OUTLINE

Introduction History Epidemiology The Recent Outbreak Mastomys natalensis The Lassa virus Pathogenesis Clinical Features Pathology Diagnosis Treatment Prevention and Control Conclusion

INTRODUCTION
Lassa fever is a viral haemorrhagic disease caused by

the Lassa virus The virus was first identified in 1950 but later named in 1969 after the town where the first outbreak occurred Lassa is a town in Borno state , Yedesram valley, near the Lake Chad Laura West was a missionary nurse who had been resident in Lassa for the past 4 years

HISTORY
Laura developed a sudden onset of fever, back pain and

sore throat, she was manged by Dr Hammer the only doctor in Lassa. The doctor was worried about her deteriorating clinical state as she developed petechiae, anuria even after she had been given CQ and procaine penicillin When she later developed convulsion , she was flown to Evangel hospital in Jos, then known as Bingham Memorial hospital A nurse , by name Charlotte Shaw, at the hospital had a finger prick at home and covered her thumb with a gauze.

HISTORY
She used her finger to clean Laura s throat and later

became ill, she died on the 11th day of her illness Postmortem was carried out on her by Dr Troupe, assisted by Penny Pineo, a head nurse. Blood and tissue samples were taken for studies A week later, Penny Pineo became ill ,his condition deteriorated over 2 weeks. He was flown to New York while his specimen was also sent to Yale arboviral research Lab The Lassa virus was isolated in the lab by Drs, Down, Jordi, Casal and Sonja Buckley

HISTORY
Jordi Casal came down with Lassa and was given

antiserum from Penny pineo, he survived. A patient on admission as well as her mother and her sister became infected. Four health care workers also suddenly became ill with similar symptoms. Dr Troup while carrying out autopsy on one of the staff that died, accidentally cut herself, she became ill and died after 10 days . Her death brought the number of cases to 19 and mortality to 10.

HISTORY
The disease became almost forgotten till 1989 when a

family was nearly erased completely in Ihumudumu Ekpoma. The diagnosis was made in the United States through tissues taken at post mortem when a team came from the CDC, Atlanta Georgia The team visited the family and the then nearest Medical school. ( the University of Benin/University of Benin Teaching Hospital).

HISTORY
For the second time Lassa was again forgotten till 1993

when, with the inception of the located near Ekpoma. A strange pattern of disease was noticed among some patients admitted at Irrua Specialist Teaching . It started with fever ,the patients later became anuric, had bleeding diasthesis and eventually died. Those that had dialysis survived while some people became deaf on recovery. Blood samples were sent to Prof Tomori in University College Hospital, Ibadan. Information arrived later that the strange disease was Lassa Fever From then on clinicians have become more vigilant and a higher index of suspicion has since been maintained.

EPIDEMIOLOGY
Endemic in West Africa countries and has been

reported in Nigeria, Liberia, Sierra Leone and Guinea

Cases of Lassa fever have been imported to Europe.
300,000 to 500,000 cases of Lassa fever and 5000

deaths occur yearly across West Africa. Lassa virus antibodies were detected in 21.3% of serum samples from Nigeria. 8-22% in Sierra Leone 4-55% in Guinea.

Epid.contd
Rodent to human transmission occurs majorly through multimammate rats (Mastomys natalensis) which serves as reservoir for the virus. a) Ingestion of food and materials contaminated by infected rodent excrement b) Inhalation of aerosolized virus from dead mastomys c) Ingestion of mastomys as a delicacy Person to person transmission through contact with an infected person(Fluids, tissue, secretions and excretions) urine, feces, saliva, vomitus, blood and semen.

Epid.contd
Affects people of all age groups irrespective of their sex . Asymptomatic in ~ 80% of infected cases, but 20% come down with severe multisystem disease.

Incubation period is 6-21 days.

Cases used to be highest during the dry season

and lowest during the wet season.

Recently: highest during the change from the dry

to the wet season.

Epidcontd
Case fatality rate increases from about 1% in sporadic

cases to about 35% -65% during outbreaks.

High rate of maternal death (29%) and foetal and

neonatal loss (87%).

The illness lasts for 7 - 31 days in non-fatal cases, and

7 - 26 days in fatal cases. Fatal cases among Doctors include; Dr JM Troup (Pathologist) died in Jos (1970). Consultant Surgeon in Adamawa state (April 2011). Two doctors have also died in the present outbreak

Epid

contd

Among the VHFs, Lassa fever affects by far the largest number of people. It now affects larger communities in West Africa, outside its already broad area of rural endemicity.( 7 cases sin the UK since 1980) May affect between 2 to 3 million people each year in certain portions of the West African region, causing a mortality of about 10000 during the same period.

Epidemics in Nigeria
Epidemics.

Community-based: Rat to Man. Hospital-based: Human to Human. Lassa (Borno state)- 1969. Jos (Plateau state)- 1970, 1993. Onitsha (Anambra state)- 1974. Vom (Plateau state)- 1975, 1977. Zankwa (Kaduna state)- 1975. Aba (Imo state)-1989 Aboh-Mbaise (Imo state)-1989

Epidemics contd
Lafia (Nassarawa state)-1993. Ekpoma (Edo state)- 1989, 1993, 1999, 2005 Irrua (Edo state)- 2004 Abuja (FCT)- 2009
Sporadic primary cases are probably common in some

more remote areas but underreported.

Epidemics in other countries

Sierra Leone: Panguma, Kenema, 197183, 1997, Liberia: Zorzor, 1972; Phebe 1972, 1977, 1982; Ganta 1977, 1982

THE 2012 SAGA

By the 5th week of the year 2012, 29 suspected cases of

Lassa fever had been reported , 8 laboratory confirmed with 12 deaths( CFR OF 41.4%) all from 4 states( Taraba, Rivers, Nasarawa and Plateau) So far a total of 196 suspected cases of Lassa fever, 51 laboratory confirmed with 29 deaths( CFR of 14.8%) have been reported.

Reported outbreaks of Lassa fever as at 10th February, 2012

As at 4 days ago the virus is said to have spread to 16

states across the federation- Anambra, Edo, Nassarawa, Ondo, Plateau, Rivers, Taraba, ,Yobe, Lagos, Ebonyi, Gombe, A total of 40 deaths have been reported including 6 health care workers More recently the MOH has reported a total of 397 cases with 87 confirmed positive for Lassa In Oyo state, there have been two suspected cases, both were confirmed negative by PCR

Map of West Africa: Outbreaks and

Serological Evidence of Human Infection.

West and Central Africa mean annual rainfall (19511989), Lassa fever nosocomial outbreaks (stars) and human seroprevalence (%).

Map of West Africa showing both Community and Nosocomial Outbreaks

Map of Nigeria showing sites of Lassa virus circulation.

Mastomys natalensis
Taxonomy unresolved; 8 distinct species are recognized, and several coexist in Lassa fever endemic areas. Family: Muridae. Other Names: Natal Multimammate Rat, Common African Rat, Soft-furred or African Softfurred Rat. One of the commonest African rodents. Females possess a superfluity of teats, more than any other rodent. (Multimammate = Latin, meaning literally "many-breasted".)

M natalensis.contd
Occupies a wide range of habitat, absent only from desert, semi-desert and mountains, but most often seen in and around human habitation(peri-domestic rodent).
It avoids large metropolises because it cannot

compete with the Black Rat.

It has been increasing in number since1972, when

it was found to be the natural host of Lassa virus.

It is persistently carries the Lassa virus and shed

the virus in their excreta.

MASTOMYS NATALENSIS

THE LASSA VIRUS

A member of the arenaviridae; enveloped, round, pleomorphic virus. A single-stranded, bisegmented RNA virus. Consists of two (S and L) single strands of RNA enclosed within a spherical protein coat. The S segment codes for the major structural components such as the internal proteins (NP) and the glycoproteins, while the L segment codes for RNA polymerase and a few structural proteins.

The protein coat has a number of T-shaped glycoproteins protruding from it, composed of GP2 which is the base and GP1 which is the T-bar.

THE ARENAVIRIDAE
Arenaviruses Lassa Junin Machupo Guanarito Sabia LCMV Origin of name Town, Nigeria Town, Argentina River Bolivia Area, Venezuela Town, Brazil Clinical disease Year 1969 1957 1962 1989 1990 1933

Physicochemical properties
The virus is inactivated by:
Low level disinfectants such as QAC, Phenols, chlorine

based products and iodophor formulations( 37 minutes at 60C 3% Acetic acid for 15 minutes Ultaviolet radiation ( 1200-2000 W/CM2) for 20 minutes Heating up to 560c Exposure to a PH of < 5.5 or . 8.5

Lassa virus.contd

Lassa Virus contd

A lifelong and silent virus carried by the M. natalensis. Can transiently infect asymptomatically a wide range of mammals including domestic herds and, possibly, birds. Lassa virus is the most virulent of the arena viruses known to cause haemorrhagic fever.

PATHOGENESIS
Pathogenesis is poorly understood.

Circulatory instability Increased vascular permeability Diffuse haemorrhagic manifestations

Viraemia is detectable 3-4 days after inoculation and may last 2 weeks or more.

Pathogenesis
Virus enters thru either RS, GIT, blood or lymphatics Lassa fever infection is initiated in the victim. Generalised infection with haemorrhagic dissemination to multiple organs and systems via the blood stream, lymph vessels, RT and GIT The blood vessels are always the most affected and the virus multiplies in cells of the RES causing capillary lesions. Infects macrophages and vascular epithelial cells

Pathogenesis
Cell mediated immune response generated The capillary permeability is increased, RBC and platelet loss followed by peripheral vasoconstriction with the presence of DIC that leads to haemorrhagic syndrome. Loss of platelet function loss of aggregation, impaired clotting haemorrhage Inhibition of neutrophil actions IgM produced wks later. Antibodies may persist for 4 5yrs after an infection

Pathogenesis.contd
Summary: Attachment to the cellular receptor for Lassa virus; -dystroglycan. This subunit of dystroglycan is an important cell surface receptor for proteins of the extracellular matrix (ECM) and is crucial for normal function and development of the organism. Lassa virus efficiently competes with ECM proteins for receptor binding and likely affects the function of dystroglycan in the host cell. Upon receptor binding, the virus undergoes endocytosis and is delivered to acidified endosomes.

Pathogenesis contd
Generally the virus causes:
Endothelial cell damage/capillary leak

Platelet dysfunction
Suppressed cardiac function Release of cytokines and other soluble mediators of shock and inflammation.

Virological & immunological parameters in a patient with fatal Lassa fever

Biochemical parameters in a patient with fatal Lassa fever

Haematological parameters in a patient with fatal Lassa fever

CLINICAL FEATURES
SYMPTOMS: Asymptomatic-90% of cases Early, Insidious symptoms
Fever Chills Rigors Headache Malaise Myalgia
Second week symptoms

Lower Abdominal Pain Intractable Vomiting Other symptoms: Tinnitus,Epistaxis,Bleeding gums, Maculopapular rash, Cough,Dizziness.

Clinical featurescontd
SIGNS: Early
Fever Flushing of face and neck area Pharyngitis (progressive over first week) Raised patch of whitish exudate on tonsillar pillar Pseudomembranes may develop Oral Ulcerations Generalized non-tender Lymphadenopathy

Later

Facial and neck swelling Conjunctivitis

Clinical featurescontd
Severe, Acute Phase

Systolic Blood Pressure below 90mmHg Pulse Pressure less than 20 Relative Bradycardia

Onset and duration of principal signs & symptoms

Clin Features contd

LASSA FEVER IN CHILDREN AND INFANTS: Significant cause of paediatric hospitalizations in some areas of West Africa. Signs and symptoms most often similar to adults. Swollen Baby syndrome: Anasarca, Abdominal distension & Bleeding. Poor prognosis. LASSA FEVER IN PREGNANCY: Maternal mortality. Placental Infection. Foetal/Neonatal mortality. Level of viraemia. Evacuation of uterus improves survival.

Clin features contd

SENSORINEURAL HEARING DEFICIT: common Typically appears during early convalescence. Not related to severity of acute illness. Occurs in one-third of cases (>other viral infns). May be bilateral or unilateral. May persist for life in up to 1/3 of cases. DIFFERENTIAL DIAGNOSIS: Malaria Bacterial meningitis Typhoid fever Arboviral infection Strep Pharyngitis Leptospirosis Bacterial sepsis Anicteric hepatitis Bacterial or Viral conjunctivitis

COMPLICATIONS
Mucosal bleeding (17%),
Sensorineural hearing deficit (4%), Pleural effusion (3%), and Pericardial effusion (2%). Alopecia Loss of coordination Psychiatric disorders

Sleep disorders

PATHOLOGICAL FEATURES
Descriptions of pathological findings are limited Liver and Spleen has most striking histopathological changes.
Gross Findings

Constant but non specific findings include: Congestion of the viscera Oedema of the soft tissue Petechiae (especially of the GIT) Pleural effusion and ascitis Luminal intestinal bleeding Congestion of meningeal blood vessels Oedema of the vocal cords

Pathological featurescontd
HISTOPATHOLOGICAL FINDINGS

Liver: Has most distinctive features and is

histologically the main target organ.

Necrosis of individual hepatocytes and foci of hepatocellular destruction with multiple portoportal and porto-central necrotic Bridges. Eosinophilic cytoplasmic inclusions with pyknosis of the nucleus. Councilman-like bodies with prominent nucleoli.

Path findingscontd

Heart: Congestion, Slight interstitial oedema and non specific pericardial infiltrates. Lungs: Congestion and oedema, interstitial pneumonitis with mononuclear cells infiltration. Kidneys: Occasional focal tubular and glomerular necrosis. Spleen: Congestion and atrophy of the white pulp with deposition of amorphous eosinophilic cellular debris and fibrin in the white pulp and infiltration of the intima of splenic veins by lymphoid cells.

Laboratory Diagnosis
Nine specialist centers have been opened across the country where diagnosis of Lassa fever can be made. The first of such is the Lassa Fever Diagnostic Laboratory Commissioned at Irrua (Edo state) in 2008. It has ultramodern diagnostic equipment donated and installed by the Harvard University, Boston, USA and Benerd-Nocht Institute of Tropical Medicine, Hamburg, Germany. Lassa Fever Isolation Ward also under construction in the same centre.

DIAGNOSIS
Early diagnosis is still difficult in almost all Nigerian health care institutions. Clinical diagnosis often difficult.

LABORATORY DIAGNOSIS
Specimens include; Blood, urine, pleural fluid, throat swab In case of death, pathological materials from liver, kidney, spleen and heart Lab diagnosis of Lassa fever is best done in a Biosafety Level 4 laboratory where there are adequate facilities for ensuring safety such as;

Lab Diagnosis

Microscopy Electron microscopy Culture Intracerebral infection of Albino mice or guinea pigs First 7 to 10 days positive cell cultures (Vero cells) Serology Sero diagnosis IgM antibody detection either by ELISA or IFA , CF, RIBA ELISA Can diagnose past infections

PRP
Molecular method
RT-PCR- Useful for detecting glycoprotein precursor

protein Useful for confirmation of cases Supportive tests Liver function tests- ALT & AST 10x normal, raised LDH Urinalysis proteinuria (may be massive) FBC lymphocytopenia, thrombocytopenia Chest x-rays, obtained if lung involvement is suspected, may show basilar pneumonitis and pleural effusions.

TREATMENT
Key to effective treatment is early diagnosis within 6 days of infection Ribavirin (guanosine analogue) Most effective when started within the first six days of illness. Best given intravenously (IV) Major toxicity: Mild haemolysis and suppression of erythropoiesis. Both reversible.

NB: Presently contraindicated in pregnancy but may be warranted if mothers life is at risk. Does not appear to reduce incidence and severity of deafness.

Diagnostics contd
Nine specialist centers have been opened across the country where diagnosis of Lassa fever can be made. The first of such is the Lassa Fever Diagnostic Laboratory Commissioned at Irrua (Edo state) in 2008. It has ultramodern diagnostic equipment donated and installed by the Harvard University, Boston, USA and Benerd-Nocht Institute of Tropical Medicine, Hamburg, Germany. Lassa Fever Isolation Ward also under construction in the same centre.

Treatment contd
Dosage:

Load: 2 grams First Maintenance: 1 gram every 6 hours for 4 days Next Maintenance: 0.5 grams every 8 hours for 6 days NB: Post-exposure prophylaxis is now practiced empirically using oral ribavirin, but its usefulness has not been systematically studied.

Treatment ctd
Supportive measures include; Fluid and electrolyte

balance, hemodynamic measures, ventilation and dialysis support. Treatment of superimposed bacterial infection.

The following drugs are contraindicated in patients

with Lassa fever; Anticoagulants Acetylsalicylate NSAIDS

Clin.. Features contd

INDICATORS OF POOR PROGNOSIS: High viraemia Serum AST level >150IU/L Bleeding Encephalitis Oedema Third trimester of pregnancy

PREVENTION AND CONTROL

Village-based programmes for rodent control and avoidance. Awareness campaigns to farmers who live on the hinterland to discourage drying their grains on road shoulders along the highway All rodent holes should be blocked and rat traps should be used for trapping and killing rodents Food should be stored in rodent proof containers

Rodents should be avoided as food source

PREVENTION AND CONTROL

Hospital training programmes to avoid nosocomial spread:

Barrier nursing and use of PPE The Federal Government has inaugrated a 23-man Lassa fever Rapid Response Committee to investigae, prevent and control further spread of the disease More Lassa fever testing centre have been established Specific antiviral chemotherapy (Ribavirin) should be readily available and accessible at no cost to the patient However, there is need for more concerted effort to wards producing an effective vaccine for prevention and treatment of disease

HOSPITAL BASED CONTROL PROGRMAMMES

A patient with VHF can come to the hospital at any

point in his or her illness, including during the IP when the possibility of exposure is often highest. Because a health worker cannot always know when a patient's body fluids are infectious, Standard Precaution should be used with all patients in the health care setting, regardless of their infection status. Standard Precautions are designed to prevent unprotected contact between the health care worker and

HOSPITAL BASED CONTROL PROGRAMME

Standard Precautions are designed to prevent

unprotected contact between the health care worker and blood and all body fluids whether or not they contain blood. When a specific diagnosis is made, additional precautions are taken, based on how the disease is transmitted.

HOSPITAL BASED CONTROL PROGRAMME

Health facilities should establish and maintain a basic, practical level of Standard Precautions that can be used . All Hospitals must have baseline protocool /guideline for ensuring safety of health workers from highly infectious disease agents. The following must be established - A source of clean water - Routine handwashing before and after contact with a patient who has fever - Safe handling and disposal of sharp instruments and equipment, including needles and syringes. - VHF Isolation facilities

HOSPITAL BASED CONTROL PROGRAMME

Isolate the patient in rooms with negative pressure

ventilation. Wear protective clothing in the isolation area, in the cleaning and laundry areas and in the laboratory. The PPE includes; a scrub suit, gown, apron, two pairs of gloves, mask, hood, eyewear, and rubber boots. All spills and waste must be disinfected before cleaning and reusable equipment must be properly disinfected. All soiled linens must be disinfected and safe laundry should be ensured.

PREVENTION AND CONTROL

Use safe disposal methods for non-reusable supplies

and infectious waste. Provide information about the risk of VHF transmission to health facility staff. Reinforce use of VHF Isolation Precautions with all health facility staff. Provide information to families and the community about prevention of VHFs and care of patients.

PPE

LASSA FEVER VACCINE

Research is still underway to develop an effective vaccine for Lassa fever.

Preferably a live vaccine which may be given as a single shot.

A killed vaccine is more stable, but usually

requires repeated shots. Live vaccine could be combined with a yellow fever vaccine, using the same cold chains. None of the vaccines underway have reached clinical trial. Programmatic use of a vaccine in endemic areas could reduce the incidence of Lassa fever.

LASSA VIRUS AN AGENT OF BIOTERRORISM

Bioterrorism has brought new resources to Lassa virus science.

Research on the use of Lassa virus as a weapon of bioterrorism as been concluded

This is because the virus can be disseminated via

aerosolization, it has a low infectious dose, it is associated with high morbidity and mortality and it also causes fear and panic in the public. All these has helped to draw a lot of public attention to Lassa fever

Conclusion
A stock clerk was sent to clean up a store room, when

he got back, he complained that the store room was really filthy and he noticed dried rat droppings in some areas. Days later he started feeling like he was coming down with a flu, he complained of headache, sore throat and began to vomit. Within 2 days he was severely ill and weak. His blood sugar was down to 66mg/dl, his eyeballs were yellow. At the emergency, he was said to be suffering from massive organ failure and died a week later.

SO MANY QUESTIONS???
Who would have related his job to his illness?
Who would remember that he said he saw rat

droppings in the store room? How many of this modern super stores are free from rats How many times have we bought canned drinks, refused to wash , but opened them and drank directly from the can? How sure are we that those cans are not encrusted with dried rat urine ?

FINALLY
Lassa remains a disease of great public health significance . It is endemic in West Africa,

particularly Nigeria. The pathogenesis is still largely poorly understood but it affects almost every organ of the body Clinical diagnosis is often difficult while Laboratory diagnosis not always available. Ribavirin is effective if given early but for now there are no vaccines available Hence good Infection control practice remains the mainstay of prevention for now.

REFERENCES:
1- Ehichioya DE et al: Current molecular epidemiology of Lassa virus in Nigeria. J Clin Microbiol; 2011; 49:1157-61 2- Ehichioya DE et al (2010); Lassa fever Nigeria 2005-2008: CDC Letter volume16 Number 6. 3- Scott M (2011); Lassa fever: Family practice notebook LLC. 4-Inegbenebor U et al (2010); Prevention of lassa fever in Nigeria: Transaction of the royal society of tropical medicine and hygiene. 5- Gnther S & Lenz O (2009); Lassa virus: Crit Rev Clin Lab Sci. 6- Senior K (2009); Lassa fever: current and future control options, The Lancet.

References contd 7- Adewuyi GM, Fowotade A, & Adewuyi BT (2009); Lassa fever: Another infectious menace, Afr Jnl Cli Exp Microbiology. 8- Premium papers on Lassa fever (2011); History, pathology, and effects on the indigenous populations: essaysample,com 9- Idemyor V (2010); Lassa virus infection in Nigeria: Clinical perspective overview, J Natl Med Assoc. 10- Ogbu O, Ajuluchukwu E, & Uneke CJ (2007); Lassa fever in West African Sub region: An Overview, J vector Borne Dis. 11- CDC Lassa Fever Fact Sheet. 12- Elisabeth F & David JR (2009); Risk maps of lassa fever in West Africa: Neglected Tropical Diseases. 13- Russel Tofts (2009); Multimammate Mice: http://homepage,ntlworld.com/jean.wright93/mm.htm

References contd
14- Susan PF et al (2004); Lassa fever vaccine: Expert review of vaccines. 15- Tribune newspaper 6th April 2011. 17- Vanguard newspaper 2nd March 2011. 18- Cummins et al (1990); Acute sensorineural deafness in lassa fever: J Amer Med Assoc. 19- Fisher-Hoch SP et al (1995); Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice, BMJ. 20- Jinn WC Jr & Walker DH (1975); The pathology of human lassa fever: Bulletin WHO Vol 52. 21- Fisher-Hoch SP (2005); Lessons from nosocomial viral haemorrhagic fever outbreaks: Br Med Bull 22- Emilie Lecomte et al (2006); Mastomys natalensis and lassa fever, West Africa: Emerging infectious diseases.

References contd
23- Bannister B (1991); Lassa fever: BMJ. 24- Peters CU et al (1989); Pathogenesis of viral haemorrhagic fevers: Rift valley fever and Lassa fever contrasted, Reviews of infectious diseases. 25- Wikipedia, The free encyclopedia: Natal Multimammate Mouse (updated sept, 2011) 26- Edington GM & White HA (1972); The pathology of Lassa fever: A tribute to the late Dr JM Troup, Trans of Royal Soc Trop Med & Hygiene. 27- Maria SS & Igor SL (2009); Vaccines against Lassa fever, Levine Ch 82, Informa Publishing, USA.

ANY QUESTIONS?