REVIEW Dengue and Other Viral Hemorrhagic Fevers in India Shally Awasthi • U. C. Chaturvedi Received: 16 September 2011 / Accepted: 14 November 2011 / Published online: 18 January 2012 Ó The National Academy of Sciences, India 2012 Abstract The important viral hemorrhagic fevers (VHF) in India spread by an arthropod vectors are Dengue fever/ Dengue haemorrhagic fever and Kyasanur forest disease. Another VHF is caused by Hanta virus infection and for this there is no known vector. The diagnosis of VHF is based on typical clinical presentation and thereafter confirmed by detection of either virus or viral RNA or by demonstration of a rise of antibody titres against it. Treatment is by and large symptomatic as there are no specific drugs available against the viruses. Dengue fever has acquired epidemic magnitude in certain parts of India and has about 10% mortality. Research is going on for the development of effective vac- cines against Dengue fever. The principles of primary pre- vention of vector borne diseases is through vector control measures, elimination of breeding sites in and around human dwellings and personal protection against vector bite. Keywords Hemorrhagic fevers Dengue Kyasanur forest disease Virion Hantaviruses Introduction Viral hemorrhagic fevers (VHF) are a distinct group of acute viral infections which result in severe multisystem syndrome due to wide spread damage to the vascular system. This results in varying degree of hemorrhage, including con- junctivitis, petechia, ecchymosis and shock, sometimes leading to death. Hemorrhagic fever viruses belong to four taxonomic families (Table 1), all being single-stranded RNA viruses and possess a lipid envelope [1]. Flaviviridae Dengue virus, Yellow fever virus, Omsk hemorrhagic fever virus, Kyasanur forest disease virus. Epidemiology/Geographic Distribution Flaviviridae include Alkhurma HF virus, Kyasanur forest disease, and Omsk HF. Alkhurma HF virus is a variant of Kyasanur forest disease virus found in Saudi Arabia and reported in a small number of patients since 1990s [2]. Yellow fever virus is found throughout sub-Saharan Africa and tropical South America but its activity is intermittent and localized [3]. The annual incidence is believed to be about 200,000 cases per year globally. Case fatality rate ranges greatly depending on the epidemic but may reach up to 50% in severe yellow fever cases. Dengue virus is found throughout the tropical Americas, Africa, Australia, and Asia. Case fatality rate for DHF is generally low 1–10% depending on available treatment [4]. Kyasanur forest virus is confined to Mysore state of India but spreading. Case fatality rate is 3–5%. Omsk Hemorrhagic fever virus is still isolated to the Omsk and Novosibirsk regions of the former Soviet Union. Case fatality is 0.5–3%. The South American HF has a case-infection ratio of more than 50% of those exposed. The mortality rate is 15–30% (Table 1) 1 [3, 4]. S. Awasthi (&) Department of Pediatrics, CSM Medical University, Lucknow, India e-mail: [email protected]U. C. Chaturvedi 201-Annapurna Apartments, No. 1, Bishop Rocky Street, Faizabad Road, Lucknow 226 007, India e-mail: [email protected]1 http://en.wikipedia.org/wiki/Flaviviridae. 123 Proc. Natl. Acad. Sci. Sect B. Biol. Sci. (January–March 2012) 82(1):69–80 DOI 10.1007/s40011-011-0006-9
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REVIEW
Dengue and Other Viral Hemorrhagic Fevers in India
Shally Awasthi • U. C. Chaturvedi
Received: 16 September 2011 / Accepted: 14 November 2011 / Published online: 18 January 2012
� The National Academy of Sciences, India 2012
Abstract The important viral hemorrhagic fevers (VHF)
in India spread by an arthropod vectors are Dengue fever/
Dengue haemorrhagic fever and Kyasanur forest disease.
Another VHF is caused by Hanta virus infection and for this
there is no known vector. The diagnosis of VHF is based on
typical clinical presentation and thereafter confirmed by
detection of either virus or viral RNA or by demonstration of
a rise of antibody titres against it. Treatment is by and large
symptomatic as there are no specific drugs available against
the viruses. Dengue fever has acquired epidemic magnitude
in certain parts of India and has about 10% mortality.
Research is going on for the development of effective vac-
cines against Dengue fever. The principles of primary pre-
vention of vector borne diseases is through vector control
measures, elimination of breeding sites in and around human
dwellings and personal protection against vector bite.
influence the clinical outcome of infection [22], though most
studies have been unable to adequately address this issue.
Laboratory evidence requires one of the following:
• Isolation of DEN from clinical material
• Detection of dengue viral RNA in clinical material
• Detection of antibodies against dengue NS1 protein
• Detection of DEN specific IgM in the serum
• A significant rise in the level of DEN specific IgG
Preventive Measures
Vaccines
The first dengue vaccine was prepared in 1945 and still no
effective vaccine is available that indicates problems in its
development. An effective dengue vaccine is a distinct
possibility because the virus causes an acute infection and
the viraemia is removed within 5 days; immunity to infec-
tion with homologous DV serotype is long lasting; and
passive transfer of virus specific antibodies are protective
against subsequent challenge with that specific viral subtype
in animal models. The major obstacles in the development of
an effective dengue vaccine are incomplete understanding
of the pathogenesis of DHF; absence of an animal model of
DHF; and pre-existing heterotypic dengue antibodies, which
are a risk factor for DHF. An effective vaccine will have to be
Table 2 Reservoirs/vectors/modes of transmission reservoirs and modes of transmission for selected hemorrhagic fever viruses found in India
Agent Reservoir Arthropod vector Modes of transmission
Dengue Humans Aedes aegypti Bite of infected mosquito
KFD virus Rodents, bats, and other small mammals;
monkeys (e. g., black-faced langur,
South Indian bonnet macaque) appear
to be amplifying hosts
Ixodid Ticks (Haemaphysalisspinigera)
Bite of infected tick
Airborne through virus-containing
aerosols in laboratory setting
Hanta virus Murid Rodents with horizontal rodent
to rodent transmission
Absent Airborne transmission from
aerosol generated from
contaminated urine, feces and
saliva of infected rodent.
Proc. Natl. Acad. Sci. Sect B. Biol. Sci. (January–March 2012) 82(1):69–80 73
123
Table 3 Differential diagnosis for viral hemorrhagic fever
Condition Agent(s) Distinguishing features
Bacterial and Rickettsial infections
Septicemia caused by
gram-negative
bacteria
Various Underlying illness is usually present
Staphylococcal or
streptococcal toxic
shock syndrome
Staphylococcus aureus Streptococcal TSS may be associated with necrotizing fasciitis.
Streptococcus pyogenes Staphylococcal TSS is often associated with characteristic epidemiologic
features (e.g., tampon use in menstruating women, antecedent trauma).
Meningococcemia Neisseria meningitidis Rapid progression to shock and often death may occur.
Secondary syphilis Treponema pallidum Maculopapular rash that begins on the trunk (palms and soles often
involved) is characteristic.
Constitutional symptoms often occur but are not as severe as would be
expected with VHF.
Septicemic plague Yersinia pestis Often occurs secondary to bubonic plague (characteristic bubo present in
groin, axilla, or cervical region).
Typhoid fever Salmonella typhi Symptoms of enterocolitis and abdominal pain may be more prominent
with typhoid fever than with VHF.
Hemorrhagic manifestations are generally less common than with VHF.
Rocky mountain
spotted fever
Rickettsia rickettsii A history of tick exposure may be obtained.
The disease occurs in April through May.
Most US cases occur in southeastern and south-central states.
Ehrlichiosis Ehrlichia chaffeensis A history of tick exposure history may be obtained.
Erhlichia phagocytophilia Petechial rash is uncommon.
Peripheral blood smear may show morulae in neutrophils of patients with
human granulocytic ehrlichiosis.
Leptospirosis Leptospira interrogans This is most often self-limited but may be severe in about 10% of
patients.
The disease is often associated with aseptic meningitis (characteristic of
the immune phase of illness).
Viral infections
Influenza Influenza virus Respiratory symptoms are prominent.
It is not associated with bleeding diathesis or rash.
It is usually seasonal (October to March in United States) or associated
with a history of recent cruise ship travel or travel to tropics.
Measles Rubeola virus Presenting features usually include cough, coryza, conjunctivitis.
Hemorrhagic features are rare.
Rubella Rubella virus Occurs in persons without history of rubella vaccination (such as migrant
workers).
Hemorrhagic features are extremely rare.
Hemorrhagic varicella Varicella-zoster virus Usually occurs in immunocompromised children.
Viral hepatitis Usually hepatitis A, B, C viruses
(hepatitis E and G virus and
other viruses also may cause)
Hepatic findings predominate.
Hemorrhagic manifestations are associated with fulminant hepatic failure.
It is most likely to mimic yellow fever or Rift Valley fever (both
characterized by icteric disease).
Parasitic infections
Malaria Plasmodium species Fever is cyclic (every 48 h for P vivax or P ovale; every 72 h for Pmalariae) or continuous with intermittent spikes (most common pattern
for P falciparum).
Hemolysis commonly occurs; hemorrhagic manifestations are less
common.
Parasites may be seen on microscopic examination of thick or thin
smears.
74 Proc. Natl. Acad. Sci. Sect B. Biol. Sci. (January–March 2012) 82(1):69–80
123
tetravalent and should induce immunity to all four DV ser-
otypes simultaneously. Selection of the most promising DV
vaccine candidates rely mostly on comparing vaccine-
induced immune responses to a profile of protective immu-
nity developed from natural DV infections [23].
The dengue vaccine research focuses on the use of live
attenuated or inactivated vaccines, infectious clone-derived
vaccines, immunogens vectored by various recombinant
systems, subunit immunogens, and nucleic acid vaccines.
Serial passages of dengue viruses in PDK cells were used to
develop live attenuated vaccine. Initially, monovalent
vaccines were prepared using each of the DEN serotypes
followed by di-, tri- and tetra-valent vaccines that were
immunogenic and well tolerated by human subjects. A
chimeric YF-dengue type 2 virus vaccine was prepared,
using a recombinant cDNA infectious clone of a Yellow
fever vaccine strain (YF17D) as a backbone, into which the
PrM and envelope E genes of DEN were inserted. This
vaccine induced neutralizing antibodies in monkeys and
protected them against challenge with a wild type of DEN.
The safety as well as protective efficacy of the recombinant
DV tetravalent vaccine has been demonstrated in a monkey
challenge model. A candidate DNA vaccine expressing DEN
PrM and E proteins was developed and used for the immu-
nization of monkeys. This vaccine induces virus-neutraliz-
ing antibodies and gave partial protection against challenge
with homologous DEN. DEN grown in Vero cells was used
for the immunization of laboratory animals after inactiva-
tion, purification and concentration. The vaccine induces the
production of protective level of antibodies in monkeys.
Recombinant DNA techniques have provided the possibility
of cloning specific genes encoding protective antigens and
expressing them in other host cells, including E. coli, yeast
and insect cell systems [24].16
The question of whether any of the candidate dengue
fever vaccines will be ready by 2012 still is an open
question, although it is the declared objective of both GSK
and Sanofi Pasteur, both of which have presented timelines
compatible with licensure by 2012.17
Public Health Measures
Dengue infection can be prevented by:
• Mosquito control measures
• Personal protection measures such as long sleeves and
mosquito repellents
• Avoidance of mosquito-prone areas.
Control of Case
Isolate the patient and prevent mosquito access until fever
subsides.
Investigate the source of infection.
Control of environment
• Search for and eliminate breeding sites of Aedes ae-
gypti in the urban area.
Table 3 continued
Condition Agent(s) Distinguishing features
Acute conditions that may be associated with a bleeding diathesis
Hemolytic uremic
syndrome
Usually occurs as complication of
infection with Escherichia coliO157:H7 or other Shiga toxin-
producing E. coli
Disease involves a triad of renal involvement, thrombocytopenia, and
hemolytic anemia.
It is more common in young children.
Antecedent diarrheal illness occurs.
Hemorrhagic manifestations are uncommon, although bloody diarrhea
often occurs
Thrombotic
thrombocytopenic
purpura
May occur as complication of
infection with E. coli O157:H7
or other Shiga toxin–producing
E. coli, although may be
noninfectious
Disease includes renal involvement, thrombocytopenia, hemolytic
anemia, neurologic involvement
Hemorrhagic manifestations are uncommon
Idiopathic
thrombocytopenic
purpura
Noninfectious Low platelet count is predominant feature
Disease is generally not accompanied by severe systemic toxicity
Acute leukemia Noninfectious Peripheral blood smear shows characteristic features of leukemia.
Collagen vascular
disease
Noninfectious Acute onset of febrile illness not likely