Lassa fever: How it all started
Currently, all eyes are on the worrisome Ebola virus disease outbreak going on in the northeast of the Democratic Republic of the Congo. However, this is not the only hemorrhagic disease that merits our attention. WHO and the Coalition for Epidemic Preparedness Innovations has identified Lassa fever as an important threat to global health and in urgent need of research and development efforts.
Lassa fever (LF) was first recognized in 1969, when three nurses in a mission hospital in Nigeria developed an illness that had not been recognized previously. Two of the nurses died and the third survived. The index case was a 69-year-old nurse who was working in a small missionary hospital in Lassa, a small town in northeast Nigeria. She apparently acquired her infection there. The second case was a 45-year-old staff nurse at Bingham Memorial Hospital in Jos, Nigeria, who was on night duty when Case 1 was admitted on Jan. 25. As part of her care of the index patient, she used a gauze dressing on her finger to clear secretions from the patient’s mouth. She realized that there was a small cut on her finger, and she washed her hand and applied antiseptics to the wound shortly afterward. She became ill and died on Feb. 13, on the 11th day of illness. The third case was a 52-year-old nurse who also worked at the Bingham Memorial Hospital. She had nursed both patients (Cases 1 and 2) and assisted with the autopsy of Case 2 on Feb. 13. Her attending physician decided to send her to the United States for diagnosis and treatment. She was flown to Lagos, Nigeria, where she was in an isolation unit for 4 days, and then she was flown to New York, attended by a missionary nurse. On March 4, she was admitted to Presbyterian Hospital and placed in isolation. She was attended by health care personnel in gowns, full masks and gloves.
Blood drawn from all three patients in Nigeria was frozen and transported to New York, and along with serum and fluid drawn by thoracentesis on March 6 from Case 3, were forwarded to the Yale Arbovirus Research Unit in New Haven, Connecticut, to isolate the virus in tissue culture. The samples were also used to inoculate mice intracerebrally. Researchers isolated Lassa fever virus (LAFV). The physician who worked with the samples became infected, but he and Case 3 both survived their serious illnesses. This was a clear indication that it was possible for an individual to become infected with LAFV in Nigeria, travel via commercial aircraft to a distant location and pass the infection along to a local laboratory worker. Fortunately, none of the health care workers in the hospital became infected, illustrating the importance of the use of personal protective equipment (PPE).
Shortly after LAFV was isolated, in January and February 1970, severely ill patients were admitted to the Evangel Hospital in Jos with symptoms similar to those of the three earlier cases. Health officials identified 26 suspected cases and 10 deaths.
LF is endemic in West Africa, specifically in Sierra Leone, Guinea, Liberia, Togo and Nigeria, causing an estimated 100,000 to 300,000 cases and 5,000 deaths each year. The past year was an active one for LAFV transmission in Nigeria. From Jan. 1 to Nov. 18, 2018, the Nigeria Centre for Disease Control reported 562 confirmed and 17 probable cases of LF, with 144 deaths.
The virus and its ecological relationships
LAFV belongs to the Old World complex of the Arenaviridae family. The lipid-enveloped spherical virus particles have a diameter of 110 to 130 nm. They are single-stranded RNA viruses. They have a grainy or sandlike appearance under electron microscopy, which was the basis for naming the family arenaviruses. There are four LAFV lineages, with extensive genetic heterogeneity between each, making it challenging to develop assays that can detect and identify all four strains.
Most affected individuals acquire their infections from rodent hosts of the virus. Virus transmission to humans occurs when people are in contact with the reservoir rodent hosts, the multimammate mouse (Mastomys natalensis and Mastomys erythroleucus) and the African wood mouse (Hylomyscus pamfi), or their excreta directly; or via aerosolized virus-contaminated particles, especially during cleaning and sweeping. These rodents can have asymptomatic, chronic or life-long infections. Considered a delicacy in many areas, rodents can also transmit LAFV when they are caught and handled in preparation for consumption. Early studies indicated that the prevalence of the virus was highest in houses and lower in surrounding agricultural and bush areas. However, the host range for LAFV may be wider than previously thought. A recent study in Nigeria found that IgG-positive species, according to the number of infected small mammals that were trapped during a 5-year period, were M. natalensis (n = 40), M. erythroleucus (n = 15), Praomys daltoni (n = 6), Mus baoulei (n = 5), Rattus rattus (n = 2), Crocidura species (n = 2), Mus minutoides (n = 1) and P. misonnei (n = 1). Multimammate mice (M. natalensis and M. erythroleucus) were the most ubiquitously infected, testing positive by either PCR or IgG in seven out of 11 localities sampled. The amount of virus shed over the lifetime of these rodents is unknown.
Human-to-human transmission can occur from infected to susceptible individuals through contact with bodily fluids, usually in hospitals. Medical staff members are at particular risk for infection. Use of PPE and barrier nursing are essential for the prevention of nosocomial infection with LAFV. The practical difficulty is that early in the course of LAFV infection, the symptoms are general and similar to those of much more common illnesses. LF is often not suspected until more serious symptoms appear, and by then, it may be too late to avoid exposure of health care workers to the virus.
The incubation period of LAFV lasts 1 to 3 weeks, followed by the onset of fever, often with pharyngitis and thoracic or abdominal pain. Approximately 80% of LAFV infections are mild and go undiagnosed or are confused with symptoms of malaria or other pathogens. WHO’s case definition for LF includes 48 hours of no clinical response to antimalarial or antibiotic treatment. Mild symptoms include low-grade fever, general malaise and fatigue. In 15% to 20% of hospitalized patients who are infected, LF can progress to more serious disease, including hemorrhage in gums, eyes or nose, respiratory distress, vomiting, facial edema and pain in the chest, back and abdomen. Shock may ensue. Neurological problems can occur as well, including encephalitis, tremors and hearing loss. Death from multiorgan failure may occur 2 weeks after the onset of symptoms in 1% of infected individuals. However, case-fatality rates can reach 50% in hospitalized patients. Death rates are high among women in the third trimester of pregnancy. Spontaneous abortion is a serious complication of infection in gravid women, with about 95% fetal mortality. Patients can continue to excrete LAFV in their urine and semen for several weeks after recovery. The most common complication in approximately a third of LF survivors is varying degrees of deafness, which may be permanent. Hearing loss may occur in survivors who have experienced mild as well as severe symptoms.
Diagnosis of LF can be made serologically by enzyme-linked immunosorbent assay detection of IgM and IgG antibodies or detection of LAFV antigens. Early in the disease, reverse transcription PCR can detect virus genomic fragments. Virus isolation should be done only in a high-containment laboratory by well-trained investigators. The virus may also be detected in formalin-fixed post-mortem tissues by immunohistochemical tests.
The only currently available pharmacologic therapy is early IV administration of the antiviral agent ribavirin. In LAFV-viremic macaques, favipiravir administered at 300 mg/kg daily for 2 weeks successfully treated infection. Supportive care is essential to maintain appropriate fluid and electrolyte balance and blood pressure.
National health agencies often employ rodent host control to prevent LAFV transmission to humans. This is not an easy task, and it must be undertaken at the village level. Communities are required to participate to deny rodent reservoirs access to homes and to the food materials in them. Use of rodent-proof containers and maintaining a good level of cleanliness and hygiene is important. Rodent control measures can be effective in reducing the rodent population in houses. A 4-year study evaluated the use of anticoagulant rodenticides in three villages, compared with three untreated villages as controls. The abundance of M. natalensis, the most commonly encountered rodent based on the number that was collected from traps, varied between 3.6% and 16.7% before treatment and decreased significantly to 1% to 2% after treatment. Villagers welcomed the intervention and trapping because mice are generally regarded as a nuisance. These results demonstrated that chemical treatment provides an effective tool to control local rodent populations and can serve as part of an effective, holistic approach that combines rodent trapping, use of local rodenticides, environmental hygiene, house repairs and rodent-proof storage of food. Sustaining long-term rodent control would require continuous public participation, something that would likely prove difficult in the absence of incentives caused by human clinical cases in the locality.
Vaccines would be a desirable measure to prevent LF cases in humans, but no approved vaccines are commercially available. Some vaccine research is underway. Progress has been made with several nonreplication-competent vaccines, including alphavirus replicons, whole-inactivated LAFV and DNA electroporation. For example, a research group at the Lab of Viral Zoonotics, University of Cambridge, has developed and successfully tested a trivalent LF, Ebola and Marburg vaccine in guinea pigs. Another group has developed an inactivated recombinant LAFV and rabies virus (RABV) vaccine candidate (LASSARAB) that expresses a codon-optimized LAFV glycoprotein and is adjuvanted by a TLR-4 agonist. LASSARAB elicited lasting humoral responses against LAFV and RABV in both mouse and guinea pig models, and it protected both guinea pigs and mice against LF. Development of a vaccine and successfully taking it through all three phases to demonstrate the safety and effectiveness required for approval is a very costly process. The market for a commercial LF vaccine is not adequate to attract companies for development. It remains to be seen if governments or nonprofit organizations will be willing to undertake such a challenge.
Risk for the future
Is LF a risk for those of us in the Western Hemisphere? In this era of rapid, long-distance international travel via commercial air transport, importation of LF cases is an ever-present possibility. LF has been imported into Europe and the U.S. in the past. Over the years, more than 20 cases of LF have been introduced into Europe, with secondary cases occurring.
Introduction of LF into the U.S. from West Africa has occurred eight times between 1969 and 2017. These individuals had acquired their infections in Sierra Leone, Nigeria, Liberia and Togo. Five of these individuals were not suspected to have LF until medical treatment was sought in the U.S., underscoring the need for a thorough travel history at the time of initial medical evaluation. The eight individuals brought to the U.S. were treated in a variety of locations, including New York City; Trenton, New Jersey; Washington, D.C.; Atlanta; Illinois; and Minneapolis.
The CDC cited one of these cases in 2015, illustrating how the appearance of such cases can occur:
“On May 25, 2015, the CDC and the New Jersey Department of Health confirmed a death from LF in a person who traveled to the United States from Liberia. The patient traveled from Liberia to Morocco to JFK International Airport on May 17. The patient did not have fever on departure from Liberia, did not report symptoms, such as diarrhea, vomiting, or bleeding during the flight and did not have fever upon arrival in the United States. On May 18, the patient went to a hospital in New Jersey with a sore throat, fever, and fatigue. According to the hospital, he was asked on May 18 about his travel history and he did not indicate travel to West Africa. The patient was sent home the same day and reported a normal temperature to the local health department on May 19 and 20.
“On May 21, the patient returned to the hospital when symptoms worsened and was transferred to a second hospital prepared to treat viral hemorrhagic fevers. Samples submitted to the CDC tested positive for LF on May 25. Tests for Ebola and other viral hemorrhagic fevers were negative. The patient was in appropriate isolation when he died there the evening of May 25.”
Could a case be imported into the U.S. again? Of course. We just do not know when, so we had best be ready.
- Abreu-Mota T, et al. Nat Commun. 2018;doi:10.1038/s41467-018-06741-w.
- Buckley SM, et al. Am J Troup Med Hyg. 1970;19(4):680-91.
- CDC. Lassa fever. https://www.cdc.gov/vhf/lassa/index.html. Accessed December 17, 2018.
- Frame JD, et al. Am J Trop Med Hyg. 1970;19:670–6.
- Hallam HJ, et al. NPJ Vaccines. 2018;doi:10.1038/s41541-018-0049-5.
- Hewson R. Euro Surveill. 2017;doi:10.2807/1560-7917.ES.2017.22.39.17-00661.
- Mari Saez A, et al. PLoS Negl Trop Dis. 2018;doi:10.1371/journal.pntd.0006829.
- Mateer EJ, et al. PLoS Negl Trop Dis. 2018;doi:10.1371/journal.pntd.0006187.
- Olayemi A, et al. Parasit Vectors. 2018;doi:10.1186/s13071-018-2991-5.
- Richmond JK, et al. BMJ. 2003;327(7426):1271-5.
- Shehu NY, et al. Front Public Health. 2018;doi:10.3389/fpubh.2018.0023.
- Siddle, KJ, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1804498.
- Troup JM, et al. Am J Troup Med Hyg. 1970;19695-696.
- Wang MK, et al. PLoS Pathog. 2018;doi:10.1371/journal.ppat.1007322.
- Warner BM, et al. Drug Des Devel Ther. 2018;doi:10.2147/DDDT.S147276.
- For more information:
- Thomas M. Yuill, PhD, is a ProMED virus diseases moderator and professor emeritus, department of pathobiological sciences and department of forest and wildlife ecology, University of Wisconsin-Madison.
- Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Disclosures: Kaye and Yuill report no relevant financial disclosures.