Hemorrhagic Fevers PDF

Denumirea cartii | 1 Chapter 9.1. Tropical diseases 9.1.3. Haemorrhagic fever (HF) Haemorrhagic fevers comprise different viral infections, varying in epidemiological and evolutionary characteristics, whose common clinical manifestation is the haemorrhagic syndrome, present in se...

Denumirea cartii | 1 Chapter 9.1. Tropical diseases 9.1.3. Haemorrhagic fever (HF) Haemorrhagic fevers comprise different viral infections, varying in epidemiological and evolutionary characteristics, whose common clinical manifestation is the haemorrhagic syndrome, present in severe forms but absent in a significant proportion of cases. The aetiological agents are RNA genomic viruses, classified into four families; - Flaviviridae: yellow fever virus, dengue fever, Omsk and Kyasanur viruses - Bunyaviridae: Nairovirus (Crimean-Congo HF), Phlebovirus (Rift Valley HF), Hantaviruses (responsible for Hantavirus pulmonary syndrome or HF with renal syndrome) - Arenaviridae: Lassa (Lassa fever), Junin (Argentinean HF), Machupo (Bolivian HF), Guanarito (Venezuelan HF) - Filoviridae: Ebola, Marburg Epidemiology. The geographical distribution of HF is highly varied, sometimes even suggested by the name of the disease or the aetiological agent. However, most illnesses occur in warm, tropical or subtropical climates. Cases of haemorrhagic fever are also reported on the European continent. Many are ‘imported’ cases in travellers returning from tropical areas. Still, there are also HFs endemic in Europe - e.g. Hantavirus Puumala in Central and Western Europe, Scandinavia, Western Russia, Nairovirus (Crimean-Congo HF) in the Balkans, Turkey and Russia. There are fears that climate change, affecting the animal reservoir and vectors (arthropods) of these viruses, will increase the number of cases worldwide. Dengue fever is widespread in Africa, America (North, South and Central), Southeast Asia and the western Pacific islands. Ebola HF (2022 - Democratic Republic of Congo, Uganda), Marburg (2023 - Tanzania, Equatorial Guinea) and Lassa (Nigeria, Sierra Leone, Liberia, Benin) have been reported mainly on the African continent. Yellow fever is endemic in parts of Africa and South America, while Crimean-Congo HF is viral in Africa, Asia, the Middle 2 | Denumirea cartii sau a sectiunii/capitolului East and the Balkans. Hantaviruses reported on the American continent are mainly responsible for a high-severity pulmonary syndrome, while in Europe and Asia, they are involved in hemorrhagic fever with renal syndrome (HFRS). The reservoir of infection is animal - rodents for Lassa and Hantaviruses, bats and primates for Ebola and Marburg, or humans (dengue fever). Transmission can occur through direct contact with infected animals (rodent bite - Hantaviruses), their urine, saliva or faeces (rodents, bats - Lassa, Hantaviruses) or indirectly through objects/food contaminated with the droppings of sick animals, i.e. airborne (inhalation of aerosolised urine/faeces particles - Hantaviruses, Arenaviridae). In addition, human-to-human transmission is possible in the case of Lassa, Ebola or Marburg viruses through direct contact with infected blood, tissues or fluids (urine, faeces, saliva, sputum) or by sexual transmission (Ebola virus can persist for two years in people’s semen who have experienced the disease). Indirect transmission through contaminated objects has also been reported for Ebola and Marburg. Medical staff and close contacts with family patients are essential risk groups. Some of the aetiological agents are arboviruses, which require insect vectors for animal-to-human transmission - ticks (Nairovirus, HF Omsk virus, Kyasanur) or Aedes mosquitoes (amaryllis virus, dengue fever virus). Four closely related viruses cause dengue infections, and post- infection immunity protects only against the serotype with which the patient has previously come into contact. In addition, a second infection with the dengue fever virus, with a different serotype, is responsible for a much more severe illness, usually accompanied by haemorrhagic syndrome (severity favoured by the presence of non-neutralising antibodies resulting from the previous infection). Yellow fever usually results in long-lasting immunity after the illness. Yellow fever vaccination elicits a sustained immune response in over 95% of subjects, with boosters recommended at 10-year intervals, although post-vaccine immunity is likely to last a lifetime in most individuals. Ebola survivors have been shown to have antibodies directed against the infecting virus serotype ten years after the initial illness. Still, it has not yet been established whether lifelong immunity or reinfection with another serotype is possible. Pathogenesis. After penetrating the host organism at the skin or mucosal level, the pathogen agent infects and replicates in dendritic cells and  Denumirea cartii | 3 macrophages and is subsequently transported to the lymph nodes in parallel with systemic dissemination. Due to infection of the liver parenchyma, impaired liver function contributes to a shortage of clotting factors aggravating the haemorrhagic syndrome. At the same time, damage to the adrenal glands is associated with deterioration of blood pressure values. On the one hand, T lymphocyte activation is inhibited, significantly reducing the effective immune response that could control viral infection. On the other hand, macrophage infection is the first step in releasing mediators that will generate an actual “cytokine storm”, resulting in vascular endothelial disruption, vasoplegia, hypotension, shock and disseminated intravascular coagulation. Clinical picture. Incubation is usually between 3-7 days for most haemorrhagic fevers but can be longer: up to 21 days for Lassa, Marburg and Ebola, 1-2, maximum 8 weeks for Hantaviruses. The severity of illness is highly varied - most cases are asymptomatic or mild with fever and flu-like syndrome - myalgia, arthralgia, asthenia, pharyngeal pain, retroorbital pain, sometimes nausea, vomiting (digestive symptoms more common in Ebola), conjunctival or facial hyperemia. In severe forms, in the second phase of the disease, 3-7-14 days after onset, haemorrhagic syndrome (bruising, purpura, epistaxis, gingivorrhagia, hematemesis, melena), shock and multiple organ failure - renal, hepatic, cardiovascular, central nervous system damage may occur. A maculopapular erythematous rash is described in some HF - Lassa, Ebola and dengue fever. In Lassa HF, the rash is transient, accompanied by pharyngeal pain, adenopathy, and a prolonged febrile syndrome - 1-3 weeks. In Ebola, the rash initially appears on the face with subsequent extension; digestive symptoms - diarrhoea, vomiting, abdominal pain and respiratory symptoms - dry cough, and chest pain, are common, and objective examination reveals hepatosplenomegaly and profuse haemorrhages. In dengue fever, the rash initially appears on the trunk, then spreads to the face and limbs, with subsequent desquamation. Yellow fever has a biphasic course. In the first stage, which lasts 4-5 days, the patient presents with a flu-like syndrome with myalgia, headache, arthralgia, epigastralgia, facial and conjunctival hyperemia, relative bradycardia (Faget’s sign), accompanied by high fever. In most cases, the clinical picture is limited to the initial phase. In severe forms, after an 4 | Denumirea cartii sau a sectiunii/capitolului apparent improvement lasting hours to days, the second phase - toxic - follows, in which fever reappears, the initial symptoms worsen, and acute liver failure occurs, resulting in jaundice and haemorrhagic syndrome. Finally, renal failure with oliguria and albuminuria, shock, metabolic acidosis, myocardial dysfunction and altered consciousness - coma, followed by death - may occur. Rift Valley Fever also has a biphasic course - two symptomatic, febrile stages separated by a brief improvement period. Complications seen in severe forms include meningoencephalitis, retinopathy, hepatic necrosis and haemorrhagic syndrome. Hantaviruses are responsible for two distinct clinical entities - Hantavirus pulmonary syndrome, characterised by acute respiratory failure, more commonly reported in America, and HF with renal syndrome, renal failure, and oliguria, described primarily in Europe and Asia. Evolution. Although most of these viral infections are mild or even asymptomatic, the severity of the disease varies widely, depending on both host characteristics (e.g. the haemorrhagic form of dengue fever is more common in children, females and Caucasians), and the pathogen-mortality ranges from 1-2% for Lassa HF (15-20% for hospitalised and pregnant patients in the third trimester), 5-30% for Crimean-Congo HF, 1-5% Rift Valley HF (50% of severe forms), 20-80% for Marburg virus infection and 40- 90% for Ebola. 50% of patients with toxic conditions of yellow fever die. Death in HF usually occurs due to hypovolemic shock or multiple organ failure. Survivors of severe forms of HF may experience sequelae, especially neurosensory or prolonged asthenia. Diagnosis. Epidemiological data raise suspicion of HF - travel to endemic areas, contact with animal/human reservoir of infection, and the bite of arthropod vectors. The clinical picture may initially be uncharacteristic - fever and flu-like syndrome, in some cases exanthema. Shock and multiple organ failure may also occur in severe forms of haemorrhagic syndrome. Laboratory confirmation can be achieved by Immunofluorescence Assay for Detection of Immunoglobulin M (IgM) antibodies, detection of viral antigens, or identification of the virus (in cell culture) or viral genome (by RT- PCR) from blood or other biological fluids.  Denumirea cartii | 5 Differential diagnosis: influenza (in the first phase of HF), malaria, typhoid fever, leptospirosis, rickettsiosis, meningococcemia, acute viral hepatitis (A-E). Treatment is primarily supportive and symptomatic. Vital function support, shock correction and hydro-electrolyte rebalancing are at the forefront. For haemodynamic and respiratory support, vasopressors and oxygen therapy may be required. Correction of haemorrhagic syndrome requires transfusions of fresh frozen plasma, thrombocyte mass, and vitamin K. Symptomatic treatment includes antipyretics, antiemetics, and analgesics. Isolation and bed rest are recommended. Antibiotics are only necessary in case of bacterial superinfection. Aetiological therapy is only available in a minority of all types of HF. Two preparations containing monoclonal antibodies (Inmazeb = atoltivimab + maftivimab + odesivimab-ebgn, respectively Ebanga = ansuvimab-zykl) directed against the glycoprotein of the Ebola virus Zair, to block virus penetration into host cells, help reduce mortality in adult and paediatric populations in case of early initiation after disease onset. Other antiviral agents, such as remdesivir and favipiravir, have also been studied but are not currently recommended by the World Health Organisation (WHO) for treating Ebola. Some studies have shown the efficacy of early-initiated ribavirin in treating Lassa, Crimean-Congo and Hantavirus infections. Prevention. Non-specific prophylactic measures are essential. HF are notifiable disease by public health authorities. Patients should be isolated, ideally in negative pressure rooms (isolation rooms). In the case of human-to- human transmission of HF, medical staff must use complete disposable personal protective equipment (FFP2 or FFP3 mask, gloves, goggles/face shield, waterproof gown/suit, hood, and rubber boots). In the case of vector- borne transmission, measures must be taken to prevent it - e.g. mosquito nets in wards. Avoid contact with the animal reservoir of viruses (rodents, primates, bats), wear long-sleeved clothing and trousers, and use insect repellents on the skin (DEET) and apparel (DEET, permethrin), including during the day (when Aedes mosquitoes are most active), mosquito nets on windows and sleeping areas. 6 | Denumirea cartii sau a sectiunii/capitolului There is no specific prophylaxis for most HF. Yellow fever vaccination with live attenuated virus vaccine (not recommended for infants under 9 months, pregnant women and the immunosuppressed) provides sustained immunity for most susceptible populations; boosters are recommended every 10 years for those with repeated exposure and travel to endemic areas. Dengue fever vaccine (3 doses every 6 months) directed against the 4 viral serotypes is recommended for people living/travelling in endemic areas who have already experienced an episode of dengue fever, as it is known that the second infection is usually of high severity. In addition, there are 2 Zair Ebola vaccines - Ervebo (single dose for adults, used in the 2018-2020 Democratic Republic of Congo Ebola outbreak) and Zabdeno-and-Mvabea (over age 1, 2 doses 8 weeks apart). Bibliography 1. Barlow G, Irving W, Moss P. Viral hemorrhagic fevers. În Feather A, Randall D, Waterhouse M. Kumar & Clark’s Clinical Medicine. Elsevier, ediția a X-a, 2021, pag 531-533. 2. Basler CF. Molecular pathogenesis of viral hemorrhagic fever. Semin Immunopathol. 2017 Jul; 39(5): 551-561 3. Debord T. Fievres hemorrhagiques virales. În Pilly E. Maladies infectieuses et tropicales. Allinea Plus, Paris, 2020, pag 494-496. 4. Hristea A, Streinu-Cercel A. Febra denga. În Hristea A, Streinu- Cercel A. Bolile infecțioase asociate călătoriilor internaționale. Editura Medicală, București, 2010, pag 25-28. 5. Hristea A, Streinu-Cercel A. Febra galbenă. În Hristea A, Streinu- Cercel A. Bolile infecțioase asociate călătoriilor internaționale. Editura Medicală, București, 2010, pag 28-32. 6. Kuhn J. Ebolavirus and Marburgvirus infections. În Hasper D, Fauci A. Harrison’s Infectious Diseases. McGraw Hill Education, ediția a III-a, 2017, pag 971-977 7. Penalba C, Galenpoix JM. Infections a Hantavirus en France. În Pilly E. Maladies infectieuses et tropicales. Allinea Plus, Paris, 2020, pag 497-498  Denumirea cartii | 7 8. www.cdc.gov 9. www.who.int