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Lassa Fever Case Report: Combination therapy with intravenous ribavirin and oral favipiravir

ClinInfectDis

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever

Published:
22 June 2017
Abstract
Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered.

Lassa fever: WHO Review

LassaFever-WHO

Lassa fever

Fact sheet
Updated March 2016


Key facts

  • Lassa fever is an acute viral haemorrhagic illness of 2-21 days duration that occurs in West Africa.
  • The Lassa virus is transmitted to humans via contact with food or household items contaminated with rodent urine or faeces.
  • Person-to-person infections and laboratory transmission can also occur, particularly in hospitals lacking adequate infection prevent and control measures.
  • Lassa fever is known to be endemic in Benin, Ghana, Guinea, Liberia, Mali, Sierra Leone, and Nigeria, but probably exists in other West African countries as well.
  • The overall case-fatality rate is 1%. Observed case-fatality rate among patients hospitalized with severe cases of Lassa fever is 15%.
  • Early supportive care with rehydration and symptomatic treatment improves survival.

Background

Though first described in the 1950s, the virus causing Lassa disease was not identified until 1969. The virus is a single-stranded RNA virus belonging to the virus family Arenaviridae.

About 80% of people who become infected with Lassa virus have no symptoms. 1 in 5 infections result in severe disease, where the virus affects several organs such as the liver, spleen and kidneys.

Lassa fever is a zoonotic disease, meaning that humans become infected from contact with infected animals. The animal reservoir, or host, of Lassa virus is a rodent of the genus Mastomys, commonly known as the “multimammate rat.” Mastomys rats infected with Lassa virus do not become ill, but they can shed the virus in their urine and faeces.

Because the clinical course of the disease is so variable, detection of the disease in affected patients has been difficult. When presence of the disease is confirmed in a community, however, prompt isolation of affected patients, good infection prevention and control practices, and rigorous contact tracing can stop outbreaks.

Lassa fever is known to be endemic in Benin (where it was diagnosed for the first time in November 2014), Ghana (diagnosed for the first time in October 2011), Guinea, Liberia, Mali (diagnosed for the first time in February 2009), Sierra Leone, and Nigeria, but probably exists in other West African countries as well.

Symptoms of Lassa fever

The incubation period of Lassa fever ranges from 6–21 days. The onset of the disease, when it is 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, fluid in the lung cavity, bleeding from the mouth, nose, vagina or gastrointestinal tract and low blood pressure may develop.

Protein may be noted in the urine. 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.

Transmission

Humans usually become infected with Lassa virus from exposure to urine or faeces of infected Mastomys rats. Lassa virus may also be spread between humans through direct contact with the blood, urine, faeces, or other bodily secretions of a person infected with Lassa fever. There is no epidemiological evidence supporting airborne spread between humans. Person-to-person transmission occurs in both community and health-care settings, where the virus may be spread by contaminated medical equipment, such as re-used needles. Sexual transmission of Lassa virus has been reported.

Lassa fever occurs in all age groups and both sexes. Persons at greatest risk are those living in rural areas where Mastomys are usually found, especially in communities with poor sanitation or crowded living conditions. Health workers are at risk if caring for Lassa fever patients in the absence of proper barrier nursing and infection prevention and control practices.

Diagnosis

Because the symptoms of Lassa fever are so varied and non-specific, clinical diagnosis is often difficult, especially early in the course of the disease. Lassa fever is difficult to distinguish from other viral haemorrhagic fevers such as Ebola virus disease as well as other diseases that cause fever, including malaria, shigellosis, typhoid fever and yellow fever.

Definitive diagnosis requires testing that is available only in reference laboratories. Laboratory specimens may be hazardous and must be handled with extreme care. 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.

Treatment and prophylaxis

The antiviral drug ribavirin seems to be an effective treatment for Lassa fever if given early on in the course of clinical illness. There is no evidence to support the role of ribavirin as post-exposure prophylactic treatment for Lassa fever.

There is currently no vaccine that protects against Lassa fever.

Prevention and control

Prevention of Lassa fever relies on promoting good “community hygiene” to discourage rodents from entering homes. Effective measures include storing grain and other foodstuffs in rodent-proof containers, disposing of garbage far from the home, maintaining clean households and keeping cats. Because Mastomys are so abundant in endemic areas, it is not possible to completely eliminate them from the environment. Family members should always be careful to avoid contact with blood and body fluids while caring for sick persons.

In health-care settings, staff should always apply standard infection prevention and control precautions when caring for patients, regardless of their presumed diagnosis. These include basic hand hygiene, respiratory hygiene, use of personal protective equipment (to block splashes or other contact with infected materials), safe injection practices and safe burial practices.

Health-care workers caring for patients with suspected or confirmed Lassa fever should apply extra infection control measures to prevent contact with the patient’s blood and body fluids and contaminated surfaces or materials such as clothing and bedding. When in close contact (within 1 metre) of patients with Lassa fever, health-care workers should wear face protection (a face shield or a medical mask and goggles), a clean, non-sterile long-sleeved gown, and gloves (sterile gloves for some procedures).

Laboratory workers are also at risk. Samples taken from humans and animals for investigation of Lassa virus infection should be handled by trained staff and processed in suitably equipped laboratories under maximum biological containment conditions.

On rare occasions, travellers from areas where Lassa fever is endemic export the disease to other countries. Although malaria, typhoid fever, and many other tropical infections are much more common, the diagnosis of Lassa fever should be considered in febrile patients returning from West Africa, especially if they have had exposures in rural areas or hospitals in countries where Lassa fever is known to be endemic. Health-care workers seeing a patient suspected to have Lassa fever should immediately contact local and national experts for advice and to arrange for laboratory testing.

WHO response

The Ministries of Health of Guinea, Liberia and Sierra Leone, WHO, the Office of United States Foreign Disaster Assistance, the United Nations, and other partners have worked together to establish the Mano River Union Lassa Fever Network. The programme supports these 3 countries in developing national prevention strategies and enhancing laboratory diagnostics for Lassa fever and other dangerous diseases. Training in laboratory diagnosis, clinical management, and environmental control is also included.


WHO: 3 African nations—Benin, Togo, and Burkina Faso—have reported recent cases of Lassa fever that could foretell more outbreaks in the region.

WHO

Lassa Fever – Benin, Togo and Burkina Faso

Disease outbreak news
10 March 2017

Benin and Togo, exported from Benin

On 20 February 2017, the Ministry of Health of Benin notified WHO of a Lassa fever case in Tchaourou district, Borgou Department, Benin, close to the border with Nigeria. The case was a pregnant woman who was living in Nigeria (close to the border with Benin).

On 11 February 2017, she was admitted to a hospital where she delivered the baby (a premature neonate) by caesarean section and passed away on 12 February 2017. Samples were tested positive for Lassa fever in the laboratory in Cotonou, Benin and later in the Lagos University Teaching Hospital Lassa laboratory in Nigeria. The newborn and father left the hospital without notice on 14 February 2017 and went to Mango in northern Togo where they were admitted to a hospital.

The newborn tested positive for Lassa fever and the father tested negative in the Institut National d’Hygiène in Lomé, Togo. The baby was treated with ribavirin and is currently in stable condition; he is still hospitalised in northern Togo for issues of prematurity and overall monitoring.

A total of 68 contacts are being followed-up in Benin and 29 contacts are being followed-up in Togo linked to the pregnant woman and newborn.

Togo, exported from Burkina Faso

On 26 February 2017, after receiving information from Togo, the Ministry of Health of Burkina Faso has notified WHO of a confirmed Lassa fever case in a hospital in the northern part of Togo. The case has originated from Ouargaye district which is in the central eastern part of Burkina Faso.

The case was a pregnant woman who was previously hospitalized in Burkina Faso. She was discharged and had a miscarriage at home. After the second hospitalization in Burkina Faso she was transmitted to a hospital in Mango, northern Togo, and passed away on 3 March 2017.

Samples from the pregnant woman tested positive for Lassa fever at the Institut National d’Hygiène in Lomé, Togo.

A total of 7 contacts have been identified in Togo linked to the pregnant woman and contact tracing is ongoing; 135 contacts in Burkina Faso have been identified linked to the pregnant woman and contact tracing is ongoing.

Togo

On 2 March 2017, a man was admitted to a health centre in the Kpendial health district for fever and melena and was referred to a regional hospital on 3 March 2017.

Samples from the male case were sent to the Institut National d’Hygiène in Lomé, Togo, and tested positive for Lassa fever. The case left the hospital on 6 March. Investigations are ongoing. The male case and his close relatives are under follow up at their home.

A total of 18 contacts were identified in Togo linked to the male case.

Public health response

Health authorities in Benin, Burkina Faso and Togo are implementing the following measures to respond to these Lassa fever cases, including:

  • Deployment of rapid response teams to the affected areas for epidemiological investigation.
  • Identification of contacts and follow-up.
  • Strengthening of infection prevention and control measures in health facilities and briefing of health workers.
  • Strengthening of cross border collaboration and information exchanges between Togo, Burkina, Mali and Benin.

WHO risk assessment

Lassa fever is an acute viral haemorrhagic fever illness. The Lassa virus is transmitted to humans via contact with food or household items contaminated with rodent urine or faeces. Person-to-person infections and laboratory transmission can also occur.

Lassa fever is endemic in neighbouring Nigeria and other West African countries and causes outbreaks almost every year in different parts of the region, with yearly peaks observed between December and February. The most recent Lassa fever outbreak in Benin occurred in the same area in January – May 2016. At least 54 cases including 28 deaths have been reported at country level. Both Burkina Faso and Togo have reported sporadic cases in the past.

Given constant important population movements between Nigeria, Togo, Burkina Faso, Niger and Benin, the occurrence of sporadic Lassa fever cases in West Africa was expected and further sporadic cases may occur in countries of the region.

However, with the ongoing control measures in Benin, Togo and Burkina Faso the risk of further disease spread from these confirmed cases is considered to be low. Considering the seasonal peaks in previous years, increase in the disease awareness, better preparedness and response in general, and strengthening of regional collaboration the risk of large scale outbreaks in the region is medium.

WHO advice

Prevention of Lassa fever relies on promoting good “community hygiene” to discourage rodents from entering homes. In health-care settings, staff should always apply standard infection prevention and control precautions when caring for patients, regardless of their presumed diagnosis.

On rare occasions, travellers from areas where Lassa fever is endemic export the disease to other countries. Although other tropical infections are much more common, the diagnosis of Lassa fever should be considered in febrile patients returning from West Africa, especially if they have had exposures in rural areas or hospitals in countries where Lassa fever is known to be endemic. Health-care workers seeing a patient suspected to have Lassa fever should immediately contact local and national experts for advice and to arrange for laboratory testing.


WHO has been notified of at least 38 suspected cases of Lassa fever in Liberia.so far this year

WHO

Lassa Fever – Liberia

Disease outbreak news 
18 May 2016

Since 1 January 2016, WHO has been notified of at least 38 suspected cases of Lassa fever in Liberia.

Suspected cases were reported from 6 prefectures: Bong (17 cases, including 9 deaths), Nimba (14 cases, including 6 deaths), Gbarpolu (4 cases), Lofa (1 case), Margibi (1 case) and Montserrado (1 case).

Between 1 January and 3 April 2016, samples from 24 suspected cases were received for laboratory testing. Of these 24 suspected cases, 7 are reported to have tested positive for Lassa fever:

  • 2 cases were identified by polymerase chain reaction (PCR);
  • 2 cases were identified through the detection of IgM antibodies using enzyme-linked immunosorbent assay (ELISA);
  • 2 cases were identified through the detection of Lassa virus antigens using ELISA;
  • information on the type of testing employed to identify the seventh case is not currently available.

All the Lassa fever confirmed cases tested negative for Ebola virus disease. Since there are no designated laboratories in Liberia that can test samples for Lassa fever by PCR, specimens are currently sent for testing to Kenema, Sierra Leone.

Public health response

To date, 134 contacts have completed the 21-day follow-up period. A total of 17 additional contacts are being monitored. None of these contacts have so far developed symptoms.

Appropriate outbreak response measures, including case management, infection prevention and control, community engagement and health education, have been put in place by the national authorities with the support of WHO and partner organizations.

WHO risk assessment

Lassa fever is endemic in Liberia and causes outbreaks almost every year in different parts of the country. Based on experiences from previous similar events, it is expected that additional cases will be reported.

Although occasional travel-associated cases of Lassa fever have been reported in the past (see DON published on 27 and 8 April 2016), the risk of disease spread from Liberia to non-endemic countries is considered to be low. WHO continues to monitor the epidemiological situation and conduct risk assessments based on the latest available information.

WHO advice

Considering the seasonal flare ups of cases during this time of the year, countries in West Africa that are endemic for Lassa fever are encouraged to strengthen their related surveillance systems.

Health-care workers caring for patients with suspected or confirmed Lassa fever should apply extra infection control measures to prevent contact with the patient’s blood and body fluids and contaminated surfaces or materials such as clothing and bedding. When in close contact (within 1 metre) of patients with Lassa fever, health-care workers should wear face protection (a face shield or a medical mask and goggles), a clean, non-sterile long-sleeved gown, and gloves (sterile gloves for some procedures).

Laboratory workers are also at risk. Samples taken from humans and animals for investigation of Lassa virus infection should be handled by trained staff and processed in suitably equipped laboratories under maximum biological containment conditions.

The diagnosis of Lassa fever should be considered in febrile patients returning from areas where Lassa fever is endemic. Health-care workers seeing a patient suspected to have Lassa fever should immediately contact local and national experts for advice and to arrange for laboratory testing.

WHO does not recommend any travel or trade restriction to Liberia based on the current information available.

Key facts

  • Lassa fever is an acute viral haemorrhagic illness of 2-21 days duration that occurs in West Africa.
  • The Lassa virus is transmitted to humans via contact with food or household items contaminated with rodent urine or faeces.
  • Person-to-person infections and laboratory transmission can also occur, particularly in hospitals lacking adequate infection prevent and control measures.
  • Lassa fever is known to be endemic in Benin, Ghana, Guinea, Liberia, Mali, Sierra Leone, and Nigeria, but probably exists in other West African countries as well.
  • The overall case-fatality rate is 1%. Observed case-fatality rate among patients hospitalized with severe cases of Lassa fever is 15%.
  • Early supportive care with rehydration and symptomatic treatment improves survival.

Symptoms of Lassa fever

The incubation period of Lassa fever ranges from 6–21 days.

The onset of the disease, when it is 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, fluid in the lung cavity, bleeding from the mouth, nose, vagina or gastrointestinal tract and low blood pressure may develop.


** Nigeria: Lassa Fever has claimed 63 lives out of 212 suspected cases reported from 62 local government areas in affected states.

Premium Times

Lassa Fever distribution map. Countries reporting endemic disease and substantial outbreaks are Guinea, Sierre Leone, Liberia, and Nigeria. Countries reporting few cases, periodic isolation of virus, or serologic evidence of Lassa virus infection are Mali, Burkina Faso, Cote d'Ivoire, Ghana, Togo, and Benin.

CDC

“…The reservoir, or host, of Lassa virus is a rodent known as the “multimammate rat” (Mastomys natalensis). Once infected, this rodent is able to excrete virus in urine for an extended time period, maybe for the rest of its life. Mastomys rodents breed frequently, produce large numbers of offspring, and are numerous in the savannas and forests of west, central, and east Africa. In addition, Mastomys readily colonize human homes and areas where food is stored. All of these factors contribute to the relatively efficient spread of Lassa virus from infected rodents to humans.

Transmission of Lassa virus to humans occurs most commonly through ingestion or inhalation. Mastomys rodents shed the virus in urine and droppings and direct contact with these materials, through touching soiled objects, eating contaminated food, or exposure to open cuts or sores, can lead to infection……..

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. 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.

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.

Approximately 15%-20% of patients hospitalized for Lassa fever die from the illness. However, only 1% of all Lassa virus infections result in death. 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.

Because the symptoms of Lassa fever are so varied and nonspecific, clinical diagnosis is often difficult. Lassa fever is also associated with occasional epidemics, during which the case-fatality rate can reach 50% in hospitalized patients….”


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