Lassa fever

Lassa fever 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, in the Yedseram river valley at the south end of Lake Chad. Clinical cases of the disease had been known for over a decade but had not been connected with a viral pathogen. The infection is endemic in West African countries, and causes 300,000–500,000 cases annually, with approximately 5,000 deaths. Outbreaks of the disease have been observed in Nigeria, Liberia, Sierra Leone, Guinea, and the Central African Republic, but it is believed that human infections also exist in Democratic Republic of the Congo, Mali, and Senegal. The primary animal host of the Lassa virus is the Natal Multimammate Mouse (Mastomys natalensis), an animal indigenous to most of Sub-Saharan Africa. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences.

Genome
Lassa fever is caused by the Lassa virus, a member of the Arenaviridae family; it is an enveloped, single-stranded, bisegmented RNA virus.

Replication for Lassa virus is very rapid, while also demonstrating temporal control in replication. There are two genome segments. The first replication step is transcription of mRNA copies of the negative- or minus-sense genome. This ensures an adequate supply of viral proteins for subsequent steps of replication, as proteins known as N and L are translated from the mRNA. The positive- or plus-sense genome then makes viral complementary RNA (vcRNA) copies of itself, which are + sense. The vcRNA is a template for producing &minus; sense progeny but mRNA is also synthesized from it. The mRNA synthesized from vcRNA are translated to make the G (spike) proteins and Z proteins. Thus, with this temporal control, the spike proteins, which are on the outside of the virus particle, are produced last, making the infection more difficult for the host immune system to detect.

Nucleotide studies of the genome have shown that Lassa has four lineages: three found in Nigeria and the fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains seem likely to have been ancestral to the others but additional work is required to confirm this.

Receptors
The Lassa virus gains entry into the host cell by means of the cell-surface receptor the alpha-dystroglycan (alpha-DG), a versatile receptor for proteins of the extracellular matrix. It shares this receptor with the prototypic arenavirus lymphocytic choriomeningitis virus. Receptor recognition depends on a specific sugar modification of alpha-dystroglycan by a group of glycosyltransferases known as the LARGE proteins. Specific variants of the genes encoding these proteins appear to be under positive selection in West Africa where Lassa is endemic. Alpha-dystroglycan is also used as a receptor by viruses of the New World clade C arenaviruses (Oliveros and Latino viruses). In contrast, the New World areanviruses of clades A and B, which include the important viruses Machupo, Guanarito, Junin, and Sabia in addition to the non pathogenic Amapari virus, use the transferrin receptor 1. A small aliphatic amino acid at the GP1 glycoprotein amino acid position 260 is required for high-affinity binding to alpha-DG. In addition, GP1 amino acid position 259 also appears to be important, since all arenaviruses showing high-affinity alpha-DG binding possess a bulky aromatic amino acid (tyrosine or phenylalanine) at this position.

Unlike most enveloped viruses which use clathrin coated pits for cellular entry and bind to their receptors in a pH dependent fashion, Lassa and lymphocytic choriomeningitis virus instead use an endocytotic pathway independent of clathrin, caveolin, dynamin and actin. Once within the cell the viruses are rapidly delivered to endosomes via vesicular trafficking albeit one that is largely independent of the small GTPases Rab5 and Rab7. On contact with the endosome pH-dependent membrane fusion occurs mediated by the envelope glycoprotein.

Pathogenesis
Lassa virus will infect almost every tissue in the human body. It starts with the mucosa, intestine, lungs and urinary system, and then progresses to the vascular system.

Vectors
Lassa virus is zoonotic (transmitted from animals), in that it spreads to man from rodents, specifically multi-mammate rats (Mastomys natalensis). This is probably the most common rodent in equatorial Africa, ubiquitous in human households and eaten as a delicacy in some areas. In these rats infection is in a persistent asymptomatic state. The virus is shed in their excreta (urine and feces), which can be aerosolized. In fatal cases, Lassa fever is characterized by impaired or delayed cellular immunity leading to fulminant viremia.

Infection in humans typically occurs via exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infective material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infective material. Transmission from person to person has also been established, presenting a disease risk for healthcare workers. Frequency of transmission via sexual contact has not been established.

Prevalence
The dissemination of the infection can be assessed by prevalence of antibodies to the virus in populations of:


 * Sierra Leone 8–52%
 * Guinea 4–55%
 * Nigeria approx. 21%

Studies show up to half a million cases of Lassa fever per year in West Africa, with 5000 resulting in death.

Like other hemorrhagic fevers, Lassa fever can be transmitted directly from one human to another. It can be contracted by an airborne route or with direct contact with infected human blood, urine, or semen. Transmission through breast milk has also been observed.

Prevention
Control of the Mastomys rodent population is impractical, so measures are limited to keeping rodents out of homes and food supplies, as well as maintaining effective personal hygiene. Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person.

Researchers at the USAMRIID facility, where military biologists study infectious diseases, have a promising vaccine candidate. They have developed a replication-competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection, test primates have survived lethal challenge, while showing no clinical symptoms.

Symptoms
In 80% of cases the disease is inapparent, but in the remaining 20% it takes a complicated course. It is estimated that the virus is responsible for about 5,000 deaths annually. The fever accounts for up to one third of deaths in hospitals within the affected regions and 10 to 16% of total cases.

After an incubation period of six to twenty-one days, an acute illness with multiorgan involvement develops. Non-specific symptoms include fever, facial swelling, and muscle fatigue, as well as conjunctivitis and mucosal bleeding. The other symptoms arising from the affected organs are:
 * Gastrointestinal tract
 * Nausea
 * Vomiting (bloody)
 * Diarrhea (bloody)
 * Stomach ache
 * Constipation
 * Dysphagia (difficulty swallowing)
 * Hepatitis
 * Cardiovascular system
 * Pericarditis
 * Hypertension
 * Hypotension
 * Tachycardia (abnormally high heart rate)
 * Respiratory tract
 * Cough
 * Chest pain
 * Dyspnoea
 * Pharyngitis
 * Pleuritis
 * Nervous system
 * Encephalitis
 * Meningitis
 * Unilateral or bilateral hearing deficit
 * Seizures

Clinically, Lassa fever infections are difficult to distinguish from other viral hemorrhagic fevers such as Ebola and Marburg, and from more common febrile illnesses such as malaria.

The virus is excreted in urine for three to nine weeks and in semen for three months.

Diagnosis
There is a range of laboratory investigations that are performed to diagnose the disease and assess its course and complications. ELISA test for antigen and IgM antibodies gives 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate aminotransferase (AST) levels in the blood.

Prognosis
About 15%-20% of hospitalized Lassa fever patients will die from the illness. It is estimated that the overall mortality rate is 1%, however during epidemics mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother.

Thanks to treatment with Ribavirin, fatality rates are continuing to decline. Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.

Treatment
All persons suspected of Lassa fever infection should be admitted to isolation facilities and their body fluids and excreta properly disposed of.

Early and aggressive treatment using Ribavirin was pioneered by Joe McCormick in 1979. After extensive testing, it was determined that early administration is critical to success. Additionally, Ribavirin is almost twice as effective when given intravenously as when taken by mouth. Ribavirin is a prodrug which appears to interfere with viral replication by inhibiting RNA-dependent nucleic acid synthesis, although the precise mechanism of action is disputed. The drug is relatively inexpensive, but the cost of the drug is still very high for many of those in poverty-stricken West African states. Fluid replacement, blood transfusion and fighting hypotension are usually required. Intravenous interferon therapy has also been used.

When Lassa fever infects pregnant women late in their third trimester, it is necessary to induce delivery for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other Lassa fever patients.

Siga Technologies is developing an antiviral drug that has been shown effective in treating experimentally infected guinea pigs. In a study conducted at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), treatment with ST-193 once a day for 14 days resulted in significant reduction in mortality (71% of the animals survived at the low dose), whereas all untreated animals and those treated with ribavirin died within 20 days of the infection.