1. LASSA FEVER AND OTHER HEMORRHAGIC FEVERS. EMEKA NWOLISA. MBBS;FWACP(PAED);MNIM;MSM.

2. Introduction.  The viral haemorrhagic fevers (VHFs) are a diverse group of diseases in which fever and hemorrhage are caused by a viral infection.  All types of VHF are characterized by fever and bleeding disorders and all can progress to high grade fever, shock and death in many cases.

3.  Five families of RNA viruses have been recognised as being able to cause hemorrhagic fevers.  The family Arenaviridae include the virus responsible for Lassa fever.  The family Bunyaviridae include the members of the Hantavirus genus that cause hemorrhagic fever with renal syndrome (HFRS), the Crimean-Congo hemorrhagic fever (CCHF).  Classes.

4. Families.  The family Filoviridae include Ebola virus and Marburg virus.  The family Flaviviridae include dengue, yellow fever, and two viruses in the tick-borne encephalitis group that cause VHF.

5. The families share the following in common  They are all RNA viruses  Enveloped in a fatty (lipid) coating.  Survival is dependent on an animal or insect host which is known as the natural reservoir.  The viruses are geographically restricted to the areas where their host species live.

6. Common features  Humans are not the natural reservoir for any of these viruses.  Humans are infected when they come into contact with infected hosts.  With some after the accidental transmission from the host, humans can transmit the virus to one another. `

7. Common features contd.  Outbreaks sporadically and irregularly.  The occurrence of outbreaks cannot be easily predicted.  With a few noteworthy exceptions, there is no cure or established drug treatment for VHFs.

8.  Viruses associated with most VHFs are zoonotic as they naturally reside in an animal reservoir host or arthropod vector.  They are totally dependent on their hosts for replication and overall survival.  For the most part, rodents and arthropods are the main reservoirs for viruses causing VHFs.

9. Vectors/reservoir.  The multimammate rat, cotton rat, deer mouse, house mouse, and other field rodents are examples of reservoir hosts.  Arthropod ticks and mosquitoes serve as vectors for some of the illnesses.  However, the hosts of some viruses remain unknown.

10. Mode of transmission.  Viruses causing hemorrhagic fever are initially transmitted to humans when the activities of infected reservoir hosts or vectors and humans overlap.  The viruses carried in rodent reservoirs are transmitted when humans have contact with urine, fecal matter, saliva, or other body excretions from infected rodents.

11. Mode of transmission.  The viruses associated with arthropod vectors are spread most often when the vector mosquito or tick bites a human, or when a human crushes a tick.  However, some of these vectors may spread virus to animals, livestock, for example. Humans then become infected when they care for or slaughter the animals.

12. Mode of transmission.  Some viruses that cause hemorrhagic fever can spread from one person to another, once an index person has become infected.  Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses are examples.  This type of secondary transmission of the virus can occur directly, through close contact with infected people or their body fluids.

13.  It can also occur indirectly, through contact with objects contaminated with infected body fluids.  Within the health sector contaminated syringes and needles have played important roles in spreading infection in outbreaks of Ebola hemorrhagic fever and the current Lassa fever.

14. Symptoms of viral hemorrhagic fever  Specific signs and symptoms vary by the type of VHF, but initial signs and symptoms often include marked fever, fatigue, dizziness, muscle aches and weakness.  Patients with severe cases of VHF often have bleeding in internal organs, or from body orifices like the mouth, eyes, or ears.

15.  In spite of this bleeding patient rarely die because of blood loss.  Severely ill patient cases may develop shock,coma, and seizures.  Some types of VHF are associated with acute renal failure

16. Lassa fever.  Lassa fever or Lassa hemorrhagic fever (LHF) is an acute viral hemorrhagic fever caused by the Lassa virus and first described in 1969 in the town of Lassa, in Borno State, Nigeria.  Lassa town is in Askira/Uba local government council.  Though the etiologic agent of Lassa fever was first described in the 1950s, it was not identified until 1969 when two missionary nurses became infected and died while working in the town of Lassa

17. introduction  Lassa frequently infects people in West Africa. There are about 300,000 to 500,000 cases annually with about 5,000 deaths.  Outbreaks of the disease have been documented in Nigeria, Liberia, Sierra Leone, Guinea, and the Central African Republic.

18. Distribution of Lassa fever

19. Current outbreak in Nigeria. States currently affected; Niger, lagos,Ekiti, FCT, Kaduna, Rivers,Kano, Bauchi,, Nasarawa, Niger, Taraba, Edo and Oyo.

20. Current status.  Present outbreak in Nigeria began Since August 2015 in Niger state.  In Lagos 20 suspected cases, 14 tested negative, 4 positive and 2 pending.  537 contacts of confirmed cases are been followed.  534 contacts of their contacts are been monitored,

21.  Last night a news media reported that there has been about 100 deaths as at 29/1/2016.  At least 25 people were diagnosed with Lassa fever in Nigeria's Edo state between 2005 and 2008.  Sadly health professionals are involved

22. Host.  The primary animal host of the Lassa virus is the Natal multimammate mouse (Mastomys natalensis), an animal found in most of sub-Saharan Africa  Mastomys natalensis is commonly known as the “multimammate rat” due to the female’s multiple and prominent mammary glands

23. Pictures of the host.

24. Factors contributing to the Lassa virus infection.  The hosts of the Lassa virus live inside houses with people, where they can shed the virus.  In addition, M.natalensis breed very frequently and they can infect their offspring at the time of birth.  This results in a chain of infection from virus to host and from host to people

25. Structure of Lassa virus Lassa virus is spherical and has dimensions of about 110-130 nm. Its helical capsid, containing RNA, is enveloped in a lipid membrane. Its surface is rough due to ribosomes acquired from their host cells.

26.  The genome of Lassa virus consists of a single-stranded RNA sequence, which consists of two segments: the small and large segments.  The small RNA segment encodes nucleoprotein (NP) and a glycoprotein precursor (GPC) while the large RNA segment encodes viral polymerase and zinc binding proteins.

27. Picture of Lassa fever virus

28.  After translation, the GPC is split into GP1 and GP2. Although the replication mechanism of Lassa virus is not completely known, it is understood that new viruses arise by budding from the surface of their host cells.  The virus encounters the host cell by binding to cellular receptors via GP1. The virus envelope fuses to the host cell and enters the cell forming a vesicle.

29.  Once inside, the endosome is acidified leading to the ejection of NP from the virus and starting replication. Once NP is expressed, the small and large segments replicate.  GPC expresses into GP1 and GP2 and they migrate to the cell’s surface. NP combines with the RNA strand. The virus completely forms and exits the host cell by budding.

30. Mode of transmission.  The virus can be transmitted directly, indirectly, or airborne.  Lassa virus can be transmitted directly if a person is exposed to the blood, urine, feces, or other body fluids from an infected person.  Transmission through sex has been documented.

31. Mode of transmission.  Indirect transmission by means of a fomite can also occur. If people come across a contaminated object, they can become infected as well.  In addition, people can contract the disease by contaminated food.  In some parts of the country, M.natalensis is used as a food source and so people can contract the disease by eating contaminated meat.  Although airborne transmission is not a characteristic of arenaviruses, the Lassa virus can be transmitted by air particles contaminated with rodent excretions

32. Pathogenesis:  The incubation period of Lassa virus is between 5-21 days.  Some people start to show symptoms as early as 10 days.  The virus starts multiplying at the site of infection.  If it enters the body via the respiratory tract, it multiplies in the lungs. The virus infects every tissue in the body and then the vascular system.  Viral replication in the tissues causes capillary lesions which leads to vascular permeability and hemorrhage in various organs”.

33. Disease progression  Signs and symptoms of Lassa fever typically occur 1-3 weeks after the patient comes into contact with the virus.  For the majority of Lassa fever virus infections (approximately 80%), symptoms are mild and are undiagnosed.  Mild symptoms include slight fever, general malaise and weakness, and headache.

34.  In 20% of infected individuals, however, disease may progress to more serious symptoms including hemorrhaging (in gums, eyes, or nose, as examples), respiratory distress, repeated vomiting, facial swelling, pain in the chest, back, and abdomen, and shock.  Neurological problems have also been described, including hearing loss, tremors, and encephalitis.  Death may occur within two weeks after symptom onset due to multi-organ failure.

35. Complications.  The most common complication of Lassa fever is deafness.  Various degrees of deafness occur in approximately one- third of infections, and in many cases hearing loss is permanent.  As far as is known, severity of the disease does not affect this complication: deafness may develop in mild as well as in severe cases.

36.  Approximately 15%-20% of patients hospitalized for Lassa fever die from the illness.  The death rates for women in the third trimester of pregnancy are particularly high.  Spontaneous abortion is a serious complication of infection with an estimated 95% mortality in fetuses of infected pregnant mothers.

37.  Lassa fever is also associated with occasional epidemics, during which the case-fatality rate can reach 50% in hospitalized patients

38. Diagnosis/Testing:  Lassa fever is hard to diagnose because of its variable manifestation and the existence of other similar diseases.  Therefore, laboratory tests are required to identify Lassa virus. The most widely used test is ELISA.  It consists of isolating the virus from blood, urine, or throat washings during the febrile phase of the disease.

39.  Lassa fever is most often diagnosed by using enzyme- linked immunosorbent serologic assays (ELISA), which detect IgM and IgG antibodies as well as Lassa antigen.  Reverse transcription-polymerase chain reaction (RT-PCR) can be used in the early stage of disease.  The virus itself may be cultured in 7 to 10 days, but this procedure should only be done in a high containment laboratory with good laboratory practices.

40.  Immunohistochemistry, performed on formalin-fixed tissue specimens, can be used to make a post-mortem diagnosis.  ELISA detects Lassa virus antibodies (IgM and IgG) as well as antigens in a patient’s serum.  Other clinical tests include leukocyte and platelet counts, albuminuria, AST level, chest x rays.

41. Treatment:  Lassa fever is treated with ribavirin, which is an antiviral agent administered intravenously.  It functions by interfering with RNA synthesis and thus affecting viral replication.  Although it can be administered at any stage of the disease, it gives better results if administered within the first 6 days of infection.

42. Treatment  Suggested administration of ribavirin is as follows: 2g of intravenously during the first day of diagnosis, four doses of 1g/day for the following 4 days and then three doses of 0.5g/day for the next 6 days.  If the patient is very sick, ribavirin along with anti-Lassa fever plasma is used if avaliable.  Patients should be given appropriate fluids and electrolytes.

43.  Patients should also receive supportive care consisting of maintenance of appropriate fluid and electrolyte balance, oxygenation and blood pressure, as well as treatment of any other complicating infections.

44. Control/Prevention:  M. natalensis is so abundant in endemic areas that their complete eradication is nearly impossible.  ‘Deratting’ can be undertaken in order to decrease their population in and around human dwellings.  To avoid transmission from host to human, people should install traps in their houses to decrease the rodent population.

45.  Use rodent proof containers.  In addition, the rodents should not be used as a food source.  People should discourage the entrance of rodents to their houses by keeping them clean

46.  Person-to-person transmission can be prevented by avoiding contact with blood and body fluids.  In hospital, medical and nursing staff must use PPE.  Develop a high index of suspicion.

47. Precautions within the health facility.  Wearing protective clothing, such as masks, gloves, gowns, and goggles.  Using infection control measures, such as complete equipment sterilization; and isolating infected patients from contact with unprotected persons until the disease has run its course.

48.  Educating people in high-risk areas about ways to decrease rodent populations in their homes will aid in the control and prevention of Lassa fever.

49. Conclusion.  There are candidate vaccines but none adjudged appropriate yet so prevention and adequate precaution still remains the gold standard.

50.  Thanks for listening.

51. References  Viral Hemorrhagic Fevers. National Center for Infectious Diseases  Centers for Disease Control and Prevention  Wikipaedia.com