”Dengue fever in Kolkata, West Bengal India with atypical presentations and its prevention

 Author

  Professor DR. Pranab Kumar Bhattacharya, MD(Calcutta University) FIc Path( India)  WBMES

 Professor and Head Department of Pathology [in charge, of DCP course of WBUHS & DLT course, Member of BOS for Pathology  & Member Secretary( For DCP) of BOS West Bengal university of Health sciences(WBUHS)  DD36 Salt lake Kolkata ]

 Dept. of Pathology, 2nd floor; Room No 10 C

  Calcutta School of Tropical Medicine

 C.R. Avenue, Kolkata-700073; West Bengal; India

 Department of Health and Family Welfare, Govt. of West Bengal (MES Wings)

  E mail  profpkb@yahoo.co.in

The disease burden of Dengue is not exactly known worldwide. But it can be said that at risk population worldwide is between 2.5 billion to increased 3.6 billion in more than 125 countries of which infection occur in 270-400millions people every year and dengue haemorrhagic fever is seen in 2 millions and yearly death from dengue is around 21,000-25,000[^3]  of which Brazil in 21st century began to occupy the first position in word ranking of Dengue fever(DF) reported cases ranging from 63.2 in 2004 to 429.9(2010) per 10,000 inhabitant^[4]

 Dengue is an acute Dengue fever in Kolkata,  febrile viral diseases of short duration, but now a days it is considered reappearing  and is distributed on continental proportion due to travelling in last 25 years. The etiological agent belongs  an arbovirus    Flave viridae family. Flavivurs gender divided into four serotypes DENV-1, DENV-2, DENv-3, DENV-4. Man is the only infection host but there are wide cycles that keep the viral circulation. There is a wide circulation recently in Kolkata West Bengal in year 2012 basically DNEV type-1, DENV type-3, DENV type 4 triggering 2012 dengue epidemic.

  First reported epidemic of Dengue Fever(DF)  occurred in1635 in West Indies and then in 1779-1780 ie around 375  years back. Confirmed epidemic simultaneously  occurred in Asia, North America &  Africa .Since then, it occurred sporadically. Major changes in epidemiology of Dengue occurred after world war II and is continued till day. The first epidemic of DHF and Dengue shock syndrome( DSS) was described in Manila, thereafter in India. DNEV was first Isolated in 1946 in kolkata. In Kolkata, West Bengal, India, DF was first documented in 1824, and several  epidemic took  place in city of Kolkata in years 1836,1906,1911, 1972,1990, 2000,2009, 2010,2012 and probably threatening in 2013.Dengue epidemic In India are cyclical mostly found in month of sept- October  and more frequent expanding geographically into rural areas now.    Dengue hemorrhagic  fever(DHF) occurred  Kolkata first in year 1963-64. The epidemic in Kolkata, West Bengal  in 2003,2004,2005 & 2006 showed predominance of DNEV-3, in 2007 it was DNEV-2, in 2008 DNEV-2 and DNEV3, in2010 it was mainly due to DNEV-2 few cases by DNEV-3 while causes of DHF was infected by multiple serotypes. The epidemic in 2012 was caused by DNEV-3 and DNEV-1 and few by DNEV-4. In 2006 there was an out break in Delhi  and Rajasthan  region of India  in month of September- October  and caused many death. In recent years Dengue has become major international Public health concern due to  billons people travel through out world by air or sea. The Mosquito born infection mostly found in tropical and sub tropical areas around the world and is leading cause of hospitalization and death in rural west Bengal too. In 1980s DF was found in china, Indonesia, Malyesia and thiland. Epedemic occurred  in Bangladesh2005.

 Social and economic issues facilitate disease dissemination. Dengue has high relationship with environmental sanitation conditions, defect in continuous water flow supply, inappropriate  solid and  waste garbage and lack of clean water storage in residences encouraging mosquito breeding. So areas of low socioeconomic conditions in cities, towns of West Bengal are most susceptible for emergence of epidemic.

 Dengue may appear as a febrile acute illness and most DF are self limiting disease and present as ample clinical spectrum from oligo symptomatic form to clinical cases of DF to severe Dengue like DHFwith bleeding and DSS , and multi organ failure. When symptomatic, the illness can range from mild to a severe form  and eventually death may occur which in most cases preceded by shock(DSS). The main mechanism  of shock  and severe Dengue  include  severe plasma leakage,  severe bleeding due to either quantitave and qualitative defect in platelet, increased PT, APT, APTT, increased micro vascular permeability , several organs involvement  like heart, Liver,CNS, . Any of  serotype DENV1 to DENV-4 can cause any form of the disease and pathogenesis depend on  pre-existing antibody, previous infection, (immune enhancement), normal antibody in infants, infecting virus strain , virulence of the virus, host genetic  status, and age of patients.  The  clinical requirements for diagnosis of  classical DF are[ fever,headache,  myalgia, prostration severe retro orbital pain and skin rashes]determined by WHO in 2005 and following laboratory criteria these individuals with positive serology for enzyme method EELISA capture of IgM capture . The resource poor health system of West Bengal, India should depend upon simple to perform,to interpret laboratory tests. It is known that early and specific diagnosis of DHF or DSS followed by supportive therapies can reduce many mortalities. In that case Ns1 antigen immuno chrmatographic  test can help in rural setup.

 Atypical presentation of Dengue found in Kolkata West Bengal in 2012 epidemic included serosities(50%) encephalitis(10%) myocardities(20%) hepatitis(60%) and cholecysties. hepatitis. DF patients in that year often showed aprrox 80% patients above normal raised AST,ALT  ranging  between 22- 800 with an average value 170+_ 192 Iu and ALT value  160+_ 150 iu  with median value 92.00iu and 101iu respectively and PT  and APTT value raised in three patients of alteration of liver function and these patients are mostly of DHF grade II usally happened by 5^th-10^th day after onset of dengue. Both protein liver enzymes, GGT,  APTT ,PT are scarcely reported related to dengue virus.  One important thing is that though serum transaminases raises and persisted even after 2 months serum bilirubin level did not raise or altered much.

Liver is  one of target organ of dengue virus and can be suspected when there is hepatomegaly increased serum gamma globulin, PT,APTT raised in serum after infection and there is negetive HBV and HepC infection by serology. Macrophage migration inhibitory factor(MIF) cytokine,TNF alpha are probable factor that cause hepatic inflammation in dengue. Active cells of immune system are also target for dengue virus infection such as dendrytic cells, NK cells, T cells & B lymho cyte.

The other atypical presentation in 2011 & 2012 DF was neurological symptoms. neurological Symptoms had been recognized for more then a century, which involves  drowsiness, irritability, Short term memory loss, agitation, depression, mono neural palsies seizure, and even death .Related  to neuron trophic effect of the virus are encephalitis, meningitis,  myosities, rhabdomyolisis, and mylities. Related to systemic complication of dengue infection are encephalopathy, Stroke( Both haemmoragic and Ischemic) hypokalemia, Paralysis, and Papilloedma,  Post infection are acute disseminated encephalomyelitis, Miller Fisher syndrome, Phrenic nueropathy, long thoracic nueropathy, occulomotor palsy, Macculopathy and complete hemiplegia due to thalamic involvement^[2]. Recent observation in West Bengal indicate that clinical presentation profile of D F  is changing and neurological complication are being reported more frequently. The exact pathogenesis of neurological complications is not yet understood but probably is due to cerebral edema, hemorrhage, heamo concentration, due to increase in vascular permiability & cougolopathy. One such case was reported from Murshidabad district of West Bengal^[2],of a female aged 10 years with stroke( glasgo coma scale was -5/15) with left sided hemiplegia and her serum IgM ELISA antibody test was postive for DNEV-3. Another 60 years male in 2011 epedemic was diagnosed to be Guillain Barre Syndrome in DNEV-3 infection and his nerve  injury in Dengue may be mediated by Immunological mechanism.

 Though most cases of Dengue fever in Kolkata seen biphasic in Spring and in summer  time(April & May), but maximum number of cases detected in 2012 epidemic in August to September. All age groups were infected but 15-40 years mostly affected with  for unknown reasons female preponderance. 70% cases of DF showed in 2012 complications particularly related to throbocytopenia induced bleeding manifestations( Platelet count< 1.5 lacks and ranged between 60,000- 1.4 lacks/mm and bleeding manifestations included Petechie, purpuria, Tourniquet test positive, hemorrhagic  gastritis, haemoptosis, maleana, epistaxis, hematuria depending on platelet count. About 10-15% patients  developed pancriatitis, Few patients developed rhabdomyolysis,   58% patients had serosities, 20% had myocardities  20% had hepatitis& a calculus cholecysities, 5% patients had CNS abnormalities. In 2012 Death toll reported in West Bengal  was more than 15 cases.

The countries those have achieved a decreased mortality by dengue it had been possible on account of awareness, prevention, development of training programme for early diagnosis of severe dengue by Rapid NS1 test and curing DHF and these countries are probably Cuba, El Salvador, Thailand. For the disease prevention  we however need better understanding of pathogenesis, pathology of this infection. The highest number of hospitalization for suspected cases of Dengue is usually seen in Spring and summer time in kolkata . This is the time which can be attributed to ambient temperature and humidity present in preceding months. Whenever there is an out break the municipal corporation attempt to kill mosquitos( Dengue is transmitted by mosquito bites  ades aegypti  with urban habits and its principal vector is Ades Aegipty and ades Albopictus in West Bengal) by spraying DDT(now resistant),Larvicide sparying  smoke, fumigation on streets, cannels which is worth less procedure as Ades lives and lays eggs within the room where these DDT or smoke or fumigation does not rich at home and there is also no vigillance from health or municipal departments. What is required is community participation and by genetic control releasing genetically sterile male mosquitoes or candidate vaccine. After decades of research by different groups around the world Dengue vaccine development reached a major mile stone in 2010 with initiation of first phase III  clinical trial to investigate a candidate vaccine. This vaccine is Sanofi Pastuer CYD Tetravalent dengue vaccine(TDV) which is now being evaluated for protective efficacy in large scale trial in Latin America and South East Asia as part of extensive clinical development purpose. The CYDTDV candidate comprises four recombinant live, attenuated vaccine based on a yellow fever vaccine 17D(YF17D) back bone, each expressing the pre-membrane and envelop genes of one of the four serotypes. This Vaccine is genetically and phenotypically stable non heppatotrophic, less neuron virulent than yellow fever YF 17D and does not infect mosquito when given by oral route[^5]. The Global clinical development programme included 45,000 participants from 15 countries. More than 23,000 individuals aged 2-45 years received at least one dose of CYD Dengue Vaccine. Vaccine safety is being monitored by independent data monitoring committee(IDMC) and so far no safety signals have been identified. A pooled analysis of safety data available till June 2011 from 5 phase-I studies(USA, Mexico, Philippines) and eight Phase-II studies  also revealed no safety concerns reports of solicited. Reaches and unsolicited adverse events were similar to those of control vaccine and trend to decrease in frequency after 2nd  and 3rd doses vaccination^[5]. The most adverse affect  are mild to moderate injection site pain, erythema, edema, severe headache, fever, malaise,  asthenia and myelgia(14-40%) after each vaccination. All three doses of TDF given 6 months apart. Consistant and balanced antibody responses to all four serotypes are observed. Until now with more than 11,000 people immunized. There were no Dengue like syndrome associated with CYD dengue vaccine. No death reported also. However four serious adverse affects occurred( fatal traffic accident, partial seizure, hepatitis A infection and  severe Upper Respiratory Tract Infection)

 Refrences

1)Gaxiola-Robels R etal" Mortality trend by Dengue in Mexico 1980- to 2009" Rev.Invest.Clini. 2012:64(5);444-451

2)Ashim Kr Mallick, Raohistyan Purkait,Tapan Kr.Singhamahapatra" Dengue fever with unusal Thalamic involvement" JIMA 2012; Vol 110; No1;48-49

3) Dengue guide lines for diagnosis, treatment,prevention and control(internet) Geneva WHO 2009 available from http://whqlibdoc.who.int./publication/2009/9789241547871-eng-pdf

4] Maria Gloria  TEXEIRA Few charecteristics of Dengue's fever epidemiology in Brazil" Rev.Inst.Med.Trop. Saopaulo 54(suppl:18) S1-S4 October 2012

5] Jean Lang " development of SANOF1 Pasteur Teravalent Dengue Vaccine" Rev.Inst.Med.Trop. Saopaulo 54(suppl:18) S15-S17 October 2012

6] Jean Lang, Lucia F Bricks Glovanini, Coel HO " Q&A Sesion o6 Oct 2011 1st international  Symposium on Dengue FMUSP- Sao Paulo" Rev.Inst.Med.Trop. Saopaulo 54(suppl:18) S28-S30 October 2012

 
Acknowledgement- The author gratefully Acknowledge the following persons for their valuable contribution to this article in one or other ways and agreed to mention their names in the acknowledgement section instead of authors

Miss Upasana Bhattacharya daughter of Prof PranabKumar Bhattacharya & student; Mr Rupak Bhattacharya Bsc(cal) Msc(JU); MrRitwik Bhattacharya B.com(cal) Miss Rupsa Bhattacharya-student; Mrs Dalia Mukherjee BA(hons) calcutta University; Mr Debasis  Mukherjee Bsc(calcutta University); Miss Oaindrila Mukherjee BA(Hons) Eng _student Calcutta Univ; Miss Ayshi Mukherjee of residence 7/51 Purbapalli; PO- Sodepur; Dist 24 Parganas(north) Kolkata-110; West Bengal; India; Dr. Soma Das MBBS,DCH(calcutta University) Dr. Anuradha De MD(AIIMS) New Delhi; Dr. Sumana Mukherjee MD(West Bengal University of Health Sciences)

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