Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine

Journal of Critical Care 42 (2017) 366–372

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Journal of Critical Care journal homepage: www.jccjournal.org

Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine☆ Jorge Hidalgo, MD a, Guy A. Richards, MD PhD b, Juan Ignacio Silesky Jiménez, MD c, Tim Baker, MB, ChB, PhD d,e, Pravin Amin, MD f,⁎ a

Division of Critical Care, Karl Heusner Memorial Hospital, Belize Healthcare Partners Belize, Central America Division of Critical Care, Charlotte Maxeke Hospital and Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa c Critical Care Unit, Hospital San Juan de Dios and Hospital CIMA, San José, Costa Rica d Department of Anaesthesia & Intensive Care, Queen Elizabeth Central Hospital, Blantyre, Malawi e Global Health – Health Systems & Policy, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden f Department of Critical Care Medicine, Bombay Hospital Institute of Medical Sciences, Mumbai, India b

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Keywords: Viral hemorrhagic fevers (VHF) Zika Dengue Hantavirus Yellow fever Lassa fever Rift Valley fever Crimean-Congo hemorrhagic fever Hantavirus Kyasanur Forest disease Marburgvirus and Ebolavirus

a b s t r a c t Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by four families of viruses namely Arenaviruses, Filoviruses, Bunyaviruses, and Flaviviruses. Humans are not the natural reservoir for any of these organisms and acquire the disease through vectors from animal reservoirs. In some conditions human to human transmission is possible increasing the risk to healthy individuals in the vicinity, more so to Health Care Workers (HCW). The pathogenesis of VHF, though poorly understood, varies according to the viruses involved. The resultant microvascular damage leads to increased vascular permeability, organ dysfunction and even death. The management is generally supportive but antiviral agents are of benefit in certain circumstances. © 2017 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . 1.1. Clinical presentation of viral hemorrhagic fevers . 1.2. Laboratory diagnosis . . . . . . . . . . . . . Yellow fever . . . . . . . . . . . . . . . . . . . . 2.1. Symptoms and signs . . . . . . . . . . . . . 2.2. Diagnosis . . . . . . . . . . . . . . . . . . 2.3. Treatment . . . . . . . . . . . . . . . . . . WEST NILE virus . . . . . . . . . . . . . . . . . . LASSA fever. . . . . . . . . . . . . . . . . . . . . 4.1. Epidemiology . . . . . . . . . . . . . . . . 4.2. Symptoms, signs, and prognosis . . . . . . . . 4.3. Diagnosis . . . . . . . . . . . . . . . . . . 4.4. Prophylaxis and treatment . . . . . . . . . . Hantavirus infections . . . . . . . . . . . . . . . . 5.1. Hemorrhagic fever with renal syndrome . . . . 5.1.1. Symptoms, signs, and diagnosis . . . . 5.2. Prognosis and treatment . . . . . . . . . . . 5.3. Hantavirus pulmonary syndrome . . . . . . . 5.3.1. Symptoms, signs, and diagnosis . . . .

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☆ On behalf of the Council of the World Federation of Societies of Intensive and Critical Care Medicine. ⁎ Corresponding author at: 12 New Marine Lines, C113, 1st floor, New Wing, Mumbai, Maharashtra 400020, India. E-mail address: [email protected] (P. Amin).

https://doi.org/10.1016/j.jcrc.2017.11.006 0883-9441/© 2017 Elsevier Inc. All rights reserved.

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5.4. Prognosis and treatment . . . . . . . . . Dengue . . . . . . . . . . . . . . . . . . . . Ebola and marburg . . . . . . . . . . . . . . . Rift valley fever. . . . . . . . . . . . . . . . . Crimean-Congo hemorrhagic fever . . . . . . . . The South American VHFs . . . . . . . . . . . Kyasanur forest disease . . . . . . . . . . . . 11.1. Management and prevention of VHF . . . 12. Conclusion . . . . . . . . . . . . . . . . . . Task force planning . . . . . . . . . . . . . . . . . Financial support . . . . . . . . . . . . . . . . . . Conflict of interest disclosures related to this manuscript References . . . . . . . . . . . . . . . . . . . . . 6. 7. 8. 9. 10. 11.

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1. Introduction The viral hemorrhagic fevers (VHF) are zoonoses that are transmitted from vertebrate animals to humans by bites of infected ticks or mosquitoes, or from infected bats and rodents. VHFs are caused by 4 families of RNA viruses, the Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae (Fig. 1). The Arenaviridae are generally associated with rodent-transmitted diseases in humans [Lassa Fever Virus (LASV) and South American HF (SAHFV) Viruses]. The Bunyaviridae are singlestranded, enveloped RNA viruses (of which there are N 300 viruses) the most important being Rift Valley fever virus (RVFV), Crimean-Congo virus (CCHF) and Hantavirus. RVF is transmitted by mosquitoes and is most commonly observed in domesticated animals (such as cattle, buffalo, sheep, goats, and camels), with the potential to infect and cause illness in humans. CCHF is caused by infection from Ixodid (hard) ticks, especially those of the genus Hyalomma, which are both reservoir and vector for the virus [1]. Hantavirus is transmitted by rodents, and has two potential clinical presentations; Hemorrhagic fever with renal syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS). The Filoviridae consist of Marburg virus (MARV) and Ebola virus (EBOV)

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which cause severe hemorrhagic fever in humans and primates and their natural reservoir is thought to be the fruit bat [2]. The Flaviviridae are single-stranded, enveloped RNA viruses. In this group, Yellow Fever Virus (YFV) and Dengue Fever virus (DFV) are transmitted by mosquitos whereas those transmitted by ticks include Kyasanur Forest disease virus (KFDV). Humans are dead-end hosts (ie, incidental to the natural cycle and ineffective in virus perpetuation) for most of the VHF, but are definitive hosts (ie, part of the natural cycle necessary for viral propagation) in urban yellow fever, phlebotomus fever, chikungunya, Zika and dengue. 1.1. Clinical presentation of viral hemorrhagic fevers The initial presentation of VHF is usually with generalized malaise and fever like other common tropical diseases such as malaria, leptospirosis, typhoid or influenza. Severe frontal headache and retro-orbital pain or severe musculoskeletal pain, conjunctival injection, vomiting, abdominal pain and diarrhoea are common clinical features. There may be petechiae and episodes of minor bleeding like epistaxis and bleeding gums. This may lead to VHF syndrome whereby the primary

Fig. 1. Agents of viral hemorrhagic fever. (permissions to be taken from (Eyal Meltzer Infect Dis Clin N Am 26 (2012) 479–49.

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pathology is endothelial dysfunction leading to capillary leak, thrombocytopenia and disseminated intravascular coagulopathy (DIC). The subsequent shock can lead to multiple organ dysfunction and even death. All VHF may cause severe disease, however those with the highest mortality overall are EBOV, MARV, LASV, CCHF and DENV. Prominent hepatic, renal or pulmonary involvement occurs with yellow fever, HFRS and HPS respectively.

and relative bradycardia then recur and the classic triad of jaundice, extreme albuminuria, and epigastric tenderness with hematemesis, appear. Oliguria or anuria, petechiae and mucosal hemorrhages are common. The patient becomes confused, apathetic and mentally obtunded. In malignant cases delirium, convulsions and coma occur terminally. Moderately severe cases may last 3 days to N1 week with a relatively short convalescence, except in the most severe cases. There are no known sequelae [16,18].

1.2. Laboratory diagnosis 2.2. Diagnosis Blood Urea Nitrogen and serum creatinine may be elevated due to fluid losses or HVRS. Leukopenia, thrombocytopenia, and elevations in creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels have been observed in patients with CCHFV and EBOV [3]. Serological markers using Enzyme-linked immunosorbent assay (ELISA) to detect virus-specific immunoglobulin IgM and IgG may be helpful in the diagnosis but lack the sensitivity and specificity of molecular diagnostic methods [4, 5]. In endemic areas, an elevated IgM may be of significance in an acute infection [6]. An exception is in Bunyaviruses infections as humans clear virus rapidly, hence the IgM assay may be diagnostic. They do however show cross reactivity with the Flaviviridae [7]. Viral culture was the gold standard but takes a considerable time and needs a highly-specialized reference laboratory [8]. As such the Reverse transcription -polymerase chain reaction (RT-PCR) and genome sequencing have become the predominant diagnostic tools [9]. Electron microscopy may be used to detect viruses based on underlying features from body fluids, including specific antibodies used to visualize these viruses. RT-PCR assays have been developed for most VHF-associated viruses [10-12]. Multiplex assays have also been developed that identify EBOV, MARV, LASV, CCHFV, RVFV, DENV, and YFV with sensitivity and specificity comparable to other RT-PCR assays [12]. Microarrays are a precise type of multiplex PCR that are highly specific and sensitive to detect VHF [13]. Loop-mediated isothermal amplification (LAMP) is a new tool for rapid diagnosis of RVFV, YFV, CCHFV, MARV, DENV, and EBOV, and whereas these tests are expensive they do facilitate rapid diagnosis and potentially reduce nosocomial transmission [14]. Immunohistochemical staining of skin biopsies has been used to confirm the diagnosis of EBOV however this is seldom used in the field [15]. 2. Yellow fever Yellow fever can present in two forms, an urban and a jungle presentation. In the urban form, the virus is transmitted by the bite of the Aedes aegypti mosquito whereas in the jungle (sylvatic) form the virus is transmitted by Haemagogus and other forest canopy mosquitoes that acquire the virus from wild primates [16-18]. 2.1. Symptoms and signs The disease is classified according to the clinical presentation: a) b) c) d)

Inapparent: b48 h of fever and headache. Mild Severe Malignant

As with all VHF an appropriate history must be obtained including areas visited, contact with animals, insect bites and known exposures. The most important laboratory finding is the presence of severe albuminuria that occurs in 90% of patients, usually on the third day, which in severe cases may be as much as 20 g/L. An initial leukopenia is common (1500 to 2500/μL) followed by a leukocytosis terminally. Hemorrhage is multifactorial, and is related to decreased synthesis of vitamin K-dependent coagulation factors secondary to hepatic dysfunction, DIC and a thrombopathia. Thrombocytopenia and prolonged clotting and prothrombin times are common but in less severe cases some of these laboratory findings may not occur. Serum bilirubin levels may be significantly elevated. The diagnosis is confirmed early in the illness (during the first 3– 4 days), however the viral RNA (by RT-PCR) is usually undetectable by the time overt symptoms occur. As such laboratory diagnosis is generally by detection of virus-specific IgM and neutralizing antibodies. It is important to obtain a yellow fever vaccination history as IgM antibodies to the vaccine can persist for several years. Because serologic cross reactivity occurs with other flaviviruses (e.g., West Nile or dengue viruses), confirmation with a more specific test such as a plaque-reduction neutralization test should be sought [19]. At autopsy the characteristic feature is midzonal liver cell necrosis. Needle biopsy of the liver during illness is contraindicated due to the risk of hemorrhage [16]. 2.3. Treatment Supportive treatment is directed toward alleviation of major symptoms. Complete bed rest and nursing care are important. Correction of fluid and electrolyte imbalance is imperative as well as the management of the hemorrhagic complication as required [16,18]. 3. WEST NILE virus This virus belongs to the flavivirus family and derived originally from Africa. The first case in the US was encountered in 1999 and has now emerged as an important public health problem. The primary vector is the mosquito (the culex species), which is seen most commonly during summer and early fall. Transmission through blood transfusion, organ transplantation, pregnancy, labor and lactation, and exposure in laboratory settings has been described. The majority of patients are asymptomatic, a small number (1–5%) develop fever and other nonspecific symptoms and 1 in 150 develop a serious, potentially fatal infection. There is no specific treatment available and as such management in symptomatic and severe cases is primarily supportive [18,20]. 4. LASSA fever

The Incubation period ranges from 3 to 6 days followed by the sudden onset of a fever of 39 to 40° C, tachycardia (and later a relative bradycardia, Faget's sign), facial flushing, conjunctival injection and a red tongue with central furring. Nausea, vomiting, constipation, headache, muscle pain, severe prostration, restlessness, and irritability are common. In mild cases, the illness ends at this stage after 1 to 3 days. In moderately severe and malignant cases, the fever falls suddenly 2 to 5 days after onset, and a remission of several hours or days ensues. The fever

LASV is a zoonosis most frequently encountered in West Africa, due to exposure to the urine of the multimammate rat (Mastomys natalensis) [20,21]. 4.1. Epidemiology The disease was first described in Lassa, Nigeria in 1969, but outbreaks have occurred in Liberia and Sierra Leone. Most human cases

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probably result from contamination of food with rodent urine, but human-to-human transmission can occur through contact with the urine, feces, saliva, vomitus, or blood of an infected patient. The outbreaks in Nigeria and Liberia have been primarily hospital-associated, with spread from an index case to hospital workers or other patients. About 2/3 of the cases have been women, a predilection that may relate to exposure rather than a difference in susceptibility [17,18,21].

4.2. Symptoms, signs, and prognosis The incubation period is 1 to 24 days with a gradual onset of severe symptoms thereafter. Most patients have symptoms such as sore throat, fever, chills, headache, myalgia, vomiting, and chest and epigastric pain for 4 to 5 days before hospitalization. The sore throat becomes more severe during the first week and patches of white or yellow exudate may appear on tonsils and coalesce into a pseudo-membrane. Early in the course a relative bradycardia is common. Generalized non-tender lymphadenopathy occurs in some patients. During the second week, severe lower abdominal pain and intractable vomiting are common. Facial and neck swelling and conjunctival edema are seen in 10 to 30% of patients. Occasionally, patients have epistaxis, bleeding from the gums and venepuncture sites, maculopapular rash, cough, dizziness and tinnitus. During the 2nd week, patients that recover defervesce, while fatally ill patients progress to shock, agitation, mental obtundation and occasionally grand mal seizures. Chest crackles and pleural effusions may also occur. The illness lasts from 7 to 31 days in those who survive and 7 to 26 in fatal cases [18,21]. Early in the disease 30% of patients will develop a leukopenia of b 4000/μL with a relative neutrophilia. Platelet counts and hematocrit remain normal. Urinalysis reveals proteinuria, which occasionally may be massive. Chest x-rays may show basilar pneumonitis and pleural effusions. AST and ALT levels rise as do CPK and LDH levels [18,21]. The severity of infection correlates with the degree of viremia, the elevation of AST and ALT and with fever. Mortality rates have varied between 16 and 45%; however, in pregnant females or those that had delivered within 1 month, the mortality is in the region of 50%. Among survivors, late sequelae include deafness in about 5% and occasionally alopecia, iridocyclitis, and transient blindness.

4.3. Diagnosis The diagnosis is made primarily by RT-PCR but can also be made by enzyme-linked immunosorbent assay (ELISA) or virus isolation by cell culture [22].

4.4. Prophylaxis and treatment Strict infection prevention and control is mandatory and techniques have been described elsewhere [19,23]. A negative pressure room with no air circulation, and positive pressure filtered air respirator are recommended, as is surveillance of contacts. Ribavirin may reduce mortality tenfold if treatment is begun within 6 days of onset [18,21].

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5.1. Hemorrhagic fever with renal syndrome 5.1.1. Symptoms, signs, and diagnosis The onset is sudden, with high fever peaking on the third to fourth day, headache, backache, and abdominal pain. On the third or fourth day, reddening of the face, conjunctival hemorrhages, palatine petechiae, and a truncal petechial rash may appear along with a relative bradycardia. Severe neurologic manifestations (seizures, neurogenic bladder) may occur in 1%. Oliguria and azotemia develop concomitant to the hemorrhagic manifestations. Urinalysis reveals proteinuria, hematuria, and pyuria. The rash subsides in about 3 days. On about the 5th day, shock or hypotension may occur; in mild cases the fall in BP is only transient but in more severe cases this may be pronounced. At this stage, the hematocrit increases, and marked proteinuria, leukocytosis, and thrombocytopenia develop, the patient develops polyuria and then recovery takes place over several weeks to months. 5.2. Prognosis and treatment The overall fatality in HFRS is 6 to 15% and most recover without sequelae [18]. Treatment is with IV ribavirin (loading dose 33 mg/kg, then 16 mg/kg q 6 h for 4 days; then 8 mg/kg q 8 h for 3 days). The only ribavirin- associated adverse effect appears to be the occurrence of reversible anemia. Supportive care, including renal replacement therapy if required is critical to survival [17,18]. 5.3. Hantavirus pulmonary syndrome 5.3.1. Symptoms, signs, and diagnosis HPS presents as a flu-like illness with acute onset of fever, myalgia, headache, and gastrointestinal symptoms. Two to 15 days later (median 4 days), acute non-cardiac pulmonary edema associated with hypotension develops. At this stage, laboratory findings include a neutrophilic leukocytosis with circulating immunoblasts, hemoconcentration and thrombocytopenia. Urinalysis shows minimal abnormality. Chest xrays may show early pulmonary edema with increased vascular markings or Kerley B lines; thereafter bilateral infiltrates develop rapidly and may be associated with pleural effusions. Modest elevation of LDH, AST, and ALT, with decreased serum albumin is usual. Elevated lactate levels are indicative of a poor prognosis. Several patients have had a combination of HFRS and HPS and mild cases of HPS have also been recognized [17,18]. 5.4. Prognosis and treatment The clinical course is striking. Patients who survive, improve rapidly after 5 to 7 days of mechanical ventilation, often being discharged without pulmonary residua after 2 to 3 weeks. Although mortality remains high at 50 to 70% it may be reduced by more aggressive therapy. Whereas initial treatment is supportive, with early admission to an ICU to maintain oxygenation, prevent fluid overload and to correct shock, in cases of refractory hypoxaemia, extra corporeal membrane oxygenation has been used successfully [24]. Intravenous ribavirin has been used, but its efficacy is uncertain [17,18]. 6. Dengue

5. Hantavirus infections Hantavirus is a member of the Bunyaviridae family and the genus includes N 50 different viruses with a wide spectrum of illnesses with two major, sometimes overlapping, clinical syndromes, HFRS and HPS. Transmission to humans is through inhalation of infectious aerosols from rodent excreta and insect vectors are not involved. There is however recent evidence of human-to-human transmission in one cluster of cases [17,18].

Dengue is by far the most prevalent human arboviral infection with an estimated 390 million (95% credible interval 284–528) infections occurring per year [25]. It is transmitted mainly by the Aedes aegypti species. Infection with any of the four serotypes DEN-1, DEN-2, DEN-3, and DEN-4, is associated with a variety of clinical manifestations ranging from mild fever to severe fatal hemorrhage and shock [26]. The illness begins abruptly after the incubation period and is followed by three phases: 1) Febrile, 2) Critical and 3) Recovery. Clinical dengue is

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categorized according to the severity as dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Severe dengue is associated with severe plasma leak, hemorrhage and organ failure. The laboratory diagnosis is made by detecting the virus and its components by RT- PCR or by serology depending on what is available. Management is based on the severity of infection and fluid resuscitation and organ support are integral to the management of severe disease. Component therapy such as platelet concentrates, fresh-frozen plasma, and cryoprecipitate is determined by the presence of bleeding and the coagulation profile.

7. Ebola and marburg Ebola Virus and Marburg viruses are categorized as a filoviruses and can cause fatal hemorrhagic fever [27]. Five distinct species have been ascribed to the EBOV genus, namely Zaire, Sudan, Taï Forest, Reston and Bundibugyo viruses [28]. These vary enormously in terms of geographical distribution and in their virulence to humans, with Ebola Zaire one of the most lethal infections known to mankind. Once the more virulent forms of the virus enter the human population, transmission is primarily through direct contact with infected body fluids such as blood, feces and vomitus potentially resulting in significant outbreaks, N20 of which have been reported since 1976. The most devastating however has been the recent West African outbreak in which by April 13, 2016, the disease had accounted for a total of 28,652 cases with 11,325 deaths including N 800 healthcare workers (HCW) [29]. MARV is thought to be more widely distributed than EBOV, but despite this there have been only 12 outbreaks between 1967 and 2014, four of which consisted of single cases without further spread [30]. There have been a total of 466 laboratory-confirmed cases with 373 deaths (average fatality rate of 80%, range 23–100%). The Egyptian fruit bat, Rousettus aegypticus appears to be the likely source of the infection [31]. Clinically the signs and symptoms of EBOV and MAVD are not dissimilar to those of the other VHF's [32]. Following an incubation period of 2–21 days (mean 4–9 days), three phases occur; initially fever, headache, and myalgia, followed by diarrhoea, vomiting and dehydration; thereafter, in the second week, there may be recovery or deterioration with collapse, neurological manifestations and bleeding that can lead to a fatal outcome. The laboratory features are not diagnostic; however, they can narrow the differential and give an indication of prognosis. Abnormal liver function is common, with 70% of patients having elevated ALT or AST Nfive times the upper limit of normal. Severe hepatitis (AST N 15 times) is more common in fatal cases (93% vs 44%), as is a higher mean haemoglobin concentration, hematocrit, and median platelet count, possibly indicating fluid depletion [33]. During an epidemic or even between epidemics a case definition must be established. If the features correspond with this definition then RT-PCR techniques on blood are the gold standard for diagnosis [34]. Management must involve access to and appropriate use of personal protection equipment and the design of the ICU should facilitate this. All Staff involved in the care of patients should be adequately trained and educated in infection control and have well-defined roles [35]. Patient management is primarily supportive, involving standard monitoring procedures and where hemodynamically unstable, fluid status, stroke volume, cardiac index and calculated systemic vascular resistance would be helpful. Where necessary, organ support should be employed, including the use of inotropes and vasopressors, mechanical ventilation and renal replacement therapy. Psychosocial support is necessary for HCW and patients alike. Numerous candidate pharmacological agents have been utilized for EBOV, however none have shown conclusive benefit and future management of epidemics should centre around prevention and containment, specifically isolation, hygiene, and vaccination [36,37].

8. Rift valley fever RVF virus, is of the genus Phlebovirus in the family Bunyaviridae and commonly causes disease in cattle, buffalo, sheep, goats, with potential for transmission to humans by infected mosquitoes. The virus is seen in sub-Saharan Africa, including West Africa and Madagascar. Most human infections are asymptomatic or present as a mild febrile illness, but ocular damage, meningoencephalitis, hemorrhagic fever or death may occur in a small subset of cases [38]. The disease presents as one of three syndromes 1.) Ocular disease (0.5–2%), 2) meningoencephalitis (b 1%) or 3), hemorrhagic fever (b 1%). Hemorrhagic fever is associated with a high mortality of 50%, with death occurring 3 to 6 days after the onset of symptoms. Hemorrhagic fever appears 2–4 days after the onset of illness, and begins with severe liver dysfunction with icterus and hemorrhagic manifestations such as hematemesis, melena and hematochezia, purpuric rash, ecchymoses, epistaxis, bleeding from the gums and venipuncture sites and menorrhagia. The major clinical characteristics of severe disease include hepatocellular failure in as many as (75.2%), acute renal failure in 41.2%, and hemorrhagic manifestations in 19.4%. Meningoencephalitis, tinnitus and retinitis may occur as late complications [39]. 9. Crimean-Congo hemorrhagic fever CCHF a Nairovirus of the family Bunyaviridae, causes an acute, tickborne disease leading to severe hemorrhagic manifestations with a high risk for mortality. Exposure to blood and other infected body fluids, can result in secondary spread to humans. CCHF is endemic in all of Africa, Eastern Europe (particularly in the former Soviet Union), throughout the Mediterranean, northwestern China, central Asia, southern Europe, the Middle East, and the Indian subcontinent [40]. Hyalomma or Ixodid (hard) ticks, are the principal vectors and reservoirs of the virus. CCHF virus is pathogenic only to humans and newborn mice [41]. Nosocomial transmission is a major worry and has led to outbreaks [42]. Clinically there are four well-defined phases: incubation, pre-hemorrhagic, hemorrhagic, and convalescence. The pre-hemorrhagic phase lasts for 3–6 days and is associated with a high-grade fever, rigors, severe headache, myalgia and abdominal pain. The hemorrhagic phase lasts 2–3 days [43] in which hemorrhage from multiple sites occurs. Cerebral and severe gastrointestinal hemorrhage in particular are associated with a poor prognosis. Death occurs at 6–10 days primarily due to hepatorenal failure and irreversible shock [41]. Treatment for CCHF is primarily supportive however administration of IV ribavirin is possibly of benefit and has resulted in quicker recovery and improvement in abnormal laboratory values [44]. Post-exposure prophylaxis with oral ribavirin for 7–10 days should be administered to HCWs exposed to body fluids [45]. 10. The South American VHFs In South America, VHF is caused by the Junin virus (Argentine HF), Machupo and Chapare viruses (Bolivian HF), Guanarito virus (Venezuelan HF) and Sabia virus (Brazilian HF) [46]. The diseases are country specific but may occur at specific times of the year. Junin virus infections for example peak during the corn harvest, when workers may be exposed to aerosolized virus. The clinical features of the new (NW) and old world (OW) arenaviruses are however similar. Following exposure to infected rodent urine and an incubation period of 7–14 days, humans develop a fever (N 38 °C), headache, anorexia, malaise and myalgia, with pain especially in the lower back. Nausea or dizziness, abdominal pain, vomiting, diarrhoea, retro-orbital pain, flushing and lymphadenopathy can also be seen. Nosocomial and person-to-person spread of both OW and NW arenaviruses is well recognized [46]. Most patients improve after a week or two, but about 30% of untreated cases become

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371

Table 1 Types of VHF, modes of transmission, virulence, therapy and mortality. Virus

Genus

Transmission

Virulence

Isolation

Treatment

Mortality %

CCHF Dengue Ebola Marburg Hanta virus Lassa RVF SAHF Yellow fever

Bunyaviridae Flaviviridae Filoviridae Filoviridae Bunyaviridae Arenaviridae Bunyaviridae Arenaviridae Flaviviridae

Tick Mosquito Primate Primate Rodent Rodent Mosquito Rodent Mosquito

Moderate Low High High Low to moderate Moderate Low to moderate Moderate Moderate

Yes No Yes Yes Extremely rare Uncommon No No No

Ribavirin Supportive Supportive Supportive Ribavirin Ribavirin Ribavirin Supportive Supportive

10–50 1–20% 50–90 50–90 5–15 30 1% RVHF, 50% of them die 30 25–50

severe and life-threatening, with fatality rates approaching 30%. In these patients hemorrhage and neurological signs are more likely. During this first week of illness, blood chemistry reveals a progressive leukopenia (1000 to 2000 white cells/mm3) and thrombocytopenia (50, 000 to 100, 000 platelets/mm3) [47]. In the first week of illness following the onset of symptoms AHF may be treated with immune plasma in a dose sufficient to neutralize the virus. This therapy is however ineffective after 8 days. For the other South American hemorrhagic fevers, the recommended therapy is intravenous ribavirin [48]. Symptomatic and supportive therapy during this period is essential. 11. Kyasanur forest disease KFDV is a member of the Flaviviridae family. Hard ticks (Hemaphysalis spinigera) are the reservoir of KFDV [49] and infection occurs in the southern parts of India, China and Saudi Arabia. Small mammals, especially rodents, the shrew, monkeys, squirrels and porcupines are reservoirs. There is however no evidence of human-to-human transmission. The incubation period is 3–8 days. Clinical features of severe disease include hemorrhagic manifestations, including intermittent epistaxis, hematemesis, melena, and frank blood in the stools [50]. There is only limited evidence that encephalitis occurs [51]. Morbidity associated with KFD ranges from 2 to 20% with a mortality of 3– 5% [52]. 11.1. Management and prevention of VHF The management includes general supportive care, with correction of coagulopathy and specific target organ support. In VHF, such as DHF/DSS, supportive care with appropriate and judicious fluid resuscitation can reduce mortality to b 1%. Blood transfusions and component therapy should be administered as applicable. Proper ICU care should be provided to all patients with VHF that require organ support (Table 1). When ribavirin is given parenterally or orally, there has been anecdotal benefit in uncontrolled studies in cases of CCHF, Lassa fever, South American HF viruses, and hemorrhagic fever with renal syndrome caused by Hanta virus. Immunoglobulin therapy with hyperimmune serum prepared from the blood of patients who recovered from CCHF or horse serum, may have some benefit. In contrast, in animal studies of EBOV, transfusion with convalescent serum with high antibody titers to the to the virus had no benefit at all. Some non-neutralizing cross reactive antibodies may worsen or aggravate the disease in conditions like Dengue and Marburg infections. 12. Conclusion VHFs remain a major menace in the Tropical regions of the world today. Certain diseases still have high morbidity and mortality, not only due to the virulence of the organisms but also due to limited

resources. The dearth of specific therapies and vaccines poses a health hazard world-wide. VHF outbreaks can occur following human to human transfer of some of these organisms, and pose a hazard to HCW. More attention should be paid to the prevention of these diseases and, once they occur, to the prevention of spread. Task force planning Jean-Louis Vincent (Belgium) John Marshall (Canada) Janice Zimmerman (USA) Pravin Amin (India) Djillali Annane (France) Lluís Blanch, CIBERES-ISCIII (Spain) Guillermo Castorena (Mexico) Bin Du (China) Edgar Jimenez (USA) Younsuck Koh (Korea) John Myburgh (Australia) Masaji Nishimura (Japan) Paolo Pelosi (Italy) Álvaro Réa-Neto (Brazil) Arzu Topeli (Turkey) Sebastian Ugarte (Chile) Financial support None. Conflict of interest disclosures related to this manuscript None declared. References [1] Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis 2001;32(6):897–928. [2] Leroy EM, Kumulungui B, Pourrut X, Rouquet P, Hassanin A, Yaba P, et al. Fruit bats as reservoirs of Ebola virus. Nature 2005;438(7068):575–6. [3] Kilinc C, Guckan R, Capraz M, Varol K, Zengin E, Mengeloglu Z, et al. Examination of the specific clinical symptoms and laboratory findings of Crimean-Congo hemorrhagic fever. J Vector Borne Dis 2016;53(2):162–7. [4] Cikman A, Aydin M, Gulhan B, Karakecili F, Kesik OA, Ozcicek A, et al. Seroprevalence of Crimean-Congo hemorrhagic fever virus in Erzincan Province, Turkey, relationship with geographic features and risk factors. Vector Borne Zoonotic Dis 2016; 16(3):199–204. [5] Ibekwe TS, Nwegbu MM, Asogun D, Adomeh DI, Okokhere PO. The sensitivity and specificity of Lassa virus IgM by ELISA as screening tool at early phase of Lassa fever infection. Niger Med J 2012;53(4):196–9. [6] Jeffs B. A clinical guide to viral haemorrhagic fevers: Ebola, Marburg and Lassa. Trop Doct 2006;36(1):1–4. [7] Papa A, Karabaxoglou D, Kansouzidou A. Acute West Nile virus neuroinvasive infections: cross-reactivity with dengue virus and tick-borne encephalitis virus. J Med Virol 2011;83(10):1861–5. [8] Blow JA, Dohm DJ, Negley DL, Mores CN. Virus inactivation by nucleic acid extraction reagents. J Virol Methods 2004;119(2):195–8.

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