count ~100 OOO/cmm); and (iv) haemoconcentration(increase in haematocrit by 20% or more relative to baselinevalues, or objective evidence of increased capillary permeability). 2

The dengue shock syndrome (DSS) consists of haemorrhagicfever and shock (hypotension or a pulse pressure of 20 mmHg orless) and haemoconcentration (haematocrit at least 20% greaterthan the initial value). This syndrome is caused by increasedvascular permeability and resultant intravascular hypovolaemia. 3.4

Cases of severe haemorrhage or even death caused by dengueinfection without evidence of increased capillary permeability arenot currently classified as DHF according to WHO criteria.P

Vector Control Research Centre, Indira Nagar, Pondicherry 605006,India '

R. LALL, V. DHANDA

Correspondence to R. LALL

© The National Medical Journal of India 1996

Dengue infection is endemic in India and outbreaks have so farbeen confined to urban areas. The majority of these have been ofthe classical dengue fever type. There has been a spurt of outbreaksof dengue fever in the rural areas. There also .appears to be amarked increase in DHF during the outbreaks in rural as well asin urban areas.v" After HIV -I infection, DHF is now the largestemerging viral disease globally. \0 The present review deals withthe occurrence of DHFIDSS in different parts of India.

EPIDEMIOLOGYDengue haemorrhagic fever, the most prominent of thehaemorrhagic fevers of Southeast Asia and India, is an acute,infectious, urban, mosquito-borne disease. It is caused by fourserotypes of the dengue virus transmitted principally by thedomestic mosquito, Aedes aegypti. Classical dengue fever isendemic in many parts of India except the Himalayan and othermountainous regions where conditions are not conducive to thepropagation of its vector. The disease has been.prevalent in Indiafor over two centuries, I1.12but is recognized only when outbreaksoccur. Serological surveillance against dengue viruses in Indiaand the ecology of the vector have been reviewed in the past. 13-15The outbreaks in India occur mostly during or after the rainyseason, which coincide with the rise in the vector population.Outbreaks have also been reported during the dry summer monthswhen widespread storage of water for domestic purposes causesa rise in the vector population.tv" Many outbreaks have beenreported since 195618 with fairly recent ones from Delhi(1988,19-21 199F2), Calcutta (199022), Madras (1987, 198923)

and Vellore (199023).Unlike the other countries of Southeast Asia, DHF in India has

usually not been a serious problem. Multiple aetiological agentsincluding the Chikungunya virus were identified during epidemicsof haemorrhagic fever. This is thought to be due to geneticdifferences between the Southeast Asian and Indian denguestrains. 24 The emergence of the DHFIDSS epidemic in Sri Lankaprovides evidence that the syndrome is not host-related but virus-related." It now appears that Indians and Southeast Asians areequally susceptible to severe dengue illness, and virus straindifferences must be the reason for the low incidence ofDHFIDSSin India. The observation of DSS occurring in Indian childrenresiding in a Yangon community during 1984-85 were no differentin incidence from the disease occurring in Myanmar children.This disproves the hypothesis that Indians may be genetically lesssusceptible to DSS than other populations."

Dengue haemorrhagic fever was first reported in India from

LALL, DHANDA : DENGUE HAEMORRHAGIC FEVER

TABLEI. Dengue haemorrhagic fever and dengue shock syndrome in. India

Place Year Dengue virus serotypeincriminated

Calcutta' ••..31

Vishakapatnam"-"

Asansol"

Kanpur":"

Veil ore"

Ajmer"Kanpur"Delhi'O

Jalore"DelhiI9.'1

Veil ore"

1963196419671968

'1968196919691970198519881990

DEN-2DEN-2

DEN-2,4

DEN-4

DEN-3,4

DEN-I, 3DEN-2DEN-I,3

DEN-2

DEN-2

Not established

Calcutta. 26The clinical picture was similar to the Thai haemorrhagicfever. Since then, all outbreaks of DHF and DSS have beenrecorded in India (Table I). Outbreaks of haemorrhagic fever inwhich dengue viruses were isolated have been broadly labelled asDHF. However, the distinctive pathophysiological change, i.e.leakage of plasma as manifested by a rising haematocrit value andhaemoconcentration and the use of the criteria for a clinicaldiagnosis of DHFIDSS laid down by the WHO in 1986,2 were notadhered to in establishing the diagnosis of DHFIDSS in the citedreports. The criteria for clinical diagnosis are: (i) acute onset, highgrade, continuous fever lasting for 2-7 days; (ii) haemorrhagicmanifestations including at least a positive tourniquet test;(iii) enlargement of the liver; and (iv) shock.

Thus, adults with dengue infection as well as, for instance,peptic ulcer and gastrointestinal haemorrhage may have beenincorrectly included as having DHFIDSS. The WHO criteria fordiagnosing DHFIDSS have been applied only in the outbreaks inDelhi (1988) and Vellore (1990).

In the first reported epidemic in Calcutta during 1963, clinicalseverity was more pronounced in the younger age groups. In astudy of 54 cases (33 males and 21 females) reported by Aikatet al., 26the largest number were between 11 and 20 years of age.There were 3 deaths-2 girls below 10 years of age and a maleaged 18. The disease was reported from Vishakapatnam in 1964,32.33where 107 cases consisting of 79 males and 28 females werestudied. The affected age group was between 12-30 years andthere was no death. An outbreak occurred in the town of Asansolin West Bengal in 1967.34 Among the 77 cases studied, there were64 males and 13 females. There was no death, though the shocksyndrome was observed in a male aged 25 years. In the Kanpurepidemic of 1968, there were 12 deaths among 224 cases ofDHF.35.36The youngest case was 2 years old and the oldest 65.Adolescents and young adults were most frequently affected. Ofthe 224 cases, 58 were in the 11-20 years age group and 89 werebetween 21 and 30 years of age. During the same year, there wasno death among 125 cases in a DHF outbreak in Vellore." During1969, among 97 cases studied in an outbreak in Ajmer, 2 cases ofclinical encephalitis were seen. 3MDengue virus serotype 3 wasisolated from the cerebrospinal fluid of one of them. No shocksyndrome was seen. In the second outbreak of DHF in Kanpur in1969, no mortality was reported among the 48 cases studied." Animportant finding was that dengue viral isolates produced lethalsickness in infant mice during the first or second passage.

In 1970, in a DHF outbreak in Delhi 4 deaths were reportedamong 273 cases." Almost all age groups were equally affected,

21

females being affected more frequently than males. Jalore inRajasthan suffered an outbreak of DHF in 1985.41 Among 110cases (80 males, 30 females) reported, there were 5 deaths.Involvement of the central nervous system was noted in 3 patientswho had encephalitis with tonic spasms and delirium. A relati velyhigh incidence (2.7%) of encephalitis indicated greater virulenceof the virus or increased susceptibility of the population duringthe outbreak. Dengue encephalopathy has also been reported onseveral other occasions from India, 21.42-45Indonesia.w" the CentralPacific" and Greece." In the DHF epidemic of Delhi in 1988,19among 21 children studied in a hospital (14 girls and 7 boysbetween 6 and 12 years of age), a clinical diagnosis of Grades IIIand IV severity was made in 14 and 7 cases respectively. Therewere 7 deaths and disseminated intravascular coagulation (DIC)was seen in one case. All the cases ofDHF in 1988 were presumedto be the result of secondary infection in individuals sensitized byprimary infection with dengue serotype 2 in the 1982 epidemic.An increased level of haem agglutination inhibition (HI) antibodyagainst the dengue serotype 2 was seen in the first blood sampletaken during the 1988 epidemic. In another report during the sameyear, 24 cases were found to be between 6 and 10 years of age."The case fatality rate was 13% in both the reports.

An epidemic involving 19 cases occurred in and aroundVellore town, the North Arcot Ambedkar district in Tamil Naduand adjoining districts in Tamil Nadu and Andhra Pradesh duringJune through November 1990,23 though isolated cases of DHFIDSS had been reported earlier in this region." The patientsincluded 13 girls and 6 boys, the ages ranging from below I yearto 12 years with most patients under six years of age. Spontaneoushaemorrhage from various sites took place in almost all the cases.Because of cross-reacting epitopes, the identity of the serotype(s)of the virus responsible for this epidemic could not be established.

The rate of DHF among dengue-infected individuals varieswith the underlying risk factors and the infecting virus strain."Estimates of this rate have ranged from 1 to 7 DHF cases per 100dengue infections.":"

RISK FACTORS

The virulence of the circulating strain is an important element inthe analysis of an epidemic," with increased virulence of certainstrains being postulated as the cause of epidemic DHFIDSS.54Dengue virus strains isolated from patients with DHFIDSS aremore virulent in the laboratory compared with strains obtainedfrom patients with milder disease.v-"

Pre-existent dengue immunity as detected by conventionalserological techniques was a significant (odds ratio ~6.5) riskfactor for the development of DHF.S7

Race is an individual risk factor since DHFIDSS has beenfound to be more prevalent in whites than in blacks."

The specific sequence of DEN-l followed by DEN-2 appearedto be associated with the greatest risk for DSS. Secondary infectionwith DEN-2 which followed primary infections with DEN-I,DEN-3 or DEN-4 was a risk factor for DSS. The risk of DSS isonly during the second infection and not in the subsequent ones.It is not known if all DEN-2 types are equally prone to cause DSSif preceded by DEN-p9

Chronic diseases such as bronchial asthma, diabetes mellitusand anaemia are additional risk factors. Enhanced DEN-2 activityhas been observed in leukocytes from asthmatic patients comparedto healthy persons, supporting the fact that bronchial asthma is arisk factor for DHFIDSS as seen on analysis of epidemiologicaldata."

22 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 9, No.1, 1996

A genetic risk for DHF has been suggested which may be animportant factor. HLA-A and -B typing on lymphocytes hasshown a positive association for HLA-A2, and HLA-B blank anda negative relationship for HLA-B\3.61

Maternal dengue antibodies playa dual role by first protectingand later increasing the risk of DHFIDSS by DEN-2. In infantswho developed DHFIDSS, there was a strong correlation betweenthe mother's DEN-2 neutralizing antibody titres and infant's ageat the time of onset of severe illness.f

VECfORAedes aegypti is the principal vector of the disease in India.DEN-l and DEN-4 viruses were first isolated from pools offemale Aedes aegypti in Vellore." All the four serotypes weresubsequently isolated from mosquito pools in the Velloreepidemic." Studies have shown that the onset of an epidemicparallels the build up of mosquito population density." Aedesalbopictus has been considered to be a viable vector of the denguevirus in India though its role has not been established. \3 TheDEN-4 virus has been isolated from Aedes albopictus at Asansolin West Bengal."

PATHOGENESISThere are several theories to explain the pathogenesis of DHF/DSS.~~Secondary infection with a heterologous dengue serotypeinduces hypersensitivity resulting in DHF.~6 Non-neutralizingantibodies to the dengue virus enhance viral uptake and replicationin monocytes. The shock syndrome associated with DHF resultsfrom an antibody-dependent enhancement (ADE) phenomenon.v'"An alternative hypothesis proposes that haemorrhage and theshock syndrome are the direct and indirect consequences ofcomplement activation." However, during an epidemic inBangkok, children exhibited DSS even on primary exposure todengue infection." In India, in contrast, even the existence of allthe four serotypes of the virus in Vellore failed to induce DHF. 64

PREVENTION AND CONTROLThe principal vector (Aedes aegypti) breeds primarily in man-made containers such as water storage vessels, old tyres, disusedair-coolers, air-conditioners and flower vases in and aroundhuman dwellings. Elimination of these breeding sites is an effectiveand definitive method for controlling the vector and preventingthe disease. ~O.~2.71New efforts are focusing on community educationand behaviour modification in an attempt to control the vectorthrough breeding site reduction."

Conventional antimosquito measures, such as fogging withinsecticides like malathion and/or space spraying with pyrethrum,have not been found suitable for vector control although thelarvicidal agent temephos SG has been found to be useful in someareas."

There is no dengue vaccine available for use, though researchcontinues on the development of a safe and effective tetravalentvaccine that would circumvent the potential hazards predicted bythe immune enhancement theory. Concurrent isolation of DEN-land DEN-4 serotypes from a 16-year-old patient in Puerto Ricowho suffered only a mild attack of dengue augurs well for amultivalent vaccine." In epidemic situations, fogging withinsecticides may be useful, but currently the most effective wayto avoid infection is through the use of insect repellants and othermosquito barriers."

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