Overview of viral haemorrhagic fevers with focus on Lassa fever.pptx

An African view point on paediatric management of Lassa Fever

1. Viral Haemorrhagic fevers with focus on Lassa Fever

2. Introduction Viral hemorrhagic fevers are a loosely defined group of clinical syndromes in which hemorrhagic manifestations are either common or especially notable in severe illness. Both the etiologic agents and clinical features of the syndromes differ, but coagulopathy may be a common pathogenetic feature

3. aetiology They are RNA viruses, meaning viruses that have ribonucleic acid (RNA) as their genetic material. These viruses are the most common cause of emerging disease in people because RNA viruses change over time at a high rate. They are covered, or enveloped, in a lipoprotein outer layer, making it easier to destroy these viruses with physical (heat, sunlight, gamma rays) and chemical (bleach, detergents, solvents) methods. They naturally exist in animal or insect populations, referred to as  host populations , and are generally restricted to the geographical areas where the host species live. They spread to people when a person encounters an infected animal or insect host. After the initial spread into the human population, some VHF viruses can continue to spread from person-to-person. Outbreaks of VHFs in people can be difficult to prevent since they can occur sporadically and cannot be easily predicted.

4. Pathophysiology The primary defect in patients with viral hemorrhagic fever (VHF) is that of increased vascular permeability. Hemorrhagic fever viruses have an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias . Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse.

5. In acute disease, patients are extremely viremic , and messenger ribonucleic acid (mRNA) evidence of multiple cytokine activation exists. In vitro studies reveal these cytokines lead to shock and increased vascular permeability, the basic pathophysiologic processes most often seen in viral hemorrhagic fever infection. Another prominent pathologic feature is pronounced macrophage involvement. Inadequate or delayed immune response to these novel viral antigens may lead to rapid development of overwhelming viremia . Extensive infection and necrosis of affected organs also are described. Hemorrhagic complications are multifactorial and are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes. 

6. Multisystem organ failure affecting the hematopoietic, neurologic, and pulmonary systems often accompanies the vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, Crimean-Congo hemorrhagic fever (CCHF), and yellow fever. Acute kidney injury with oliguria is a prominent feature of hemorrhagic fever with renal syndrome (HFRS) seen in Hantavirus infection and may be seen in other VHFs as intravascular volume depletion becomes more pronounced. Bleeding complications are particularly prominent with Ebola, Marburg, CCHF, and the South American arenaviruses .

7. Virus Family Disease (Virus) Natural Distribution Usual Source of Human Infection Incubation (Days) Arenaviridae         Arenavirus Lassa fever Africa Rodent 5-16   Argentine HF (Junin) South America Rodent 7-14   Bolivian HF (Machupo) South America Rodent 9-15   Brazilian HF (Sabia) South America Rodent 7-14   Venezuelan HF (Guanarito) South America Rodent 7-14 Bunyaviridae         Phlebovirus Rift Valley fever Africa Mosquito 2-5 Nairovirus Crimean-Congo HF Europe, Asia, Africa Tick 3-12 Hantavirus Hemorrhagic fever with renal syndrome, Hantavirus pulmonary syndrome Asia, Europe, worldwide Rodent 9-35 Filoviridae         Filovirus Marburg and Ebola Africa Fruit bat 2-21 Flaviviridae         Flavivirus Yellow fever Tropical Africa, South America Mosquito 3-6   Dengue HF Asia, Americas, Africa Mosquito Unknown for dengue HF, 5-7 for dengue

8. Lassa Fever

9. Introduction Lassa fever was first discovered in 1969 in Nigeria following the death of two missionary nurses in Lassa town, Borno State. In Nigeria, Lassa fever is one of the seven epidemic prone notifiable diseases reportable under the Integrated Disease Surveillance System (IDSR), a suspected case is considered an alert threshold and one confirmed case an epidemic threshold.

10. Epidemiology The disease is endemic in West Africa countries of Sierra-Leone, Liberia, Guinea and Nigeria where about 300,000 to 400,000 cases occur annually with approximately 5,000 deaths. Most cases are reported in the “Lassa belt” of western Africa. In Guinea, Liberia, Nigeria, and Sierra Leone, cases are considered to be hyperendemic , and cases have been reported in Benin, Ghana, Mali, and Togo. The disease is endemic in 3 states in Nigeria – Ondo , Edo and Bauchi The disease is also has the tendency to cause epidemics Outbreaks in Africa occur primarily in the dry season (November to April), and 338 suspected cases were reported in the first half of 2017 in Nigeria.

11. Children under age 10 years are considered most vulnerable, with 1 study showing 15% seropositivity for Lassa virus in that population in West Africa. In a study carried out in Irrua specialist teaching Hospital, Benin by Akpede et al to study the trend of Lassa fever from 2001-2018, it accounted for about 0.3% of all admissions in 2001 which steadily rose to 3.4% in 2018 The annual CF declined from 94% in 2001 to 15% in 2018

12. In another study by Dalhat et al in Nigeria, the disease pattern was studied from 2018 to 2021. There were a total of 3,162 confimed cases with 550 mortalities (CFR – 17.4%) 418 of the cases and 70 of the mortalities were children and adolescents (CFR – 16.7%) Bulk of the cases were in the 1 st quarter of the year Male gender, age under 5 years and elderly were found to have worse case fatality rates

13. Aetiology Lassa fever is caused by Lassa virus, an RNA virus from the Arenaviridae family The incubation period is 7- 21 days

14. Transmission The Lassa virus reservoir is Mastomys natalensis or the multimammate rat. These rats are primarily found in west and central Africa and are attracted to houses in rural areas where they seek out accessible food sources. The virus is shed in the rodents’ urine and feces and then can be transmitted from rats to humans through contact with these materials via inhalation of the virus or direct contact with open cuts or sores on humans. Butchering and preparation of rats for cooking are believed to be another route of transmission. The virus is spread from human to human by direct contact with body fluids from symptomatically infected individuals or corpses. Nosocomial outbreaks have been reported.

15. Clinical presentation Range from asymptomatic to viral haemorrhagic fever and death The onset of the disease, when symptomatic, is usually gradual, starting with fever, general weakness, and malaise. After a few days, headache, sore throat, muscle pain, chest pain, nausea, vomiting, diarrhoea , cough, and abdominal pain may follow. In severe cases facial swelling, pleural effusion, mucosal bleeding. Proteinuria may occur. Shock, seizures, tremor, disorientation, and coma may be seen in the later stages. Deafness occurs in 25% of patients who survive the disease. In half of these cases, hearing returns partially after 1–3 months. Transient hair loss and gait disturbance may occur during recovery. Death usually occurs within 14 days of onset in fatal cases. The disease is especially severe late in pregnancy, with maternal death and/or fetal loss occurring in more than 80% of cases during the third trimester.

16. STAGE SYMPTOMS 1 (days1-3) General weakness and malaise. High fever > 39°C, constant with peaks of 40-41°C 2 (days4-7) Sore throat (with white exudative patches) very common; headache; back, chest, side, or abdominal pain; conjunctivitis; nausea and vomiting; diarrhea; productive cough; proteinuria; hypotension (systolic < 100 mm Hg); anemia 3 (after7 days) Facial edema; convulsions; mucosal bleeding (mouth, nose, eyes); internal bleeding; confusion or disorientation 4 (after14 days) Coma and death

17. DIAGNOSIS Lassa virus infections can only be diagnosed definitively in the laboratory using the following tests: Reverse transcriptase polymerase chain reaction (RT-PCR) assay antibody enzyme-linked immunosorbent assay (ELISA) antigen detection tests virus isolation by cell culture.

18. Supportive investigations FBC + diff E/U/Cr Clotting profile Liver function tests Abdominopelvic USS Brain imaging Chest x-ray urinalysis Audiology

19. Case definition ALERT CASE Any person who has an unexplained fever (i.e., malaria and other common causes of fever have been ruled out), with or without bleeding. OR Any person who died after an unexplained severe illness with fever and bleeding.

20. SUSPECTED CASE Patient with fever for 3-21 days with a measured temperature of 38OC or more with one or more of the following: vomiting, diarrhea, sore throat, myalgia (muscle pain), generalized body weakness, abnormal bleeding, abdominal pain. In Neonates: Maternal Lassa fever +/- signs and symptoms Patient has not responded to standard anti-malaria treatment and treatment for other common infectious causes of fever within 48-72 hours History of recent contact with a probable or confirmed case of Lassa fever within 21 days of onset of fever Patient with history of fever and history of travel to high risk/burden area of Lassa fever Contact with body fluids or tissues of a dead patient with a febrile illness, symptoms and signs highly suggestive of Lassa fever leading to death.

21. PROBABLE CASE A suspected case who has one or more of the following - Hearing loss, Facial or neck swelling, Seizures, Restlessness, Confusion, Hypotension (SBP< 90mmHg in adults and <70mmHg in children) Oliguria (<0.5ml/kg/h for 6 hours), Abnormal bleeding and ANY of the following supporting laboratory features: Proteinuria and/or microscopic hematuria Elevated urea ≥ 45 mg/dl or creatinine ≥ 2 mg Elevated transaminases (liver enzymes, ALT & AST) Reduced platelets count ≤ 90,000 cells/ml3

22. CONFIRMED CASE A suspected or probable case with a positive laboratory test using real time polymerase chain reaction

23. MANAGEMENT Begins with triaging case definition into suspected, probable and confirmed Clinical Screening Criteria Fever more than 48hrs but less than 3 weeks Any symptoms: sore throat, malaise, cough nausea, vomiting diarrhea, retrosternal pain, hearing loss or a woman with abnormal vaginal bleeding; OR Any complications, such as encephalopathy (seizure, coma, irritability, confusion), shock, bleeding, Acute Kidney Injury, spontaneous abortion Travel to an endemic area less than 21 days AND contact with rodents History of contact with Lassa Fever patient less than 21 days before presentation

24. Initial management of suspected case Put patient in a holding area and institute infection prevention measures Alert the relevant authorities: infectious disease team or responsible physician Notify relevant public health authorities e.g. State Epidemiologist, LGA Disease Surveillance and Notification Officer) Start rehydration. Commence Fluid therapy Monitor vital signs every 4 hours (Pulse Rate, Blood Pressure, Respiratory Rate, Temperature) Monitor Urinary output

25. Initial management of probable case Initial step for suspected case Transfer patient to suspect bay of the treatment unit/centre Commence supportive care Start treatment with Ribavirin. Assess Patient for possible complications and manage accordingly Review Ribavirin treatment with PCR result. If PCR is negative, continuation of treatment with Ribavirin is at the discretion of the Managing Physician

26. Initial management of confirmed case Transfer patient to the treatment unit/centre Commence supportive care Continue treatment with Ribavirin if patient has been on it prior to confirmation Start treatment with Ribavirin, if patient is newly confirmed for Lassa fever Assess patient for possible complications and manage accordingly

27. Definitive treatment - Ribavirin

28. Precautions to ensure in Lassa fever Strict infection and prevention control NSAIDS are contraindicated due to risk of bleeding Avoid intramuscular injections to prevent hematoma formation Use cotton wool to clean the mouth of patients instead of hard toothbrush Any skin ulcers must be cleaned and dressed gently Avoid nasogastric tube, urinary catheter insertion unless strongly indicated DO NOT remove old blood clots from previous bleeding sites. NEVER RECAP needles. Do not enter a patient’s room or get in contact with a patient with suspected or confirmed Lassa fever without putting on full PPE.

29. Complications Acute kidney injury (AKI) Severe dehydration (from vomiting or diarrhoea ) Sepsis/septic shock Encephalopathy Acute Respiratory Failure Severe Bleeding/ Anaemia

30. Anaemia and haemorrhage Recognize massive bleeding (evidenced by cardiorespiratory decompression tachycardia, bounding pulse, hypotension, breathlessness and features of heart failure to guide further intervention) Pressure packing to control bleeding Tranexamic acid @ 10mg/kg IV Vitamin K 5mg stat then 1-3mg dly for 5 days Secure IV access using 2 large bore cannula Collect blood samples for grouping and cross-matching Give Oxygen if SpO2 is <94% Transfuse pack cells at a dose of 15-20mls/kg in pediatric patients,

31. Give crystalloid fluid and start transfusion with packed red blood cells (PRBC), platelets and plasma according to national transfusion policies Consider transfusion of other blood products Platelet –over 30-60min per unit FFP-at a dose of 15ml/kg over 30-60 min Cryoprecipitate a dose of 15ml/kg over 30-60 min

32. Management of AKI Recognize AKI Secure IV Access Correct shock with crystalloid fluids (+/- vasopressors) Avoid nephrotoxic agents Correct electrolyte disorders Consider dialysis if indication(s) established

33. Severe dehydration and Shock Early recognition of severe dehydration and shock Patient should be commenced on oxygen Administer IV Fluids R/Lactate or Normal Saline at 20mls/kg bolus. Can be repeated up to 3 times If there is no response GXM 15-20mls of whole blood to transfuse

34. Sepsis and septic shock Recognize septic shock Start oxygen therapy Place IV access and administer targeted resuscitation with crystalloid fluids (+/- vasopressors).

35. Encephalopathy Recognize neurologic emergencies Secure IV access Correct glucose and electrolyte abnormalities Treat seizures if present Correct shock with crystalloid fluids +/- vasopressors Avoid unnecessary sedatives unless there is absolute indication(s)

36. Respiratory failure Airway management – suction and clear secretions High flow oxygen therapy Intubation followed by lung protective ventilation If there are effusions – chest tube

37. Contacts Tracing Any person who has been exposed to an infected person, or to an infected person’s secretions, excretions, or tissues within three weeks of last contact with a confirmed or probable case of Lassa fever Categorized into - Category 1: No-risk Category 2: Low-risk Category 3: High-risk

38. Category 1 – No direct contact with the patient or body fluids Casual contact,e.g.,sharing a room with the patient, without direct contact with body fluids or other potentially infectious material. Handling of laboratory specimens under contained conditions Action – monitor closely for 21 days

39. Category 2 Direct contact with the patient, e.g.,routine medical/nursing care, while wearing appropriate PPE Handling body fluids wearing appropriate personal protective equipment Breach of laboratory containment without direct contact with specimen Action – monitor closely for 21 days

40. Category 3 Unprotected exposure of broken skin or mucous membranes to potentially infectious blood or body fluids and secretions (including splash injury) clothing and bedding. This includes: unprotected handling of clinical/laboratory specimens; mucosal exposure to splashes; penetration of skin by contaminated sharp instrument e.g. needle-stick injury and kissing and/or sexual contact; breastfeeding. HCWs involved in emergency/exposure prone procedures i.e. surgery/CPR/ intubation /suctioning on confirmed cases and without use of appropriate PPE. Prolonged (i.e. for hours) and continuous contact in an enclosed space without use of appropriate PPE Infant of a RT-PCR Lassa virus positive mother

41. Action Commence PEP and monitor patients Ribavirin at 500mg 6 hrly for 7 days Alternatively 100mg/kg stat not to exceed 2.64g Conduct a RT-PCR for Lassa virus if they develop signs and symptoms of Lassa fever

42. Prevention General Health Promotion Environmental sanitation Hand hygiene Health education Specific protection Isolation of suspected cases Avoiding contact with Mastomys Rodents Use of rodent proof cntainers Elimination of rodents where possible

43. Early diagnosis and prompt treatment Isolation of suspected cases Confirm diagnosis using PCR Administration of Ribavirin Adequate Fluid, calories and electrolyte replacement

44. Limitation of disability Cardiovascular support Haematologic support Renal support Respiratory support GIT support CNS support

45. Rehabilitation Hearing aids for those with hearing loss Renal replacement therapy Speech therapy Occupational therapy

46. CONCLUSION

47. REFERENCES Dalhat MM, Olayinka A, Meremikwu MM, Dan- Nwafor C, Iniobong A, Ntoimo LF et al. Epidemiological trends of Lassa fever in Nigeria, 2018-2021. PLoS One. 2022 Dec 30;17(12):e0279467. doi : 10.1371/journal.pone.0279467. PMID: 36584167; PMCID: PMC9803109. Robert JS, Troy DM, Joseph RS, Foday A, Michael G, Augustine G et al. Lassa Fever among Children in Eastern Province, Sierra Leone: A 7-year Retrospective Analysis (2012–2018). Am. J. Trop. Med. Hyg ., 104(2), 2021, pp. 585–592 doi:10.4269/ajtmh.20-0773

48. Akpede GO, Asogun DA, Okogbenin SA, Dawodu SO, Momoh MO, Dongo AE et al. Caseload and Case Fatality of Lassa Fever in Nigeria, 2001–2018: A Specialist Center’s Experience and Its Implications. Front. Public Health 7:170. doi : 10.3389/fpubh.2019.00170 Greenky D, Knust B, Dziuban EJ. What Pediatricians Should Know About Lassa Virus. JAMA Pediatr . 2018 May 01; 172(5): 407–408. doi:10.1001/jamapediatrics.2017.5223 Kliegman RM, St Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, Behrman RE ( ed ). Nelson Textbook of Paediatrics. 21 st edition. Philadelphia, Elsevier Inc ; 2020

49. Nigerian centre for disease control National guideline for management of Lassa Fever. Published November 2018 WHO fact sheet on Lassa Fever. Published on 31 st July, 2017 CDC fact sheet on Lassa Fever. Published on 26 th April, 2022