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Highlights
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Lassa virus is carried by rodents; contact between rodents and humans is the main source of infection, although Lassa fever can also be transmitted person to person. |
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The disease is endemic in West Africa, where it causes up to 20000 deaths annually. |
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Early treatment with ribavirin can be effective in stemming the course of the illness. |
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Although a vaccine is feasible, no company has yet expressed interest in developing it. |
Rodents are culprits
"Lassa fever is a disease that I've worked on for many years and it is one of my favorite topics," said Joseph B. McCormick of the University of Texas Houston Health Science Center in his presentation on the clinical aspects of the illness. Named for the village in Northern Nigeria where the disease was first detected and isolated, Lassa fever is caused by the Lassa arenavirus, which is particularly prevalent in West Africa, covering countries from Guinea to Nigeria. The region is home to more than 200 million people, "so there is a fairly large population at risk," said McCormick.
He and his colleagues initiated long-term studies of Lassa fever that ran from the 1970s through the early 1990s in Eastern Sierra Leone. Much of the data on incidence, morbidity, and mortality come from these studies, he said, although the civil war that has raged there over the last 15 years has hampered efforts to further investigate and curtail the spread of disease.
The Lassa arenavirus is particularly prevalent in West Africa.
Lassa fever is a rural disease that occurs primarily when individuals come in contact with persistently infected Mastomys natalensis rodents in and around their homes. The virus is transmitted to humans mainly through rodent urine, although transmission may also occur when people catch and prepare rodents for food, thereby coming into contact with rodent blood. Other risk factors include caring for or coming into direct contact with an individual who is ill with Lassa fever, or convalescing.
The disease takes a high toll, McCormick continued. The case fatality is in the range of 2% to 4%, resulting in about 200,000 to 300,000 infections and 10,000 to 20,000 deaths annually throughout West Africa. "In Sierra Leone alone, over a one-year period in our study hospitals, patients with Lassa fever made up 13% of all adult medical admissions and 27% of all of the adult deaths," he noted.
Despite its reputation for being an epidemic disease, "we learned fairly early on that Lassa fever is in fact an endemic disease, that patients are always coming to the hospital, and that admissions occur year round," he said. In some villages in Guinea, for example, there is no evidence of infection, whereas in Liberia and Sierra Leone, residents had antibody to the virus in 6% to 40% of villages.
The disease causes 10000 to 20000 deaths annually.
Lassa fever can cause hospital epidemics, however. In one situation, a patient came into a small rural hospital in Nigeria for treatment of sickle cell crisis. He received several injections and intravenous treatment, went back home, then came back to the hospital with more severe disease and high fever. Following his admission, a large group of patients were infected with Lassa virus, including a physician who died and other individuals who became severely ill but survived.
"This was one of a number of nosocomial outbreaks, most of which occur from sharing needles and syringes within hospitals," McCormick said. "Often staff are poorly trained and patients are given antibiotics from the same needle and syringe. Numerous outbreaks of Ebola and Marburg viruses have also occurred for the same reasons."
 A hemorrhagic fever
Lassa fever is a hemorrhagic fever that causes a modest amount of bleeding, most of which is from the mucosa-the mouth, nose, bowel and sometimes prominently in the sclera, as well as often from the vulva. "Unfortunately, when you see bleeding, it carries a fairly grim prognosis because people who start to bleed tend to do more poorly than those who don't," McCormick said.
When patients get past the crisis point of being severely ill with Lassa, they seem to recover quickly.
The disease usually has a slow onset. Affected individuals feel a bit of fever, weakness and fatigue for the first few days, then get progressively ill, with headaches, severe sore throat, and-a hallmark of disease progression-fairly severe retrosternal chest pain. Abdominal pain is also common, occurring in more than 60% of the patients, and is often associated with nausea and vomiting.
"Sometimes the pharyngitis is so severe that people cannot even swallow their own saliva, and you see patients with little cups next to their bedside where they deposit their saliva because it's simply too painful to swallow," McCormick noted. "Along with abdominal pain, they will often have some abdominal tenderness, and more than one patient has been taken to surgery because health care workers thought they had an acute abdomen when in fact they had Lassa fever with severe abdominal tenderness."
Conjunctivitis occurs in almost 40% of patients, and the 15% to 20% of patients who progress to severe disease generally have edema in the upper abdomen, chest, neck, or head. Death is usually the result of hypovolemic shock leading to cyanosis and coma.
By contrast, when patients get past the crisis point of being severely ill with Lassa, they seem to recover quickly. "It's not unusual for a patient to be very, very ill, then 48 hours later sitting up and even taking some nourishment," said McCormick. "This illustrates the delicate balance between giving supportive therapy and trying to maintain blood pressure. Giving too much IV fluid therapy pushes patients into pulmonary edema, whereas not enough causes them to go into shock. It's a continuous dilemma when caring for severely ill Lassa patients."
One of the clinical consequences of Lassa is deafness. In a study of patients with acute Lassa fever in Sierra Leone, approximately 29% had some degree of deafness, either unilateral or bilateral. For 64% of those affected, substantial hearing loss was permanent. In individuals with previous Lassa virus infection-those who were seropositive in the general population-22% had significant hearing loss in one or both ears. Finally, nearly 80% of those with hearing loss in the community had antibody to Lassa virus.
The virus also causes a very high degree of fetal mortality, McCormick continued. When pregnant women are infected, overall fetal mortality is greater than 90%. Uterine evacuation "greatly improves" the outcome of women who get infected during pregnancy, significantly reducing mortality, he observed.
Prognosis linked to viremia
Lassa fever severity seems to be driven by virus replication, McCormick said. Mean levels of viremia among survivors are slightly more than one log of virus versus close to four logs of virus in patients who died.
Although contact with infected blood is the principal route of transmission, virus in sites other than blood may play an important role in person-to-person transmission. For example, the virus has been isolated from blood in the urine, from the throat and spinal fluid, and also from breast milk. The latter is likely to be the route of infection for children who are breast feeding.
Studies of virus levels in various tissues show that the highest levels are in the placenta, which correlates with the extent of fetal mortality described earlier. Levels are also high in the liver and spleen.
Virus has been isolated in urine, the throat, spinal fluid, and breast milk.
Hepatic enzyme levels-particularly aspartate aminotransferase (AST)-also appear to be very high, as they are in other hemorrhagic fevers. In addition to viremia, higher levels of AST are linked with fatal outcomes.
A low lymphocyte count is another hallmark of Lassa fever. Early in the course of disease, overall white cell counts tend to drop "dramatically," said McCormick. "By the sixth or seventh day, you have a rather low white count and a particularly low lymphocyte count." The white count can go quite high towards the end of the disease, however, mainly because of a large spike in neutrophils.
What is the humoral immune response to Lassa fever, and how important is it to prognosis? "Unfortunately, it doesn't seem to matter with patients have antibodies or not," said McCormick. In fact, many patients do have antibodies upon admission to the hospital; however, the survival rate is about the same among patients with antibody titers less than or equal to 1:8 and those with titers greater than 1:8. "Those who died had higher levels of virus compared with those who survived, but the level of antibody didn't seem to influence the level of virus. Therefore, antibody titers do not seem to have much effect on the outcome of disease." On the other hand the cellular immune response appears critical to recovery.
Treatment and prevention
Ribavirin is the standard treatment for Lassa fever. Studies have shown that 19% of patients on ribavirin therapy with an AST (Aspartate aminotransferase) level greater than or equal to 150 died, compared with 55% of similar patients who did not receive therapy. Among patients with AST levels greater than or equal to 150 who received IV ribavirin less than seven days after onset, only 5% died compared with 61% of those who were not treated.
In patients with high viremia as well as AST levels greater than 150, ribavirin therapy at any time in the disease reduced mortality by 40% (33% fatality rate compared with 73% for no therapy). For those who had lower levels of viremia, the death rates were lower. Ribavirin still offered some protection, but not a significant level of improvement in outcome.
With respect to vaccines, said McCormick, "we saw from earlier clinical studies that the level of antibody didn't seem to matter for Lassa, and this was borne out by our first [animal] study of an inactivated Lassa virus vaccine." Despite developing high levels of antibodies in response to virus challenge, vaccinated animals also had high levels of virus replication and ultimately died, as did unvaccinated animals. As with humans, "when you induce only antibody in these animals, it does not protect them when they're challenged with Lassa virus."
By contrast, when the group tested a vectored glycoprotein vaccine, 9 of 10 animals were protected, whereas 10 of 10 unprotected animals died. In terms of protection, concluded McCormick, "what seems to matter, and what was induced by our vaccine, is the level of cellular immunity. That has now been borne out by a whole series of studies. Although it has not yet been tested in humans, we believe this is a pure T-cell vaccine and that it could be a very effective way of preventing Lassa fever." |
