CHAPTER Viral Hemorrhagic

11 Debasis Chakrabarti

INTRODUCTION • Human cases or outbreaks of hemorrhagic Viral hemorrhagic fevers (VHFs) refer to a group of caused by these occur sporadically and illnesses that are caused by several distinct families of irregularly. The occurrence of outbreaks cannot be viruses. In general, the term “viral hemorrhagic fever” is easily predicted. used to describe a severe multisystem syndrome (multiple With a few noteworthy exceptions, there is no cure or organ systems in the body are affected). Characteristically, established drug treatment for VHFs. the overall vascular system is damaged, and the body’s ability to regulate itself is impaired. These symptoms are General characteristics of these viral families can be found often accompanied by hemorrhage (). While some in this table below. types of hemorrhagic fever viruses can cause relatively TRANSMISSIONS mild illnesses, many of these viruses cause severe, life- Viruses causing hemorrhagic fever are initially threatening . transmitted to humans when the activities of infected ETIOLOGY reservoir hosts or vectors and humans overlap. Some A wide range of viruses can cause viral hemorrhagic fever viruses that cause hemorrhagic fever can spread from (VHF) and hence are designated as hemorrhagic fever one person to another, once an initial person has become viruses. infected. , , Lassa and Crimean-Congo hemorrhagic fever viruses are examples. This type of • The family Arenaviridae include the viruses secondary transmission of the can occur directly, responsible for and Argentine, Bolivian, through close contact with infected people or their body Brazilian and Venezuelan hemorrhagic fevers. fluids. It can also occur indirectly, through contact with • The family Bunyaviridae include the members objects contaminated with infected body fluids. For of the Hantavirus genus that cause hemorrhagic example, contaminated syringes and needles have played fever with renal syndrome (HFRS), the Crimean- an important role in spreading in outbreaks of Congo hemorrhagic fever (CCHF) virus from the Ebola hemorrhagic fever and Lassa fever. Nairovirus genus, and the (RVF) PATHOPHYSIOLOGY virus from the genus. The primary defect in patients with viral hemorrhagic • The family includes Ebola virus and fever (VHF) is that of increased vascular permeability . Finally, the family due to multiple activations. Hemorrhagic includes dengue, , and two viruses in fever viruses have an affinity for the vascular system, the tick-borne encephalitis group that cause VHF: leading initially to signs such as flushing, conjunctival virus and Kyasanur injection, and petechial hemorrhages, usually associated Forest virus. with fever and . Later, frank mucous membrane hemorrhage may occur, with accompanying , COMMON CHARACTERISTICS shock, and circulatory collapse. • They are all RNA viruses, and all are covered, or enveloped, in a fatty (lipid) coating. Inadequate or delayed immune response to these novel viral may lead to one hand rapid development • Their survival is dependent on an animal or insect of overwhelming viremia and other hand pronounced host, called the natural reservoir. activation with extensive damage of affected • The viruses are geographically restricted to the organs. Hemorrhagic complications are multifactorial and areas where their host species live. are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes. • Humans are not the natural reservoir for any of these viruses. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF, and • Humans are infected when they come into contact yellow fever. Renal failure with oliguria is a prominent with infected hosts. However, with some viruses, feature of HFRS seen in Hantavirus infection and may after the accidental transmission from the host, be seen in other VHFs as intravascular volume depletion humans can transmit the virus to one another. becomes more pronounced. Bleeding complications are 46 Table 1: Viruses causing Hemorrhagic Fever Virus Diseases Incubation Case Case Natural Usual Target Population Period Infection Fertility Distribution Source of (Days) ratio Rate Human Infection Arenaviridae: Lassa Fever 5-16 Commonly 15% West Africa Rodent All ages Both Arena virus mild sexes infection Argentine 7-14 >1/2 15-30% South Rodent All ages Both sex HF America result in Disease Bolivian HF 9-15 >1/2 15-30% South Rodent Countryside:Men. infections America Village: All age INFECTION result in both sexes Disease Venezuelans 7-14 >1/2 15-30% South Rodent All ages both HF infections America sexes result in Disease Bunia viridae Rift valley 2-5 1:100 50% Sub-Saharan Mosquito All age both i. Phlebo Fever Africa, sex, Men virus Madagaskar, more exposed, Egypt Liver disease Predisposed ii. Nairo Crimean- 3-22 ≥1:5 15-30% Europe, Asia, Tick All age both virus Congo HF Africa sex, Men more exposed iii. Hanta HF with 9-35 Hantan Hantan Worldwide Rodent Adult male more virus renal > 1:1.25 5-15% depending prone syndrome Puumala Puumala on rodent 1:20 <1% reservoir Hanta virus 7-28 Very high 40-50% Americas Rodent Adult male more Pulmonary prone syndrome Filoviridae Marburg 3-16 High 25-90% Sub Saharan Unknown All ages both sex, Filovirus and Ebola Africa Child less exposed virus

Flavivirus Yellow fever 3-6 1:2 – 1:20 20% Africa, South Mosquito All ages both America sexes adult more exposed, preexisting flaviirus immunity may cross protect New New Arena Luzo virus 2 weeks Very high Highly Lusaka Rodent, All ages both virus (Discovered fatal (Zambia), Bat sexes in 2008) Johannesburg (South Africa) New Flavi Alkhumra Few weeks Very high 25% Saudi Arabia Sheep, Al ages both sexes virus hemorrhagic Goat, fever Rodent. Mosquito CHAPTER 11 47 Avoid intramuscular injections and the use of use the and injections intramuscular Avoid anticoagulants. or other aspirin of the risk procedures because invasive Minimize sharp from with viral transmission associated objects Prevent nonessential entering the room staff and visitors and gloves wear should room the entering staff All from gowns Persons coming within 3 feet of the patient should shields or surgical masks with eye face wear filter HEPA use shields); side (including protection prominent respiratory, GI, if patients have masks or hemorrhagic symptoms. If large amounts of blood are present in the environment, leg use and shoe or other body fluids coverings. protective used all discard room, the exiting Before with a hospital shoes clean barriers and or solution of household bleach. If possible, use an anteroom for barriers and for storing removing protective putting on and supplies. Because many of the hosts that carry hemorrhagic fever viruses are rodents, disease prevention effort include: Controlling of rodent populations PREVENSION • • include the following: control measures Infection • • • • • • • No specific antiviral therapy serum convalescent Marburg virus infection. The use of available is for Ebola or infection) is survived (ie, sera from patients who have suggested as a possible therapy. Lassa fever and have been HFRS treated effectivelyrecommended with due been intravenoushas this, and oral of to Because ribavirin. Hantavirus infection viruses and bunya as a potential treatment for other arena viruses. Treatment is most effectivein when the given early clinical course. Ribavirin antiviral Other potential for post exposure prophylaxis. also is benzimidazole recommended novel include fever Lassa against therapies heterocyclic related other and ST-193 as such compounds compounds. Recently proposed guidelines for the use of ribavirin for the use of oral recommend post exposure prophylaxis ribavirin exclusively for definitive, high-risk exposures, such as contaminated needle stick injury, mucous membrane or no intact skin exposure with contaminated blood or suctioning), (eg, intubation, procedures resuscitative body fluids,or prolonged close contact in an enclosed space with participation infected patients without appropriate personal protective in emergency equipment. 1. a. Administer blood and blood products as clinically indicated. Bleeding patients of 30% about in (eg, manifestations patients of proportions occur and in hemorrhagic fever with Ebola or Marburg in fever). with Rift Valley only about 1% of patients variable rash may be noted early in the A maculopapular some forms of VHF (notably in clinical course in hemorrhagic fevers) Ebola and Marburg is a characteristic pharyngitis exudative Severe fever. early feature of Lassa meningoencephalitis in agents cause Several addition to VHF (eg, Rift Valley fever, Kyasanur viruses). fever Forest disease, Omsk hemorrhagic Jaundice may be a infections (eg, Ebola and Marburg hemorrhagic prominent feature in fever). yellow fever, Valley Rift Lassa fever, fevers, some TREATMENT INVESTIGATIONS COMMON CLINICAL FEATURES COMMON Fluid resuscitation and supportive care are the mainstays Fluid resuscitation and supportive of emergency department therapy. monitoring oxygen, and cardiac crystalloids, Intravenous in the treatment appropriate initial steps are the most (VHF) is of patients in whom viral hemorrhagic fever suggested. Other measures include the following: • There may be leucopenia, thrombocytopenia with elevated with elevated There may be leucopenia, thrombocytopenia time, activated hepatic enzymes, raised prothombin partial thromboplastin time and hepatopathy. product in patients with hemorrhages and fibrin degradation tests, serologic using made be can diagnosis viral Specific including enzyme-linked immunosorbent assay (ELISA) require may cases Difficult reaction. chain polymerase and tissue cultures. During the Ebola outbreak 2000-2001 in transcriptase-PCR (RT-PCR) emerged as Uganda, reverse patient in virus Ebola detecting for means effective very a serum, plasma, and whole blood. Report all (VHF) immediately to cases of viral hemorrhagic fever suspected local and state public health departments and to the CDC. Because of the initiate contact containment and handling of these viruses, need (CDC; for with the Centers for Disease Control and Prevention specialized as soon as possible and prior to transport of GA) microbiologic Atlanta, specimens for virus-specific diagnosis. Specific state and the shipment of highly infectious federal statutes govern disease agents. • • • • Although clinical features vary somewhat for the various for the various somewhat vary clinical features Although presentations clinical the viruses, fever hemorrhagic febrile agents cause a All of the substantially. overlap prostration; of degrees with varying associated prodrome include the following. other notable features • particularly prominent with Ebola, Marburg, CCHF, and and CCHF, Marburg, with Ebola, prominent particularly viruses. arena American the South 48 b. Discouraging rodents from entering and living in Transmission homes or workplaces. Most Dengue epidemic occurs post monsoon, due to c. Encouraging safe cleanup of rodent nest and increase in vector population. However virus maintenance droppings. during inter epidemic period has been attributed to transoverian transmission of . Dengue virus 2. Vaccines: primarily transmitted to human through an infected is readily available and is mosquito bite. Humans are the main amplifying host of both safe and effective. A bivalent vaccine is being the virus. After a blood meal virus infect the mosquito and developed from the preexisting 17D yellow fever stays in its gut for 8-12 days of extrinsic incubation period. vaccine that would express not only yellow fever Virus again reenter the human body after subsequent glycoprotein’s but also Lassa glycoprotein’s, bite. Aedes aegypti is one of the most efficient vector for theoretically stimulating a protective immune because it is highly anthrophilic, frequently response against both viruses. bites several times before completing oogenesis, and thrives in close proximity to Humans. A recent study evaluating the safety and efficacy

INFECTION of a tetravalent dengue vaccine demonstrated full Pathogenesis seroconversion against all WHO dengue serotypes Replication of the dengue virus occurs within mononuclear in flavivirus-naive adults. cells including skin dendritic cells, tissue , peripheral blood monocytes, and hepatocytes. At present, Argentine HF (Junín) vaccine is also effective and the host cell receptors involved in the viral entry are may protect against Bolivian HF as well. mostly unknown. Primary or first infection in nonimmune Rift Valley fever and Hantan (HFRS) vaccines are persons usually causes DF. Subsequent dengue infection also available. by a different serotype causes more severe illness, such as DHF/DSS. The key manifestations of DHF/DSS are Although there is no approved vaccine for either sudden onset of shock, capillary leakage, and hemorrhagic Ebola or Marburg virus, significant progress has diathesis/thrombocytopenia occurring at the time of been made in developing an effective experimental defervescence. Pathogenesis is not well-defined, but it is vaccine using a vesicular stomatitis virus-based suggested that during secondary infection with a different vaccine. serotype, cross-reactive nonneutralizing antibodies bind Other efforts to create a viable (and marketable) to DENV and facilitate uptake via Fc receptors, resulting Ebola vaccine have led to the development of in enhanced viral replication. The resultant higher an experimental bivalent vaccine that confers viral load leads to an exaggerated activation protection against both and Ebola virus. of cross-reactive dengue specific T cells. Biological mediators released by the activated T cells as well as COMPLICATION virus-infected cells along with complement activation Complications from viral hemorrhagic fever (VHF) by viral proteins and immune complexes are implicated infection include retinitis, orchitis, encephalitis, hepatitis, in increasing vascular permeability and coagulopathy. transverse , and uveitis. This phenomenon is known as antibody-dependent In patients who recover from Lassa fever infection, enhancement. deafness is the most common complication. Clinical features Renal insufficiency is associated with HFRS infection. This model for classifying dengue has been suggested by an expert group (Geneva, Switzerland, 2008) and is DENGUE HEMORRHAGIC FEVER currently being tested in 18 countries by comparing its Introduction performance in practical settings to the existing WHO Dengue virus, belong to a family Flaviviridae and have case classification (Table 2). four serotypes (DEN 1, 2, 3, 4). They are transmitted mainly by Aedes aegypti and Aedes albopictus mosquito. Diagnosis Among the four serotype DEN 2 is more virulent and The nonspecific nature of the illness mandates laboratory most of DHF are due to infection of DEN 2. verification for diagnosis. Dengue is a mosquito borne , which has For confirmation of Dengue infection, Govt of India raised concern globally, due to alarming 30 fold increase recommends use of ELISA- based virus specific antigen in its incidence in last few decades. Almost 75% of global (NS1) for diagnosing the cases from the first day onwards population exposed to dengue live in Asia-Pacific region. and antibody detection test IgM capture ELISA (MAC- In India first major epidemic of DHF was observed in ELISA) for diagnosing the cases after the fifth day of 1996 involving Delhi, Lucknow, Kolkata and Chennai. In disease onset. 2015 India also faced a major outbreak affected worstly in Govt of India introduced ELISA- based NS1 antigen in Delhi and Punjab followed by West Bengal and Gujarat 2010 in addition to MAC- ELISA tests which can detect having total mortality of 90000 with 180 deaths. the case during ay 1 to day 5 of illness. CHAPTER 11 49 Clinico-laboratory 2004; 50:301–305. J Trop Pediatr Criteria For Severe Dengue Severe For Criteria Severe plasma leakage plasma Severe Shock with severe Fluid accumulation distress. respiratory by as evaluated bleeding Severe clinician. organ involvement. Severe CNS: Impaired consciousness Heart and other organs Revised recommendations for yellow fever Ebola hemorrhagic fever: fact sheet. Revised Dec spectrum of dengue infection and risk factors viral a retrospective with dengue hemorrhagic fever: associated online Sep 30) study. BMC Infect Dis 2015 (published Localization KT. Wong SK, Lam S, Devi MY, Fong K, Jessie by human tissues, of dengue virus in naturally infected in situ hybridization. J Infect and immunohistochemistry Dis 2004; 189:1411–1418.[PubMed] guidelines World Health Organization. Comprehensive and control of Dengue and Dengue for prevention Preface. World Health Organization Hemorrhagic fever. Asia.2011. Regional office for south East World Health Organization. Global strategy for Dengue WHO; 2012. and control 2012-2020. Geneva: prevention P N. Outbreak of Shah I, Deshpande G C and Tardeja for dengue markers Predictive and dengue in Mumbai shock syndrome; 2011. WHO. Epidemiol 2011.Wkly for international travelers, vaccination Rec 2011; 86:401-11. et al. AS, Adnan AH, Khan TH, Mallhi Ebola hemorrhagic fever. Lancet Ebola hemorrhagic fever. Feldmann H, Geisbert TW. 2011; 377:849-62 [Abstract] WHO. 9. 10. 11. 12. 7. 8. 5. 6. Viral Viral infections in Viral hemorrhagic hemorrhagic Viral Warning Signs Warning Warning Signs* Warning pain or tenderness Abdominal vomiting Persistent accumulation Clinical fluid Mucosal bleeding Lethargy, Restlessness 2cm enlargement > Liver in HCT with Laboratory: Increase count. rapid decrease in and (*requiring strict observation medical intervention) 1988; 37:1–16 (Sea buckthorn, SBT) leaf extract has been Known cases and outbreaks of Ebola hemorrhagic fevers: current status of endemic disease and strategies for fevers: Am 2006; 20:359-93 control. Infect Dis Clin North Centers for Disease Control (CDC). Management of Control (CDC). Management Centers for Disease MMWR fever. hemorrhagic viral patients with suspected Morb Mortal Wkly Rep. al. et RB, Porwancher AJ, Ricketti DJ, Cleri fever, in chronological order. 2011 Oct 12[Full text] fever, Banerjee K, Gupta NP, Goverdhan MK. laboratory personnel. Indian J Med Res 1979; 69:363-73 CDC. Liver: AST/ALT> 1000 AST/ALT> Liver: Any warning signs Any warning Leucopenia Tourniquet test positive Aches and pains Rash Nausea, vomiting Laboratory confirmed Dengue Laboratory confirmed no signs of plasma (important when leak) 7. 6. 5. 4. 3. 2. Probable Dengue Probable to Dengue endemic in or travel Live area. criteria : of the following and 2 Fever 1. Table 2: ExpertClassification Dengue for Group Table Dengue For Criteria REFERENCES 1. 4. 3. shown to have a significant anti-dengue activity. a significant anti-dengue shown to have 2. The management of dengue virus infection is essentially The management of dengue virus infection supportive and symptomatic. No specific have which studies Indian there are However, available. treatment is contributed in terms of better management of DHF/DSS. fresh frozen plasma A rapid response to platelet and Anti-D has (FFP) transfusion is reported in a study. refractory and severe been used in children with DHF study pre-feeding thrombocytopenia. In experimental (CrP) in drinking chromium picolinate mice with trivalent water could abolish the adverse effects of DV infection parameters. Hippophae of the hematological on most rhamnoides Treatment