Medicine for Africa - Medical Information Service

ASSA FEVER

Definition:

Lassa fever is caused by the Lassa virus, an enveloped, single-stranded RNA (ribonucleic acid) virus of the Arenaviridae family.

The Arenaviridae are part of a diverse five-member group of RNA viruses, causing human and animal illnesses, which are termed collectively as ‘viral hemorrhagic fevers’.  The other four members of the virus family are Bunyaviridae (such as the Hantavirus and Rift Valley fever virus), Flaviviridae (e.g. Dengue fever, Yellow fever), Filoviridae (Ebola virus, Marburg virus), and the Togaviridae (e.g. the Eastern, Western and Venezuelan equine encephalitis viruses, the Rubella virus).

All viruses that belong to these families cause a viral hemorrhagic fever (VHF) of various extent, overall characterized by fever and bleeding disorders, which can progress to a life-threatening disease, shock and death in severe cases (e.g. the Ebola and Marburg viruses).

The Lassa virus replicates fast in a well controlled process – first ensuring sufficient future protein supply by making mRNA (messenger RNA) copies, followed by producing viral complementary RNA (vcRNA) which will finally result in new viral copies.

The primary host or reservoir of the virus is a rat, the so-called ‘multimammate rat’ of the genus Mastomys (M. natalensis). The Mastomys rats produce large numbers of offspring within a short period of time, and like to colonize human dwellings. These rodents are at home in savannas and forests in West, Central and East Africa.

Transmission usually occurs via contact with the rat’s urine and droppings which contain the virus. This ‘contact’ can be by way of ingesting contaminated food (e.g. rat infested grain stores or silos), or through direct contact with the virus via cuts or sores.  However, airborne transmission can also occur by inhaling tiny particles in the air that are contaminated with the virus.  In areas where rodents are part of the diet, the virus can also be transmitted by consuming infected rats.

Person-to-person transmission can occur via contact with virus-infected blood products, tissues, secretions (including sneezing and coughing), and excretions such as urine or feces.  The virus can also be present in semen and mucous (vaginal) secretions, and thus be transmitted sexually during intercourse. Occasional reports have described a viral transmission through breast milk.  And finally, it can also be transmitted through contaminated medical equipment that is not sufficiently sterilized, or if needles are reused.  Casual contact (without the exchange of body fluids) does usually not spread the virus.

          Historic Review

While the disease was first described in Sierra Leone in the 1950s, the virus itself was only identified in 1969 by Dr. Jordi Casals-Ariet and his team from Yale University. The virus received its name from the town of Lassa in northern Nigeria, located at the southern end of Lake Chad in the Yedseram river valley.

Dr. Casals identified the virus in the blood of three American missionary nurses at a local hospital. Two nurses died, the third was flown to the USA, and survived after nine weeks. Early laboratory research of the virus caused one technician to die of the virus, while Dr. Casals himself also fell severely ill, but survived. Thus, further research was transferred to a ‘maximum-security laboratory’ at the Centers for Disease Control and Prevention in Atlanta.

Disease outbreaks have been reported in the Central African Republic, the Democratic Republic of the Congo, Guinea, Liberia, Mali, Nigeria, Senegal and Sierra Leone.  In some areas of Liberia and Sierra Leone, 10% to 15% of all patients admitted to a hospital have Lassa fever, and it is estimated that about 6% of all residents in endemic areas have antibodies to the Lassa virus. 

Symptoms:

Clinically, Lassa fever is often difficult to distinguish from common febrile illnesses such as malaria, dengue fever, typhoid fever, yellow fever, and others, or even from other even more serious viral hemorrhagic fevers (VHFs), caused by the Ebola virus or Marburg virus.

The Lassa virus usually enters the body through the mucosa into the blood stream, respiratory tract and/or digestive tract, and then multiplies in the reticuloendothelial system of the body causing capillary lesions.  These vascular lesions lead to the loss of red blood cells (erythrocytes) and platelets, resulting in various degrees of thrombocytopenia (low platelet count) and a subsequent tendency towards bleeding.  The increase in vascular permeability causes hemorrhage in various organs, such as the stomach and small intestine, but also in the kidneys, lungs and even the brain.

The incubation period ranges from one to 24 days with a mean of about 10 days. Most patients have experienced symptoms for about four to five days when seeking treatment at a hospital or health care facility.

Typical symptoms include a slow onset of fever and general feeling of malaise. As the fever increases over the next couple of weeks, myalgia (muscle pain) and severe prostration (exhaustion) accompany the involvement of specific organs. Often, patients complain of retrosternal pain (pain behind the sternum) and present with (severe) coughing.  Proteinuria (protein in the urine) and facial swelling are frequent.
 
Additional symptoms include abdominal pain with nausea and vomiting, diarrhea or constipation, as well as inflammation of mucous membranes, causing conjunctivitis and pharyngitis, and pleural effusion due to the increased vascular permeability. 

While only about 30% of patients present with bleeding symptoms (e.g. from the gums), they are associated with a significantly higher risk of death. In severe cases, the dysfunction of the endothelial system and platelets (thrombocytes) can result in vascular collapse and shock, pleural effusion and rales (crackling noise over the lungs on auscultation), as well as mental status changes such as agitation, clouding or even ‘grand mal’ seizures, prior to death.

Four symptoms that are associated with a 2.5 increase in mortality are:

• Sore throat;
• Vomiting;
• Tachypnea (rapid breathing);
• Hemorrhage (bleeding).

Patients who survive the initial stages begin to defervesce about three weeks after the onset of the disease.  During convalescence, subsequent conditions such as pericarditis (inflammation of the cardiac sac, occurs especially in males), aseptic meningitis, encephalitis and global encephalopathy with seizures, and in up to 30%, deafness (temporary or permanent) in one or both ears, can develop.

Almost 70% of cases occur in women which may be the result of increased exposure to the virus, rather than an increased susceptibility of women to the disease.  However, in late pregnancy, the disease can turn severe, resulting in maternal death and/or fetal demise in more than 80% of cases during the third trimester.

Most of the time, the course of Lassa fever is usually mild, or associated with a minor symptom complex, in about 80% of people who are infected with the virus.  However, the remaining 20% have a severe disease progress with multisystem involvement, and often lethal outcome, usually within about 14 days of onset.  While the overall case-fatality rate lies at about 1%, it increases to around 15% among hospitalized patients and can reach up to 50% during an occasional epidemic in endemic areas. 

 
Diagnosis:

A definite diagnosis of the Lassa virus requires the detection of the Lassa antigen, or antibodies by laboratory tests such as enzyme linked immunosorbent serologic assays (ELISA). Three ways of diagnosing the Lassa virus include:
 

• Directly – by isolating the virus from blood, urine, throat washings etc. and culturing it in seven to 10 days. It can also be detected by the so-called reverse transcription-polymerase chain reaction (RT-PCR), a highly sensitive, but also expensive technique, usually reserved for research purposes.
• Indirectly – by identifying the presence of IgM (immunoglobuline M) antibodies (the ‘early antibody’) to the virus – about 90% sensitive and specific to the virus.
• Late, indirectly – by showing a four-fold increase of IgG antibody (the ‘late stage antibody’) in serum between the acute phase of the disease and its convalescent phase.

The specimen for laboratory testing may be highly contagious (see Historic Review), and thus must be handled with extreme care.

Of course, the virus can also be identified by immunohistochemistry, performed on tissue specimens, diagnosing the disease in a post-mortem autopsy.

Blood tests may reveal:

• Leucopenia (low white blood cell count), but leukocytes can also be normal or moderately increased;
• Thrombocytopenia (low number of platelets);
• ALT (alanine transaminase, previously SGPT) and AST (aspartate aminotransferase, previously SGOT) are elevated up to 10x times normal.
• Proteinuria and albuminuria (increased amount of albumin proteins in the urine).

The prognosis of Lassa fever correlates directly with the levels of viremia (the amount of viruses in the blood), it does not correlate with the development of IgM or IgG antibodies, as these antibodies do not seem to be able to neutralize the virus.

The virus can be excreted in urine for three to nine weeks and in semen for up to three months, making a survivor of the disease a carrier and potential source of infection for close contacts.

 
Treatment:

The drug of choice is ribaverin, by way of an aggressive treatment schedule as soon as possible after diagnosis. Ribaverin is a member of the group of nucleoside antimetabolited drugs, which interfere with the duplication of genetic material in both DNA and RNA viruses.  It is a so-called pro-drug, meaning that ribaverin is actually only the chemical precursor for the molecule that possesses the pharmacologically active ingredients.  Thus, after the administration of ribaverin, the body will convert it into its desired chemical compound that ultimately interferes with the RNA metabolism of the virus, and thus prevents viral replication.

Given intravenously (i.v.), ribaverin is said to be at least twice as effective as when given orally.  While the cost of the drug is fairly inexpensive, it is still quite costly for developing countries in Africa with very limited financial health care resources.

In addition to ribaverin, supportive therapy consisting of appropriate electrolyte and fluid replacement, blood transfusions (to combat the widespread hemorrhage) and measurements to fight hypotension are also required.  Antibiotics may also have to be administered, in order to fight opportunistic bacterial infections, and at times, i.v. application of interferon has also been performed.

Women, who are pregnant in their third trimester when becoming infected, should abort their pregnancy, in order to increase the chances of survival for the mother.  Since the virus has a large affinity to blood and thus, to highly vascular tissues, such as the placenta, the fetus of an infected mother would have only a 10% chance, at best, to survive the mother’s infection, provided the mother herself will survive the illness.

Prevention:

At this point in time, there is no effective prophylactic or preventive treatment available.  Some sources recommend the administration of a prophylactic dose of ribaverin for people who travel into high-risk areas and may be exposed to contacts with viremic (virus carrying and potentially spreading) people.

Of course, primary prevention should consist of avoiding exposure to the contact with Mastomys rodents/rats, especially in high-risk geographical areas. In addition, general sanitary measurements and the storage of food and food products in ‘rodent-resistant’ containers will help to prevent the rat from entering human dwellings.

Health care personnel, taking care of Lassa fever infected patients, should take careful preventive measurements when being in contact and treating Lassa patients, including isolation, wearing protective clothing, such as gloves, surgical masks, gowns, and even goggles.  Obviously, all medical equipment requires thorough sterilization procedures, prior to being reused on another patient.

Local educational programs, in association with family planning classes, should be conducted in all risky and high-risk areas, in order to educate the population on basic procedures as to how to prevent a potential infection. 

It would be welcome, not only for Africa, but also for tourists to Africa, and thus to the world, if in the near future, rapid diagnostic test procedures (RDTs), and an effective vaccine (which is in research), could become reality and help to eradicate this disease within the foreseeable future.

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