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Exotic viral hepatitis: A review on epidemiology, pathogenesis, and treatment

  • Leanne P.M. van Leeuwen
    Affiliations
    Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands

    Travel Clinic, Erasmus MC, University Medical Center Rotterdam, Zimmermanweg 7, 3015 CP, Rotterdam, the Netherlands
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  • Wesley de Jong
    Affiliations
    Department of Internal Medicine, Maasstad Ziekenhuis, Maasstadweg 21, 3079 DZ, Rotterdam, the Netherlands
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  • Laura Doornekamp
    Affiliations
    Department of Medical Microbiology and Infectious Diseases, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
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  • Eric C.M. van Gorp
    Affiliations
    Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands

    Travel Clinic, Erasmus MC, University Medical Center Rotterdam, Zimmermanweg 7, 3015 CP, Rotterdam, the Netherlands

    Department of Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
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  • Pieter J. Wismans
    Affiliations
    Department of Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
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  • Marco Goeijenbier
    Correspondence
    Corresponding author. Address: Department of intensive care, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
    Affiliations
    Department of Intensive Care, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands

    Department of Intensive Care, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, the Netherlands
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Open AccessPublished:July 08, 2022DOI:https://doi.org/10.1016/j.jhep.2022.06.031

      Summary

      Certain “exotic” viruses are known to cause clinical diseases with potential liver involvement. These include viruses, beyond regular hepatotropic viruses (hepatitis A, -B(D), -C, -E, cytomegalovirus, Epstein-Barr virus), that can be found in (sub)tropical areas and can cause “exotic viral hepatitis”. Transmission routes typically involve arthropods (Crimean Congo haemorrhagic fever, dengue, Rift Valley fever, yellow fever). However, some of these viruses are transmitted by the aerosolised excreta of rodents (Hantavirus, Lassa fever), or via direct contact or contact with bodily fluids (Ebola). Although some exotic viruses are associated with high fatality rates, such as Ebola for example, the clinical presentation of most exotic viruses can range from mild flu-like symptoms, in most cases, right through to being potentially fatal. A smaller percentage of people develop severe disease with haemorrhagic fever, possibly with (fulminant) hepatitis. Liver involvement is often caused by direct tropism for hepatocytes and Kupffer cells, resulting in virus-mediated and/or immune-mediated necrosis. In all exotic hepatitis viruses, PCR is the most sensitive diagnostic method. The determination of IgM/IgG antibodies is a reasonable alternative, but cross-reactivity can be a problem in the case of flaviviruses. Licenced vaccines are available for yellow fever and Ebola, and they are currently under development for dengue. Therapy for exotic viral hepatitis is predominantly supportive. To ensure that preventive measures can be introduced to control possible outbreaks, the timely detection of these viruses is very important.

      Keywords

      Introduction

      A number of viruses that are prevalent in specific geographical areas and are often referred to as “exotic” can affect the liver or even cause hepatitis. The most important group of these exotic viruses are the viral haemorrhagic fever (VHF) viruses, which encompass a group of diseases caused by enveloped RNA viruses that are derived from 4 taxonomic families: Arenaviridae; Bunyaviridae; Filoviridae; and Flaviviridae. VHF viruses lead to extremely diverse clinical syndromes, ranging from asymptomatic infections to life-threatening febrile illness with vascular damage. In advanced disease, haemorrhages can occur, especially when the patient has thrombocytopenia or platelet dysfunction. However, the incidence of haemorrhage varies extensively between the different viruses. In addition to the cardiovascular system, VHF viruses can affect many other organ systems, including the liver.
      • Paessler S.
      • Walker D.H.
      Pathogenesis of the viral hemorrhagic fevers.
      Many VHF viruses can cause (seasonal) outbreaks when human populations are exposed to infected animals or arthropods, and these viruses are mainly present in tropical areas.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      • Guzman M.G.
      • Harris E.
      Dengue.
      • Hartman A.
      Rift Valley fever.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.
      VHF viruses are a high priority on the World Health Organization (WHO)’s shortlist of emerging pathogens. This is because of their potential to cause severe outbreaks in the near future and there being no substantial preventive or therapeutic measures available against most of them.
      • Griffiths P.D.
      • Ellis D.S.
      • Zuckerman A.J.
      Other common types of viral hepatitis and exotic infections.
      ,
      WHO
      WHO publishes list of top emerging diseases likely to cause major epidemics.
      It follows therefore, that international travel and climate change may spread VHF viruses to areas where they are currently non-endemic.
      • Guzman M.G.
      • Harris E.
      Dengue.
      Many western-world clinicians are unfamiliar with the clinical presentation of these viruses, especially in patients not presenting with the classical triad of symptoms. For this reason, this narrative review aims to provide an up-to-date overview of the epidemiology, pathogenesis, clinical syndromes, and treatment of the most prevalent exotic viruses, all VHF viruses, that can cause hepatitis. The viruses included in this review are: Crimean Congo haemorrhagic fever virus (CCHFV), dengue, Ebola, Hantavirus, Lassa virus, Rift Valley fever virus (RVFV), and yellow fever virus (Table 1, Table 2).
      Table 1Clinical signs and symptoms, treatment and prevention.
      VirusIncubation timeSigns and symptomsClinical chemistry analysisHepatic involvementTreatmentPrevention
      Crimean Congo1-5 days following a tick bite, 5-7 days following contact with infected bloodFever, flu-like symptoms, hepatosplenomegaly, petechial rash progressing to large cutaneous ecchymoses, progressing to gastrointestinal-, urogenital- and/or cerebral-haemorrhage, acute liver failure, shock.(Extreme) thrombocytopenia

      AST levels and ALT levels >3x the ULN, with increased AST/ALT ratio. In patients with haemorrhagic symptoms AST can increase to >10x the ULN.

      Severe disease: prolonged PT and aPTT, increased D-dimers and fibrin degradation products, increased blood urea nitrogen, increased creatinine.
      Extensive: Kupffer-cell hyperplasia and hepatocellular necrosisSupportive, ribavirin
      Low quality of evidence.
      , high dose methyl prednisolone
      Low quality of evidence.
      No FDA-/EMA-approved vaccine available
      Dengue4-7 days40-80% asymptomatic. Fever, retro-orbital pain and headache, myalgia, arthralgia, rash, maculopapular exanthema, hepatomegaly, jaundice, haemorrhage, respiratory distress. Acute liver failure ± 0.5% of all cases.AST levels and ALT levels >3x the ULN, with increased AST/ALT ratio. In some cases transaminases are increased to >10x the ULN.

      Thrombocytopenia, leukopenia.
      Mild-moderate:

      Kupffer-cell hyperplasia and hepatocellular necrosis
      SupportiveMosquito-repellent measures. Vaccine available in limited situations.
      Ebola2-21 daysFever, myalgia, asthenia, nausea, vomiting, diarrhoea which may progress to dehydration and multi-organ failure (including acute kidney injury, pancreatitis, adrenal failure, and hepatitis). Hepatosplenomegaly can be found in severe cases. Jaundice is rare.In 70% of cases, AST or ALT is 5x ULN. Severe disease: prolonged PT and aPTT, increased D-dimers and fibrin degradation products, increased blood urea nitrogen, increased creatinine.Mild-moderate: Kupffer-cell hyperplasia and hepatocellular necrosisSupportive, monoclonal antibodiesTwo vaccines licensed
      Hanta2-4 weeksHaemorrhagic fever with renal syndrome with a classic triad of fever, renal failure and coagulopathy. In case of Seoul Hantavirus HFRS hepatitis might occur.In case of HFRS hepatitis, elevation of ALT, AST and thrombopenia.Mild-moderate: necrosis in hepatic lobulesSupportive, could benefit from early ribavirin treatment
      Low quality of evidence.
      Preventive measures: avoid exposure to rodents.
      Lassa1-3 weeks80% mild. 20% more severe including haemorrhage, respiratory distress, facial oedema, neurological problems and hepatitis.Elevation of AST and ALT >3x the ULN. Bilirubin, prolonged clotting times.Mild-moderate: inflammatory responses with cellular damageSupportive, early ribavirin treatment
      Low quality of evidence.
      Preventive measures: avoid exposure to rodents.
      Rift Valley2-6 daysOften asymptomatic or flu-like symptoms. Severe cases (5%): ocular complications, signs of meningoencephalitis, haemorrhagic fever with jaundice, acute liver failure.Mean AST levels and ALT levels >10x the ULN, with increased AST/ALT ratio. Prolonged coagulation times, thrombocytopenia.Extensive: virus-induced hepatocellular necrosisSupportiveVaccination available for veterinary use
      Yellow fever3-6 days15% develop severe disease (with 20-60% CFR) with fever, flu-like symptoms, jaundice, hepatomegaly, acute liver failure, acute kidney failure, bleeding, shock.AST levels and ALT levels >10x the ULN, with increased AST/ALT ratio. Elevated direct bilirubin, thrombocytopenia, reduced coagulation factors, prolonged PT and aPTT, increased D-dimers and fibrin degradation products (DIC), increased blood urea nitrogen, increased creatinine.Extensive: pronounced injury in midzonal area with TGF-β-induced apoptosisSupportiveVaccine available. Mosquito-repellent measures.
      ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CFR, case fatality rate; DIC, disseminated intravascular coagulation; HFRS, haemorrhagic fever with renal syndrome; PT, prothrombin time; ULN, upper limit of normal.
      Low quality of evidence.
      Table 2Epidemiology and transmission.
      VirusFamily(Endemic) areasHost/natural reservoirTransmission route
      Crimean CongoBunyaviridaeAfrica, Asia and Europe (Balkan region)Mammals, only symptomatic in humansArthropod-borne: Ticks, mainly hyalomma species. Contact with blood of infected animals. Nosocomial transmission. Reports about possible sexual, and maternal transmission.
      DengueFlaviviridae(Sub)tropical areas of America, Africa, Middle East, Asia, Pacific islandsMammals, predominantly humansArthropod borne: Aedes aegypti, Aedes albopictus mosquitoes
      EbolaFiloviridaeMostly Central and West AfricaFruit batsDirect contact or via bodily fluids
      HantaBunyaviridaeHFRS in Europe and Asia

      HCPS in North and South America
      RodentsVirus containing aerosols in rodent excreta
      Lassa feverArenaviridaeWest AfricaMultimammate rat (Mastomys natalensis)Virus containing aerosols in rodent excreta
      Rift ValleyBunyaviridaeAfrica and the Arabian PeninsulaMammalsArthropod borne, predominantly mosquitoes (Aedes and Culex species)
      Yellow feverFlaviviridaeAfrica (A) and South America (SA)PrimatesSylvatic cycle: Aedes africanus (A), Haemagogus species (SA) Sabethes species (SA). Urban cycle: Aedes aegypti (A, SA)

      Crimean Congo haemorrhagic fever

      In 1973, CCHFV was identified as the cause of Crimean fever (identified in 1944) and the Congo fever (identified in 1956).
      • Garrison A.R.
      • Smith D.R.
      • Golden J.W.
      Animal models for crimean-Congo hemorrhagic fever human disease.
      CCHFV belongs to the order Bunyaviridae and it is endemic across a large geographic region that includes Africa, Asia and southern Europe (Fig. 1).
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      What these regions have in common is the presence of Hyalommaw ticks, the main vector of CCHFV. The virus is spread by infected ticks on migratory birds and the international shipment of livestock.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      Global incidence is hard to estimate because the virus causes sporadic cases and outbreaks. Therefore, up to 90% of infections can be subclinical.
      Figure thumbnail gr1
      Fig. 1World maps of viral haemorrhagic fever viruses.
      (A) Countries with risk of yellow fever transmission.
      World Health Organization
      Countries with risk of yellow fever transmission and countries requiring yellow fever vaccination (May 2021).
      (B) Countries with frequent dengue cases (dark) and countries with sporadic dengue cases (light). (C) Countries in which Rift Valley fever outbreaks have been reported. (D) Countries with Lassa fever infections/outbreaks. (E) Countries in which Ebola outbreaks have been reported.
      Centers for Disease Control and Prevention
      Ebola (Ebola virus disease).
      (F) Countries in which Crimean-Congo haemorrhagic fever virus outbreaks have been reported.
      Centers for Disease Control and Prevention
      Crimean-Congo hemorrhagic fever (CCHF).
      (G and H) Countries in which Hantavirus haemorrhagic fever with renal syndrome and Hantavirus (cardio) pulmonary syndrome cases have been reported. However, the reservoir host’s habitat is more widespread. This figure has been made with great care, based on trustworthy sources. Nevertheless, it may contain inaccuracies.

      Transmission and host

      CCHFV is transmitted exclusively by ixodid (hard shield) ticks, with the Hyalomma species being the main vector. These ticks can become infected in several ways and that infection lasts throughout their lifetime. During the spring and summer months, larvae and nymphs feed on rodents, hares, ground-feeding birds and other small animals. Adult ticks feed on sheep, cattle and other large mammals, with humans functioning as accidental hosts. Hyalomma ticks actively hunt their hosts, and can travel up to 400 metres to reach them.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      Multiple large CCHFV outbreaks have been explained by the repopulation of abandoned (farm) areas, were humans were seen as welcome guests by adult ticks looking for large mammals for their next blood meal.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      The 50o north latitude parallel forms the current natural border of Hyalomma ticks. Above this line, low cumulative autumn temperatures prevent their full maturation.
      • Estrada-Peña A.
      • Jameson L.
      • Medlock J.
      • Vatansever Z.
      • Tishkova F.
      Unraveling the ecological complexities of tick-associated Crimean-Congo hemorrhagic fever virus transmission: a gap analysis for the western Palearctic.

      Clinical signs and symptoms

      The clinical syndrome associated with CCHFV infection can be divided into 4 phases. The first of these, the incubation phase, starts after viral inoculation and lasts for 1-7 days. After incubation, the second, pre-haemorrhagic phase (lasting 1-7 days), is typically a severe fever with a variety of “flu-like” symptoms. Some patients will rapidly progress to the third, or haemorrhagic, phase, which typically lasts 1-3 days. In this phase, haemorrhagic manifestations usually start with a petechial rash, which can be followed by large ecchymosis, mucous bleeding and bleeding from the gastrointestinal and urinary tract. Vaginal bleeding, musculature bleeding and cerebral haemorrhage have also been reported.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      ,
      • Ergönül O.
      Crimean-Congo haemorrhagic fever.
      In a significant number of patients, death occurs within 2 weeks of the start of the first symptoms, as a result of haemorrhage, severe liver necrosis causing acute liver failure (ALF), multi-organ failure and shock. For the remaining patients, the haemorrhagic phase turns into the (fourth) convalescence phase.
      • Zivcec M.
      • Safronetz D.
      • Scott D.
      • Robertson S.
      • Ebihara H.
      • Feldmann H.
      Lethal Crimean-Congo hemorrhagic fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy.
      Case fatality rates vary between 5 and 40%.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      ,
      WHO
      Crimean-Congo haemorrhagic fever.
      A number of viruses that are prevalent in specific geographical areas and often referred to as “exotic” can present with liver involvement.

      Pathophysiology

      Due to a lack of animal models, little is known about the pathogenesis of CCHFV. For a few decades, genetically manipulated mouse models, with interferon-deficient mice, have been used to investigate CCHFV-specific pathogenesis.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      ,
      • Bereczky S.
      • Lindegren G.
      • Karlberg H.
      • Åkerström S.
      • Klingström J.
      • Mirazimi A.
      Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice.
      Viral RNA or antigens, in particular, have been found in lymphoid cells, endothelial cells, hepatocytes and splenocytes.
      • Burt FJl
      • Swanepoel R.
      • Shieh W.J.
      • Smith J.F.
      • Leman P.A.
      • Greer P.W.
      • et al.
      Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis.
      Direct and indirect viral activation of endothelial cells leads to increased vascular permeability, endothelial damage, and the activation of the coagulation cascade, resulting in disseminated intravascular coagulation (DIC) and bleeding. CCHFV also replicates in the liver and causes apoptosis of hepatocytes. In histopathologic studies, multiple foci of necrosis have been found in the liver. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels correlate with the extent of necrosis.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      ,
      • Akıncı E.
      • Bodur H.
      • Leblebicioglu H.
      Pathogenesis of Crimean-Congo hemorrhagic fever.
      In this context, AST is increased more profoundly than ALT. Other common laboratory findings in severe CCHFV disease are thrombocytopenia, prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT), as well as decreased haemoglobin level (Table 1).
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.

      Diagnostics and treatment

      Reverse-transcription PCR (RT-PCR) of serum specimens is the most reliable diagnostic method, because severely ill patients fail to produce CCHFV-specific antibodies. In these patients, treatment is mainly supportive.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      In a systematic Cochrane review,
      • Johnson S.
      • Henschke N.
      • Maayan N.
      • Mills I.
      • Buckley B.S.
      • Kakourou A.
      • et al.
      Ribavirin for treating Crimean Congo haemorrhagic fever.
      ribavirin, a purine nucleoside used against hepatitis C, was not found to have an effect on mortality or length of hospital stay. However, one non-randomised study found lower mortality rates in patients who were given ribavirin soon (within 4 days) after the onset of symptoms.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo hemorrhagic fever patients: a case-control study.
      High-dose methylprednisolone (usually given in combination with fresh frozen plasma and intravenous immunoglobulins) has been shown to increase platelet counts and reduce fever in small cohorts of paediatric cases.
      • Mendoza E.J.
      • Warner B.
      • Safronetz D.
      • Ranadheera C.
      Crimean-Congo haemorrhagic fever virus: past, present and future insights for animal modelling and medical countermeasures.
      ,
      • Erduran E.
      • Bahadir A.
      • Palanci N.
      • Gedik Y.
      The treatment of crimean-Congo hemorrhagic fever with high-dose methylprednisolone, intravenous immunoglobulin, and fresh frozen plasma.

      Prevention

      Currently the only effective measure to prevent CCHF is to avoid tick bites, as no licensed vaccine is available. A formalin-inactivated CCHFV vaccine developed in the former Soviet Union in 1970 is used in Bulgaria, although elicited neutralising antibody titres are low and controlled efficacy studies are lacking.
      • Bente D.A.
      • Forrester N.L.
      • Watts D.M.
      • McAuley A.J.
      • Whitehouse C.A.
      • Bray M.
      Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity.
      Candidate vaccines include a DNA-based vaccine, tested on non-human primates, which led to the successful production of CCHFV-specific antibodies and a significant reduction of viremia after viral challenge.
      • Hawman D.W.
      • Ahlén G.
      • Appelberg K.S.
      • Meade-White K.
      • Hanley P.W.
      • Scott D.
      • et al.
      A DNA-based vaccine protects against Crimean-Congo haemorrhagic fever virus disease in a Cynomolgus macaque model.

      Dengue

      Dengue virus is a flavivirus belonging to the family of Flaviviridae. The first identified dengue epidemics occurred more or less simultaneously in Asia, Africa and North America in the 1780s. In the 20th century it was acknowledged that human dengue infections occur primarily through virus transmission via Aedes spp. mosquitoes.
      • Guzman M.G.
      • Harris E.
      Dengue.
      The prevalence of these mosquitoes in tropical and subtropical countries currently poses risks of virus transmission to about half the world’s population and its travellers (Fig. 1). Four distinct dengue virus serotypes are known and because an infection does not induce cross immunity, reinfections over a person’s lifetime are possible. Up to 80% of infections occur asymptomatically and a maximum of about 5% of symptomatic cases are classified as severe and might need hospitalisation. Severe infections are associated with secondary infections by heterologous serotypes.
      • Bhatt S.
      • Gething P.W.
      • Brady O.J.
      • Messina J.P.
      • Farlow A.W.
      • Moyes C.L.
      • et al.
      The global distribution and burden of dengue.
      ,
      • Katzelnick L.C.
      • Gresh L.
      • Halloran M.E.
      • Mercado J.C.
      • Kuan G.
      • Gordon A.
      • et al.
      Antibody-dependent enhancement of severe dengue disease in humans.

      Transmission and host

      Humans are the main reservoir for dengue virus. After inoculation with the dengue virus, it is estimated that humans have a viraemic period of 5 days. During that time, Aedes spp mosquitoes can take up the virus during a bloodmeal and transmit it to other humans.
      • Martina B.E.
      • Koraka P.
      • Osterhaus A.D.
      Dengue virus pathogenesis: an integrated view.
      A number of factors facilitate the ongoing spread of dengue virus, such as poor vector control, overpopulation, climate changes and increased international travel.
      • Guzman M.G.
      • Harris E.
      Dengue.

      Clinical signs and symptoms

      The average incubation period of dengue virus is 4-7 days. People developing symptoms experience signs of headache, retro-orbital pain, myalgia, arthralgia and a maculopapular rash. In severe dengue, defined as dengue haemorrhagic fever and dengue shock syndrome, patients show signs of severe plasma leakage, leading to shock or fluid accumulation accompanied by respiratory distress, severe bleeding and multi-organ failure. Clinical evidence of liver involvement is common in dengue haemorrhagic fever and dengue shock syndrome (present in 60-90% of patients). Symptoms include hepatomegaly, jaundice and increased AST and ALT (>3 times the upper limit of normal [ULN]). In this case, the AST/ALT ratio is often increased. An extreme increase of serum transaminases (>10 times the ULN) is found in 4-15% of these cases.
      • Samanta J.
      • Sharma V.
      Dengue and its effects on liver.
      In a recent multicentre study it was demonstrated that AST and ALT could serve as prognostic factors from day 4-6 of the clinical disease.
      • Huy B.V.
      • Toàn N.V.
      Prognostic indicators associated with progresses of severe dengue.
      In total, 0.5% of patients with severe dengue develop ALF, which is associated with high mortality.
      • Guzman M.G.
      • Harris E.
      Dengue.
      Other chronic liver conditions, such as cirrhosis, are also associated with a higher risk for all-cause mortality within 30 days of dengue diagnosis (odds ratio 3.42).
      • Lien C.E.
      • Chou Y.J.
      • Shen Y.J.
      • Tsai T.
      • Huang N.
      A population-based cohort study on chronic comorbidity risk factors for adverse dengue outcomes.
      Similarly, an age-adjusted odds ratios of 3.41 was found in those who were overweight/obese, in whom co-existing non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is likely.
      • Badawi A.
      • Velummailum R.
      • Ryoo S.G.
      • Senthinathan A.
      • Yaghoubi S.
      • Vasileva D.
      • et al.
      Prevalence of chronic comorbidities in dengue fever and West Nile virus: a systematic review and meta-analysis.

      Pathophysiology

      While classically known as a non-hepatotropic virus, the liver is commonly affected by dengue virus infections. Dengue virus can replicate in both hepatocytes and Kupffer cells. Hepatocellular injury occurs in 60-90% of symptomatic patients and comprises mild-to-moderate midzonal hepatocellular necrosis. This necrosis is caused by direct dengue-induced apoptosis and the cytolytic and/or cytokine-mediated effects of dengue-specific CD4+ and CD8+ T cells.
      • Martina B.E.
      • Koraka P.
      • Osterhaus A.D.
      Dengue virus pathogenesis: an integrated view.
      ,
      • Teerasarntipan T.
      • Chaiteerakij R.
      • Komolmit P.
      • Tangkijvanich P.
      • Treeprasertsuk S.
      Acute liver failure and death predictors in patients with dengue-induced severe hepatitis.
      ,
      • Seneviratne S.L.
      • Malavige G.N.
      • de Silva H.J.
      Pathogenesis of liver involvement during dengue viral infections.
      Dengue virus infection of endothelial cells and the subsequent release of cytokines and other mediators results in endothelial cell dysfunction and the development of coagulation disorders, causing, in severe cases, haemorrhagic shock.
      • Martina B.E.
      • Koraka P.
      • Osterhaus A.D.
      Dengue virus pathogenesis: an integrated view.

      Diagnostics and treatment

      Viral genome detection using RT-PCR techniques on serum samples is considered both the most sensitive and quickest option, and is available in acute, resource-rich settings.
      • Gubler D.J.
      Dengue and dengue hemorrhagic fever.
      Alternatively, sensitive assays – preferably RT-PCR but also ELISA or antigen-based rapid testing – can be used to detect the NS1 (non-structural 1) dengue antigen. These might be complemented by serological diagnostics to evaluate the current stage of infection and seroconversion.
      • Raafat N.
      • Blacksell S.D.
      • Maude R.J.
      A review of dengue diagnostics and implications for surveillance and control.
      Cross-reactivity in patients with previous flavivirus exposure due to natural infection or vaccination is commonly seen; hence, a thorough review of medical, travel and vaccination history is warranted.
      • Guzman M.G.
      • Harris E.
      Dengue.
      The treatment of hospitalised patients is mainly supportive and comprises fluid replenishment and acetaminophen. Aspirin and non-steroidal anti-inflammatory drugs are contra-indicated owing to their anticoagulant properties.

      Prevention

      For people living in endemic areas, the Dengvaxia vaccine is FDA approved for the prevention of dengue in children aged 9–16, and EMEA approved for people aged 6-45. In both cases the vaccine is only indicated after a laboratory-confirmed previous dengue virus infection. This is because the vaccine increases the risk of severe dengue when given to naïve recipients. In seropositive recipients, the vaccine protects against the increased severity of a second dengue infection.
      • Halstead S.
      • Wilder-Smith A.
      Severe dengue in travellers: pathogenesis, risk and clinical management.

      Ebola (virus disease)

      The Ebola virus derived its name from the Ebola River, which crosses the northern part of the Democratic Republic of the Congo. The virus was first discovered in this country, which was then known as Zaire.
      • Pattyn S.
      • van der Groen G.
      • Jacob W.
      • Piot P.
      • Courteille G.
      Isolation of Marburg-like virus from a case of haemorrhagic fever in Zaire.
      Zaire Ebola virus (ZEBOV) is one of the 6 known Ebola virus species, the others being Sudan (where another outbreak was ongoing in 1976), Reston, Taï Forest, Bundibugyo and Bombali Ebolavirus. Together with Marburg virus, which was discovered a few years earlier, Ebola virus belongs to the family of Filoviridae. ZEBOV still causes most human infections, mainly in Central and West Africa,
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      with the largest outbreak (in West Africa from 2013-2016) causing nearly 29,000 human infections (Fig. 1).
      • Richards G.A.
      • Baker T.
      • Amin P.
      Ebola virus disease: report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.
      ,
      • Goeijenbier M.
      • van Kampen J.J.
      • Reusken C.B.
      • Koopmans M.P.
      • van Gorp E.C.
      Ebola virus disease: a review on epidemiology, symptoms, treatment and pathogenesis.
      Most patients initially present with non-specific febrile illness, but may quickly develop multi-organ failure.

      Transmission and host

      Multiple epidemics have led back to contact with wild animals, mostly non-human primates, or the consumption of bush meat.
      • Georges-Courbot M.C.
      • Sanchez A.
      • Lu C.Y.
      • Balze S.
      • Leroy E.
      • Lansout-Soukate J.
      • et al.
      Isolation and phylogenetic characterization of Ebola viruses causing different outbreaks in Gabon.
      However, non-human primates are unlikely reservoirs of Ebola virus, as they do not survive infection in the long term. Fruit bats of the Pteropodidae family are considered probable natural reservoirs. Once introduced into a human population, the virus can spread from person-to-person via direct contact or via contact with bodily fluids.
      Some exotic viruses are known for their high fatality rate, but these are not exclusively caused by liver failure.

      Clinical signs and symptoms

      Classically, Ebola was referred to as Ebola haemorrhagic fever. However, bleeding has been shown to be a less prominent feature than was previously thought.
      • McElroy A.
      Understanding bleeding in ebola virus disease.
      The incubation period ranges from 2-21 days (usually 6-10 days). Patients present with fever (about 90%), myalgia and asthenia.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      ,
      • Rojek A.
      • Horby P.
      • Dunning J.
      Insights from clinical research completed during the west Africa Ebola virus disease epidemic.
      In a second stage, usually after about a week, patients may also develop nausea, vomiting, diarrhoea and, as a consequence, dehydration. In a tertiary phase, multi-organ failure can occur, resulting in an average case fatality rate (CFR) of 50%.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      AST and ALT are commonly elevated (>5x ULN, whereby AST >ALT) and are strong predictors of an adverse outcome.
      • Richards G.A.
      • Baker T.
      • Amin P.
      Ebola virus disease: report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.
      ,
      • Sharma N.
      • Cappell M.S.
      Gastrointestinal and hepatic manifestations of ebola virus infection.

      Pathophysiology

      The virus first targets macrophages and dendritic cells, causing increased cytokine release and the subsequent migration of the virus to the spleen, lymph nodes and other organs, including the liver. Pro-inflammatory cytokines cause endothelial activation, which results in endothelial damage, DIC, and bleeding complications.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      ,
      • Beeching N.J.
      • Fenech M.
      • Houlihan C.F.
      Ebola virus disease.
      In the liver, Ebola replicates in hepatocytes and Kupffer cells (Fig. 2). Foci of necrosis appear in the liver, caused by the direct lytic effect of viral replication and by virus-induced attacks of natural killer cells.
      • Fausther-Bovendo H.
      • Qiu X.
      • He S.
      • Bello A.
      • Audet J.
      • Ippolito G.
      • et al.
      NK cells accumulate in infected tissues and contribute to pathogenicity of Ebola virus in mice.
      ,
      • Rasmussen A.L.
      Host factors involved in ebola virus replication.
      Figure thumbnail gr2
      Fig. 2Simplified model of a liver sinusoid during different exotic virus infections.
      (A) Normal liver sinusoid: Mixed arterial- and portal-blood flows through the hepatic sinusoid in the direction of the central vein. The sinusoid is lined by liver sinusoidal endothelial cells and Kupffer cells (macrophages). The liver can be functionally divided into three zones: Zone 1 encircles the portal triad (periportal zone); zone 3 is located around central veins; and zone 2 is located in between (midzone). (B) Common pathologic changes during exotic viral hepatitis: (1) Necrotic/apoptotic regions, often midzonal or periportal. In a liver biopsy, stained with H&E, dying hepatocytes can be seen as Councilman bodies (acidophilic globules of cells, representing an apoptotic or necrotic phase). (2) Ballooning degeneration of hepatocytes and Kupffer cell hyperplasia. (3) Viral antigen in hepatic cells.

      Diagnostics and treatment

      The gold standard in detecting the enveloped negative-sense RNA virus is a RT-PCR on serum samples. If this is not available, oral fluids can be used for molecular testing.
      • Richards G.A.
      • Baker T.
      • Amin P.
      Ebola virus disease: report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.
      , Viral RNA levels of patients with Ebola remain high during illness. On recovery, the virus becomes undetectable after about 3 weeks.
      • Vernet M.A.
      • Reynard S.
      • Fizet A.
      • Schaeffer J.
      • Pannetier D.
      • Guedj J.
      • et al.
      Clinical, virological, and biological parameters associated with outcomes of Ebola virus infection in Macenta, Guinea.
      Diagnostic tests to detect ZEBOV antigens or anti-ZEBOV antibodies are available (e.g. applying a drop of blood with a finger stick on a lateral flow assay), but they are not as sensitive as PCR.
      • Coarsey C.T.
      • Esiobu N.
      • Narayanan R.
      • Pavlovic M.
      • Shafiee H.
      • Asghar W.
      Strategies in Ebola virus disease (EVD) diagnostics at the point of care.
      Although supportive care remains the cornerstone of management of Ebola virus disease, new antiviral therapies are available. Recently, the FDA approved 2 monoclonal antibodies for the treatment of a ZEBOV infection: Inmazeb (REGN-EB3) and Ebanga (mAb114). Inmazeb, a mixture of 3 monoclonal antibodies (atoltivimab/maftivimab/odesivimab), and Ebanga, a single human monoclonal antibody (ansuvimab), proved to be superior to ZMapp and remdesivir in the PALM trial in the Congo in 2018-2019.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      ,
      • Mulangu S.
      • Dodd L.E.
      • Davey jr., R.T.
      • Tshiani Mbaya O.
      • Proschan M.
      • Mukadi D.
      • et al.
      A randomized, controlled trial of ebola virus disease therapeutics.
      However, we have to take into account that baseline aminotransferase levels were higher in the study groups treated with ZMapp and remdesivir. Although treatment with Inmazeb or Ebanga led to a significant decline in death rate within 28 days, a third of patients still died.
      • Mulangu S.
      • Dodd L.E.
      • Davey jr., R.T.
      • Tshiani Mbaya O.
      • Proschan M.
      • Mukadi D.
      • et al.
      A randomized, controlled trial of ebola virus disease therapeutics.

      Prevention

      After the Ebola outbreak in West Africa, the rapid development of vaccines took place and resulted in the licensing of 2 vaccines. Ervebo (rVSV-ZEBOV-GP), a live-attenuated vector vaccine, has shown a very high efficacy after a single shot (up to 97.5%) in a randomised controlled trial in Guinea.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      Although this vaccine offers fast and high protection against ZEBOV, it is unclear how long the protection will last. The administration of the heterologous regime of Zabdeno-and-Mvabea (a shot of Ad26.ZEBOV-GP followed by a shot of MVA-BN-Filo 8 weeks later) requires more time to induce protection. However, it might offer protection over a longer period and against more filoviruses too.
      • Feldmann H.
      • Sprecher A.
      • Geisbert T.W.
      Ebola.
      ,
      • Voysey M.
      • Clemens S.A.C.
      • Madhi S.A.
      • Weckx L.Y.
      • Folegatti P.M.
      • Aley P.K.
      • et al.
      Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

      Hantavirus disease

      Hantaviruses, named after the Hantaan river in South Korea, form a genus within the Bunyaviridae family. The pathogenic strains of these viruses cause 2 different types of disease in humans. They are haemorrhagic fever with renal syndrome (HFRS) in Eurasia, and Hantavirus (cardio) pulmonary syndrome (HCPS), which is mainly seen in North and South America (Fig. 1).
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      Pathogenic Hantaviruses are all carried by chronically infected rodents that act as reservoirs. For the purposes of this review, HFRS caused by infection through the Seoul Hantavirus (SEOV) is of particular interest, since it is the only Hantavirus that can cause a disease presenting as hepatitis.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.

      Transmission and host

      Until now, more than 70 Hantavirus species have been identified in rodents, insectivores and bats. Around 30 of these Hantavirus species, all of which are rodent-borne, are associated with disease in humans.
      • Noack D.
      • Goeijenbier M.
      • Reusken C.
      • Koopmans M.P.G.
      • Rockx B.H.G.
      Orthohantavirus pathogenesis and cell tropism.
      In general, each Hantavirus is associated with one reservoir host species. As a rule of thumb, Hantaviruses are transmitted from infected rodents to humans by the inhalation of virus-containing aerosolised excreta. Case reports suggest other transmission routes via rat bites or the handling of laboratory rats, but it remains difficult to prove these non-aerosol transmissions.
      • Noack D.
      • Goeijenbier M.
      • Reusken C.
      • Koopmans M.P.G.
      • Rockx B.H.G.
      Orthohantavirus pathogenesis and cell tropism.

      Clinical signs and symptoms

      In Eurasia the most prevalent Hantaviruses are Puumala, Dobrava, Seoul and Hantaan. Patients infected with one of these Old-World Hantaviruses classically present with the triad of fever, renal failure, and potentially haemorrhage. In the New World (North and South America), Hantaviruses like Andes virus and Sin Nombre virus can cause HCPS, which, unlike HFRS, mainly affects the lungs and heart of infected individuals. Acute respiratory distress can develop very rapidly after symptoms of fever, myalgia, and non-specific upper respiratory tract manifestations present during the first phase.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      HCPS is particularly characterised by (pulmonary) oedema as a result of endothelial dysfunction, eventually leading to respiratory distress, which is the main cause of death in patients with HCPS. Although elevated liver enzymes have been described in SEOV, and case reports describe hepatitis as the presenting feature in acute SEOV HFRS, no reports of acute liver failure have been published.

      Pathophysiology

      Case reports of Hantavirus SEOV infection specifically mention increased liver enzymes and signs of hepatitis.
      • Goeijenbier M.
      • Verner-Carlsson J.
      • van Gorp E.C.
      • Rockx B.
      • Koopmans M.P.
      • Lundkvist A.
      Seoul hantavirus in brown rats in The Netherlands: implications for physicians--Epidemiology, clinical aspects, treatment and diagnostics.
      ,
      • Chan Y.C.
      • Wong T.W.
      • Yap E.H.
      • Tan H.C.
      • Lee H.W.
      • Chu Y.K.
      • et al.
      Haemorrhagic fever with renal syndrome involving the liver.
      Although not generally seen in other Hantavirus infections, elevated liver enzyme levels are of interest since these were also present in the other European SEOV case in the United Kingdom.
      • Elisaf M.
      • Stefanaki S.
      • Repanti M.
      • Korakis H.
      • Tsianos E.
      • Siamopoulos K.C.
      Liver involvement in hemorrhagic fever with renal syndrome.
      The pronounced elevation of liver enzymes made the treating physicians first suspect viral hepatitis or leptospirosis as the causative pathogens. This is generally not mentioned in the classical clinical picture of HFRS. Actually, it has been suggested that liver involvement could be seen as one of the key differentiators between SEOV infection and other Hantavirus infections.
      • Goeijenbier M.
      • Verner-Carlsson J.
      • van Gorp E.C.
      • Rockx B.
      • Koopmans M.P.
      • Lundkvist A.
      Seoul hantavirus in brown rats in The Netherlands: implications for physicians--Epidemiology, clinical aspects, treatment and diagnostics.
      ,
      • Hart C.A.
      • Bennett M.
      Hantavirus infections: epidemiology and pathogenesis.

      Diagnostics and treatment

      Although the extent of viremia varies greatly between Hantavirus-related syndromes, in many cases the viraemic stage is short and the time period in which Hantavirus can be detected by PCR usually coincides with the virulence of the relevant virus.
      • Vapalahti O.
      • Mustonen J.
      • Lundkvist A.
      • Henttonen H.
      • Plyusnin A.
      • Vaheri A.
      Hantavirus infections in Europe.
      SEOV can be detectable up to 8-10 days after onset.
      • Bi Z.
      • Formenty P.B.
      • Roth C.E.
      Hantavirus infection: a review and global update.
      In practice, in many cases the diagnosis of Hantavirus infections relies on the demonstration of Hantavirus-specific IgM and/or IgG serum antibodies by ELISA, or an immunofluorescence assay, although cross-reactivity between the different Hantaviruses does occur.
      • Avšič-Županc T.
      • Saksida A.
      • Korva M.
      Hantavirus infections.
      Since effective antiviral treatment for Hantavirus disease is lacking, the initiation of prompt and proper symptomatic and supportive treatment for HFRS and HCPS is crucial.
      • Goeijenbier M.
      • Verner-Carlsson J.
      • van Gorp E.C.
      • Rockx B.
      • Koopmans M.P.
      • Lundkvist A.
      Seoul hantavirus in brown rats in The Netherlands: implications for physicians--Epidemiology, clinical aspects, treatment and diagnostics.
      There is a low level of evidence to suggest that, by reducing the risk of haemorrhagic events and the severity of renal insufficiency, ribavirin treatment may be useful in the very early phase of HFRS.
      • Ogbu O.
      • Ajuluchukwu E.
      • Uneke C.J.
      Lassa fever in West African sub-region: an overview.

      Prevention

      Prevention entails minimising contact with rodents. There are currently no FDA-approved vaccinations available for Hantavirus disease.
      • Brocato R.L.
      • Hooper J.W.
      Progress on the prevention and treatment of hantavirus disease.

      Lassa fever

      Lassa fever, with a largely epidemic character, affects 2 to 3 million people in West Africa annually, with an estimated CFR of 15-20% in hospitalised cases.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      First described in 1969 in Lassa, a town in northeast Nigeria, the virus was considered the causative agent of a haemorrhagic fever with the potency of fulminant disease. The disease is caused by the Old-World arenavirus Lassa. The virus is endemic in several West-African countries (Fig. 1).
      • Ogbu O.
      • Ajuluchukwu E.
      • Uneke C.J.
      Lassa fever in West African sub-region: an overview.
      A small number of imported cases to Europe are described, with a comparatively high fatality rate (35%).
      • Wolf T.
      • Ellwanger R.
      • Goetsch U.
      • Wetzstein N.
      • Gottschalk R.
      Fifty years of imported Lassa fever: a systematic review of primary and secondary cases.
      Most exotic viruses do not clinically present as a classical viral hepatitis. However, sole clinical signs could be liver inflammation.

      Transmission and host

      The African multimammate rat (Mastomys natalensis) is considered the only reservoir host. Other Mastomys species do not seem to shed Lassa virus. This rodent breeds frequently, produces large numbers of offspring and is distributed widely throughout western, central and eastern parts of the African continent.
      • Bell-Kareem A.R.
      • Smither A.R.
      Epidemiology of Lassa fever.
      Mastomys natalensis is a commensal rodent that readily colonises human settlements, thereby increasing the risk of rodent-human contact. When infected, these rodents carry and excrete the virus lifelong. Human infection occurs after inhalation of aerosolised excreta (often urine), consuming contaminated foods or by direct contact with abraded skin.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      Human-to-human transmission may occur through direct contact with blood or bodily secretions from infected persons.
      • Wolf T.
      • Ellwanger R.
      • Goetsch U.
      • Wetzstein N.
      • Gottschalk R.
      Fifty years of imported Lassa fever: a systematic review of primary and secondary cases.

      Clinical signs and symptoms

      Up to 80% of patients infected with the Lassa virus will develop subclinical or mild disease, especially in endemic areas. After an incubation period of 1-3 weeks, characteristic pharyngitis, headache, vomiting and abdominal pain are observed as the main symptoms according to a recent systematic review.
      • Merson L.
      • Bourner J.
      • Jalloh S.
      • Erber A.
      • Salam A.P.
      • Flahault A.
      • et al.
      Clinical characterization of Lassa fever: a systematic review of clinical reports and research to inform clinical trial design.
      When progressing to the next stage (after 7 days), clinical hallmarks typically include facial oedema, neurological disorders, such as convulsions, encephalopathy, and bleeding. Haemorrhagic manifestations vary from mucosal bleedings (gums, nose, eyes) to severe internal bleeding from the stomach, bowel, kidney, brain and heart. These conditions only occur in a third of patients and they are associated with a CFR of between 38-52%. Patients may die in a later stage (>14 days) from shock and respiratory distress due to pleural effusion, possibly complicated with haemoptysis.
      • Asogun D.A.
      • Günther S.
      • Akpede G.O.
      • Ihekweazu C.
      • Zumla A.
      Lassa fever: epidemiology, clinical features, diagnosis, management and prevention.
      When patients recover, deafness, hair loss and long-term psychiatric complications are reported.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      Hepatitis has been reported in varying percentages in different cohort studies, with no homogenous definitions and validated cut-off values. AST levels above 150 IU/L have been mentioned in over 50% of published reports. However, the quality of the data is limited.
      • Merson L.
      • Bourner J.
      • Jalloh S.
      • Erber A.
      • Salam A.P.
      • Flahault A.
      • et al.
      Clinical characterization of Lassa fever: a systematic review of clinical reports and research to inform clinical trial design.

      Pathophysiology

      Most Lassa virus lesions seem to occur in the liver. There are 4 principal features of Lassa hepatitis: focal cytoplasmic degeneration of hepatocytes; randomly distributed multifocal hepatocellular necrosis; monocytic reaction to necrotic hepatocytes; and hepatocellular mitoses.
      • McCormick J.B.
      • Walker D.H.
      • King I.J.
      • Webb P.A.
      • Elliott L.H.
      • Whitfield S.G.
      • et al.
      Lassa virus hepatitis: a study of fatal Lassa fever in humans.
      Post-mortem analyses of patients with Lassa fever focused on hepatic tissue showed varying degrees of hepatic damage.
      • McCormick J.B.
      • Walker D.H.
      • King I.J.
      • Webb P.A.
      • Elliott L.H.
      • Whitfield S.G.
      • et al.
      Lassa virus hepatitis: a study of fatal Lassa fever in humans.

      Diagnosis and treatment

      Serological diagnostics are performed by an ELISA detecting anti-Lassa IgM and/or IgG antibodies. Due to persistent high viraemia for at least 10-15 days, PCR techniques on blood plasma remain useful for a long time.
      • Happi A.N.
      • Happi C.T.
      • Schoepp R.J.
      Lassa fever diagnostics: past, present, and future.
      Viral RNA has been isolated from patients’ semen up to 3 months post infection.
      • Goeijenbier M.
      • Wagenaar J.
      • Goris M.
      • Martina B.
      • Henttonen H.
      • Vaheri A.
      • et al.
      Rodent-borne hemorrhagic fevers: under-recognized, widely spread and preventable - epidemiology, diagnostics and treatment.
      The use of ribavirin is considered beneficial against Lassa fever during any stage of the disease. However, the treatment should start as soon as possible, preferably during the first 6 days. A 10-day dosage of 15 mg/kg in acute disease was shown to effectively decrease the CFR. Ribavirin has also proven useful for post-exposure prophylaxis in individuals at high risk.
      • Hadi C.M.
      • Goba A.
      • Khan S.H.
      • Bangura J.
      • Sankoh M.
      • Koroma S.
      • et al.
      Ribavirin for Lassa fever postexposure prophylaxis.
      Despite the availability of antiviral treatment, additional supportive care is also warranted. Fluid replacement and blood transfusions may be necessary.

      Prevention

      An increased risk of infection is associated directly with exposure to rodents. Minimising contact with rodents is therefore seen as an important precaution. This could be achieved by improving housing conditions, for example.
      • Ogbu O.
      • Ajuluchukwu E.
      • Uneke C.J.
      Lassa fever in West African sub-region: an overview.
      ,
      • Usuwa I.S.
      • Akpa C.O.
      • Umeokonkwo C.D.
      • Umoke M.
      • Oguanuo C.S.
      • Olorukooba A.A.
      • et al.
      Knowledge and risk perception towards Lassa fever infection among residents of affected communities in Ebonyi State, Nigeria: implications for risk communication.
      • Cummins D.
      Lassa fever.
      • Bonner P.C.
      • Schmidt W.P.
      • Belmain S.R.
      • Oshin B.
      • Baglole D.
      • Borchert M.
      Poor housing quality increases risk of rodent infestation and Lassa fever in refugee camps of Sierra Leone.
      While no vaccine has yet been approved, there are some promising experimental vaccine candidates.
      • Iroezindu M.O.
      • Unigwe U.S.
      • Okwara C.C.
      • Ozoh G.A.
      • Ndu A.C.
      • Ohanu M.E.
      • et al.
      Lessons learnt from the management of a case of Lassa fever and follow-up of nosocomial primary contacts in Nigeria during Ebola virus disease outbreak in West Africa.

      Rift Valley fever

      Rift Valley fever virus (RVFV) was first identified in 1930 during an investigation into an outbreak among sheep on a farm in Kenya’s Rift Valley.
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      RVFV belongs to the order of Bunyaviridae, and is endemic in several African countries, as well as in the Arabian Peninsula (Fig. 1).
      • Hartman A.
      Rift Valley fever.
      ,
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      Outbreaks occur regularly, with an estimated 200,000 human infections during the largest recent outbreak (in Egypt 1977-1979). Human infection mostly presents as an incapacitating febrile illness, but 1-2% of infections result in severe disease with a wide range of symptoms and high associated mortality. RVFV predominantly infects domestic livestock, with high reported animal losses and high abortion rates, which have enormous local socio-economic consequences.
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.

      Transmission and host

      RVFV can be transmitted by several species of mosquitoes (mostly Aedes and Culex). At least one species, Aedes mcintoshi, is capable of transmitting the virus to their offspring via their eggs.
      • Linthicum K.J.
      • Davies F.G.
      • Kairo A.
      • Bailey C.L.
      Rift Valley fever virus (family Bunyaviridae, genus Phlebovirus). Isolations from Diptera collected during an inter-epizootic period in Kenya.
      This is thought to be an important mechanism for prolonging RVFV outbreaks. These outbreaks are often preceded by excessive rainfall, resulting in increased mosquito populations. If they carry the RVFV, mosquitoes can cause increased infection among livestock, which further boosts viral amplification. Infection in humans can develop after being bitten by infected mosquitoes. However, most human infections are caused by contact with infected animal tissue and fluid.
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.

      Clinical signs and symptoms

      Disease manifestations in humans are typically benign and include headache, fever, backache, and generalised muscle- and joint-ache. Symptoms generally last 4-7 days, after an incubation period of 2-6 days. Around 5% of the symptomatic cases develop complications and/or severe disease. Severe disease can be categorised into 3 syndromes: ocular disease; meningoencephalitis; and haemorrhagic fever. In the first 2 syndromes, patients may suffer a permanent loss of vision, or (severe) residual neurological deficits.
      • Hartman A.
      Rift Valley fever.
      ,
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      ,
      • Javelle E.
      • Lesueur A.
      • Pommier De Santi V.
      • De Laval F.
      • Lefebvre T.
      • Holweck G.
      • et al.
      The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal.
      , In severe cases, with intense RVFV replication in the liver, this heavily targeted organ becomes damaged, leading to jaundice and haemorrhagic disease.
      • Hartman A.
      Rift Valley fever.
      ,
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      ,
      • Javelle E.
      • Lesueur A.
      • Pommier De Santi V.
      • De Laval F.
      • Lefebvre T.
      • Holweck G.
      • et al.
      The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal.
      Both AST and ALT are elevated in these patients (>10 times ULN). Blood coagulation times are prolonged, and platelet counts and haemoglobin levels are reduced.
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      Mortality rates in these cases are high (50%).
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      ,
      • Javelle E.
      • Lesueur A.
      • Pommier De Santi V.
      • De Laval F.
      • Lefebvre T.
      • Holweck G.
      • et al.
      The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal.
      Next to the haemorrhagic syndrome, some patients die from (DIC) or renal failure.
      • Ikegami T.
      • Makino S.
      The pathogenesis of rift valley fever.

      Pathophysiology

      In mouse models, the liver serves as a primary site of RVFV replication (Fig. 2).
      • Smith D.R.
      • Steele K.E.
      • Shamblin J.
      • Honko A.
      • Johnson J.
      • Reed C.
      • et al.
      The pathogenesis of Rift Valley fever virus in the mouse model.
      Liver necrosis is seen in human autopsy studies and animal models.
      • Smith D.R.
      • Steele K.E.
      • Shamblin J.
      • Honko A.
      • Johnson J.
      • Reed C.
      • et al.
      The pathogenesis of Rift Valley fever virus in the mouse model.
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      • Gould L.H.
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      The presence of RVFV antigens in hepatocytes and Kupffer cells suggests direct virus-induced cellular necrosis.
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      • et al.
      Pathologic studies on suspect animal and human cases of Rift Valley fever from an outbreak in Eastern Africa, 2006-2007.
      The necrosis can be focal or diffused and involves the mid to central zones of the hepatic lobule.
      • Odendaal L.
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      • Venter E.H.
      Insights into the pathogenesis of viral haemorrhagic fever based on virus tropism and tissue lesions of natural Rift Valley fever.

      Diagnostics and treatment

      Surveillance and early detection of RVF outbreaks are important factors in limiting the burden imposed by the disease.
      • Wright D.
      • Kortekaas J.
      • Bowden T.A.
      • Warimwe G.M.
      Rift valley fever: biology and epidemiology.
      ,
      • Mansfield K.L.
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      • et al.
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      Viral load is high during its (acute) febrile phase, when RT-PCR can be used on serum samples to detect a RVF infection, in both humans and animals. Four days after infection, RVF IgM-antibodies are detectable using ELISA. After 8 days, IgG-antibodies are also present, but previous or convalescent samples will be needed to distinguish between past or current infection. A virus-neutralisation assay forms the gold standard for serological testing, in both humans and animals.
      • Mansfield K.L.
      • Banyard A.C.
      • McElhinney L.
      • Johnson N.
      • Horton D.L.
      • Hernández-Triana L.M.
      • et al.
      Rift Valley fever virus: a review of diagnosis and vaccination, and implications for emergence in Europe.
      Treatment of severe RVF cases is supportive because no therapeutics have been approved for RVF. Although in vitro results with ribavirin were promising, a clinical trial did not show efficacy in patients.
      • Javelle E.
      • Lesueur A.
      • Pommier De Santi V.
      • De Laval F.
      • Lefebvre T.
      • Holweck G.
      • et al.
      The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal.
      ,
      • Atkins C.
      • Freiberg A.N.
      Recent advances in the development of antiviral therapeutics for Rift Valley fever virus infection.
      Favipiravir is also highly effective in vitro and has been shown to protect rodents against acute hepatitis. However, it leads to more late-onset neurological complications in these animals. Several new agents targeting viral components or host cellular pathways have demonstrated antiviral effects against RVFV in vitro. Most of them have not yet been investigated in animal studies.
      • Atkins C.
      • Freiberg A.N.
      Recent advances in the development of antiviral therapeutics for Rift Valley fever virus infection.

      Prevention

      Outbreaks in livestock can be prevented by vaccines. Several inactivated or live-attenuated vaccines are available for veterinary use in endemic countries.
      • Mansfield K.L.
      • Banyard A.C.
      • McElhinney L.
      • Johnson N.
      • Horton D.L.
      • Hernández-Triana L.M.
      • et al.
      Rift Valley fever virus: a review of diagnosis and vaccination, and implications for emergence in Europe.
      ,
      • Dungu B.
      • Lubisi B.A.
      • Ikegami T.
      Rift Valley fever vaccines: current and future needs.
      Other vaccine types, such as subunit vaccines, DNA vaccines and virus-like particle vaccines
      • Mansfield K.L.
      • Banyard A.C.
      • McElhinney L.
      • Johnson N.
      • Horton D.L.
      • Hernández-Triana L.M.
      • et al.
      Rift Valley fever virus: a review of diagnosis and vaccination, and implications for emergence in Europe.
      ,
      • Dungu B.
      • Lubisi B.A.
      • Ikegami T.
      Rift Valley fever vaccines: current and future needs.
      are currently under development. Despite the availability of vaccines, defining effective vaccination strategies is challenging. Outbreaks typically occur at 10- to 20-year intervals, making regular and periodic vaccination campaigns economically unviable. Early-warning systems based on climate-prediction models, could be implemented in certain areas to prepare for outbreaks using targeted vaccination programmes. The development of multivalent vaccines, that protect against both RVF and other veterinary diseases, could be another approach to improving herd immunity.
      • Dungu B.
      • Lubisi B.A.
      • Ikegami T.
      Rift Valley fever vaccines: current and future needs.
      Insights into epidemiology, clinical signs and symptoms, diagnosis and, if available, the treatment of hepatitis in exotic viral infections are presented in this review. These insights can be of use to all clinicians.

      Yellow fever

      Yellow fever virus (YFV) belongs to the Flaviviridae family. The disease is endemic in (sub)tropical regions of Africa and South America
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.
      ,
      • Griffiths P.D.
      • Ellis D.S.
      • Zuckerman A.J.
      Other common types of viral hepatitis and exotic infections.
      (Fig. 1). It is thought that YFV originated several thousand years ago in Central Africa and was transferred via West-Africa to the Americas during the slave trade about 400 years ago.
      • Beck A.
      • Guzman H.
      • Li L.
      • Ellis B.
      • Tesh R.B.
      • Barrett A.D.
      Phylogeographic reconstruction of African yellow fever virus isolates indicates recent simultaneous dispersal into east and west Africa.
      ,
      • Bryant J.E.
      • Holmes E.C.
      • Barrett A.D.
      Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas.
      The clinical syndrome of YF varies from asymptomatic or mild flu-like symptoms to a severe acute illness with fever, hepatitis with jaundice, liver failure, renal failure, haemorrhage, cardiac injury, and shock. Among the 15% who develop severe illness, case fatality differs between 20-60%, with lower rates in Africa (around 20%) compared with South America (40-60%).
      • Tuboi S.H.
      • Costa Z.G.
      • da Costa Vasconcelos P.F.
      • Hatch D.
      Clinical and epidemiological characteristics of yellow fever in Brazil: analysis of reported cases 1998-2002.
      The global incidence of YF has been estimated at 200,000 cases per year, including around 30,000-60,000 deaths.
      • Bailey A.L.
      • Kang L.I.
      • De Assis Barros D'Elia Zanella L.G.F.
      • Silveira C.G.T.
      • Ho Y.L.
      • Foquet L.
      • et al.
      Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury.
      Despite the availability of a vaccine since 1936, YF still poses a major threat to public health.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.

      Transmission and host

      YFV is transmitted by the bite of infected mosquitoes, which causes a productive infection in human- and non-human primates. Two main transmission cycles have been identified: the sylvatic (jungle) cycle; and the urban cycle. In the sylvatic cycle, non-human primates serve as the main host and humans are occasionally infected when visiting these areas. In the urban cycle, YF is transmitted from human to human, mostly by the mosquito Aedes aegypti (Table 1). Although the exact epidemiology of yellow fever has yet to be unravelled, the following factors are associated with recent outbreaks: excessive rainfall, and/or prolonged rainy seasons; increases in average temperatures; deforestation; the colonisation of endemic areas by unvaccinated migrants; and an increase in long-distance travel.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.
      ,
      • Vasconcelos P.F.
      • Costa Z.G.
      • Travassos Da Rosa E.S.
      • Luna E.
      • Rodrigues S.G.
      • Barros V.L.
      • et al.
      Epidemic of jungle yellow fever in Brazil, 2000: implications of climatic alterations in disease spread.

      Clinical signs and symptoms

      Between 3-6 days after infection, the disease presents with fever- and flu-like symptoms, lasting for 3-5 days. This stage is followed by a period of remission (0.5-2 days). Unfortunately, in a significant number of patients, the disease will progress to the intoxication stage, characterised by fever and jaundice. This can further develop into multi-organ dysfunction with liver failure, kidney failure, haemorrhagic symptoms, and cardiovascular instability. In severe disease, patients suffer from jaundice and hepatomegaly. AST and ALT are raised (often >10 times ULN) and these are proportional to disease severity, with AST often exceeding ALT.
      • Tuboi S.H.
      • Costa Z.G.
      • da Costa Vasconcelos P.F.
      • Hatch D.
      Clinical and epidemiological characteristics of yellow fever in Brazil: analysis of reported cases 1998-2002.
      Additionally, increased bilirubin, thrombocytopenia, reduced coagulation factors, prolonged PT and aPTT, and increased D-dimers and fibrin degradation products (indicating DIC) are often present in really severe cases.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.
      ,
      • Quaresma J.A.
      • Pagliari C.
      • Medeiros D.B.
      • Duarte M.I.
      • Vasconcelos P.F.
      Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever.

      Pathophysiology

      After the inoculation of the YFV by a blood-feeding mosquito, dendritic cells transport the virus to draining lymph nodes. Following primary replication in these lymph nodes, the virus then spreads to several visceral organs and tissues (liver, myocardium, kidney, spleen, endothelium) where viral replication continues.
      • Monath T.P.
      • Barrett A.D.
      Pathogenesis and pathophysiology of yellow fever.
      Extensive hepatic involvement is characteristic of yellow fever. Pathological studies, mainly derived from animal models, have demonstrated intense injury in the midzonal area with steatosis, necrosis, and extensive apoptosis (Fig. 2). The reasons for this midzonal pattern are not fully understood. However, a multifactorial model has been hypothesised. Firstly, viral tropism for midzonal hepatocytes and the subsequent immune response, including the role of cytokines (especially transforming growth factor-β, which induces apoptosis of these hepatocytes), are considered important. Secondly, infectious vasculopathies, caused by viral tropism for endothelial cells and excessive cytokine release causing activation and consumption of clotting factors, can result in hypoxic cell injury.
      • Quaresma J.A.
      • Pagliari C.
      • Medeiros D.B.
      • Duarte M.I.
      • Vasconcelos P.F.
      Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever.
      • Monath T.P.
      • Barrett A.D.
      Pathogenesis and pathophysiology of yellow fever.
      • Quaresma J.A.
      • Duarte M.I.
      • Vasconcelos P.F.
      Midzonal lesions in yellow fever: a specific pattern of liver injury caused by direct virus action and in situ inflammatory response.
      • ter Meulen J.
      • Sakho M.
      • Koulemou K.
      • Magassouba N.
      • Bah A.
      • Preiser W.
      • et al.
      Activation of the cytokine network and unfavorable outcome in patients with yellow fever.

      Diagnostics and treatment

      Generally speaking, the diagnose of a YFV infection is through the detection of anti-YFV antibodies using IgM-ELISA. However, cross-reaction with other flaviviruses can occur. Quantitative RT-PCR can be used for a more accurate determination.
      • Escadafal C.
      • Faye O.
      • Sall A.A.
      • Faye O.
      • Weidmann M.
      • Strohmeier O.
      • et al.
      Rapid molecular assays for the detection of yellow fever virus in low-resource settings.
      ,
      • Kwallah A.
      • Inoue S.
      • Mulgai A.W.
      • Kubo T.
      • Sang R.
      • Morita K.
      • et al.
      A real-time reverse transcription loop-mediated isothermal amplification assay for the rapid detection of yellow fever virus.
      Treatment consists of supportive care.
      • de Freitas C.S.
      • Higa L.M.
      • Sacramento C.Q.
      • Ferreira A.C.
      • Reis P.A.
      • Delvecchio R.
      • et al.
      Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo.
      Some case reports have described successful liver transplantation in patients with yellow fever-related liver failure.
      • Vieira V.
      • Pacheco L.
      • Demetrio L.
      • Balbi E.
      • Bellinha T.
      • Toledo R.
      • et al.
      Liver transplantation for acute liver failure due to yellow fever: a case report.
      ,
      • Song A.T.W.
      • Abdala E.
      • de Martino R.B.
      • Malbouisson L.M.S.
      • Tanigawa R.Y.
      • Andrade G.M.
      • et al.
      Liver transplantation for fulminant hepatitis attributed to yellow fever.
      Ribavirin has been shown to be active against YFV in vitro and in rodent models, but studies in non-human primates have not been successful.
      • Monath T.P.
      Treatment of yellow fever.
      Recent studies have highlighted sofosbuvir, a direct-acting antiviral used against hepatitis C, as a possible novel therapeutic option. These studies relate to preclinical evidence (in vitro and in mice) and its compassionate use in 2 patients with yellow fever, both of whom had good clinical outcomes.
      • de Freitas C.S.
      • Higa L.M.
      • Sacramento C.Q.
      • Ferreira A.C.
      • Reis P.A.
      • Delvecchio R.
      • et al.
      Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo.
      ,
      • Mendes É.A.
      • Pilger D.R.B.
      • Santos Nastri A.C.S.
      • Malta F.M.
      • Pascoalino B.D.S.
      • Carneiro D'Albuquerque L.A.
      • et al.
      Sofosbuvir inhibits yellow fever virus in vitro and in patients with acute liver failure.
      Furthermore, a retrospective study suggested that the administration of a stress dose of corticosteroids, in order to treat the “cytokine storm”, might be associated with a lower mortality rate.
      • Vellozzi C.
      • Mitchell T.
      • Miller E.
      • Casey C.G.
      • Eidex R.B.
      • Hayes E.B.
      Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and corticosteroid therapy: eleven United States cases, 1996-2004.

      Prevention

      Although an effective vaccine had already been developed back in 1936, many people outside endemic regions have still not been vaccinated. Therefore, yellow fever still constitutes a serious threat, particularly in regions that already host the appropriate vector.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.

      Conclusion

      This narrative review describes the epidemiology, pathogenesis, and treatment of VHF viruses. We have also focused on the hepatic involvement of these viruses, as this can be a prominent symptom. Sometimes liver involvement is limited, as is the case with dengue, Ebola, Hanta and Lassa fever disease. However, extensive liver disease occurs in severe cases of CCHVF, RVF and yellow fever. Knowledge of these viruses can help clinicians, in both endemic and non-endemic areas, to make proper differential diagnoses and to apply adequate diagnostic methods. Travel history is important in non-endemic areas, where a disease will present shortly after return, due to the relatively short incubation times of VHF viruses. Liver enzyme levels will often be elevated and associated with disease severity. Unlike the “non-exotic” hepatitis viruses, such as (chronic) hepatitis B and C, AST typically exceeds ALT. It is hypothesised that this is caused by simultaneous damage to (cardio)myocytes.
      • Monath T.P.
      • Vasconcelos P.F.
      Yellow fever.
      PCR techniques on serum samples are important for diagnosis. Treatment is virtually always supportive and, in most cases, vaccines are still under development. It stands to reason therefore, that if we are to initiate the necessary measures to control outbreaks, the timely detection and recognition of these viruses is crucially important.

      Abbreviations

      ALF, acute liver failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CCHFV, Crimean-Congo haemorrhagic fever virus; CFR, case fatality rate; HCPS, Hantavirus cardiopulmonary syndrome; HFRS, haemorrhagic fever with renal syndrome; RT-PCR, reverse-transcription PCR; SEOV, Seoul Hantavirus; ULN, upper limit of normal; VHF, viral haemorrhagic fever; WHO, World Health Organization; YFV, yellow fever virus; ZEBOV, Zaire Ebola virus.

      Financial support

      The authors did not receive financial support for this project.

      Authors’ contributions

      LL: conceptualisation, literature search, writing original draft, figures, writing (review and editing). WJ: conceptualisation, writing original draft, writing (review and editing). LD: conceptualisation, writing original draft, writing (review and editing). EG: writing (review and editing). PW: writing original draft, writing (review and editing). MG: conceptualisation, writing original draft, writing (review and editing).

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors wish to thank Sabrina Meertens-Gunput from the Erasmus MC Medical Library for her help in developing the search strategies.

      Supplementary data

      The following are the supplementary data to this article:

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