Lassa Fever Symptoms and Pathogenesis: Comparison
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Lassa virus (LASV) is the causative agent of Lassa fever (LF). LF symptoms typically appear 1–3 weeks post-infection. Eighty percent of cases are asymptomatic or present with mild, non-specific febrile symptoms such as fever, sore throat, headache, and general malaise, that may be misdiagnosed as typhoid, malaria, or appendicitis.

  • arenaviruses
  • Lassa virus
  • viral hemorrhagic fevers
  • Lassa fever

1. Introduction

Lassa virus (LASV) is the causative agent of Lassa fever (LF). The virus was first isolated from two missionary nurses who died from LF in Nigeria in 1969 [1,2,3][1][2][3]. A third nurse was infected and brought to the United States; her plasma was used to treat a fourth patient who was exposed by handling infected blood samples [1]. LASV is a mammarenavirus from the Arenaviridae family and has a single-stranded, negative-sense, bisegmented RNA genome. LASV is endemic throughout Western Africa, especially in Nigeria, Liberia, Guinea, and Sierra Leone, where it is transmitted by the Natal mastomys (Mastomys natalensis) rodent, although recent work suggests viral presence in the reddish-white mastomys (Mastomys erythroleucus) and the “African wood mouse” (Hylomyscus pamfi) rodents as well [2,4][2][4]. LASV isolates of different geographic and host origins are highly diverse in genomic sequences and phylogenetically classified into up to seven lineages, with each lineage predominately localized in specific countries (refer to Table 1 for the LASV isolates covered here) [5,6,7,8,9][5][6][7][8][9]. A recent deep sequencing analysis revealed that the sequence variations could be as high as 25% and 32% in the viral genomic small (S) and large (L) segments, respectively, among different strains [5]. LASV causes zoonotic infections in humans, typically through the ingestion of contaminated food and/or water or inhalation of tainted aerosols from infected rodents; person-to-person transmission occurs via contact with bodily fluids [2]. Estimates from the Centers for Disease Control and Prevention (CDC) place the number of new LASV infections each year as high as 300,000 with around 5000 deaths from LF [2,10][2][10]. The average case fatality rate is approximately 1%, which can dramatically elevate to 15–20% for hospitalized cases [2]. However, a more recent report indicated only 633 confirmed cases and 171 deaths in Nigeria in 2018, with a 27% case fatality rate [11]. In the recent 2018–2019 Nigerian LF outbreaks, approximately 25% of patients died from the infection [12,13,14][12][13][14]. Therefore, it is necessary to re-evaluate the annual incidence of LASV infections and deaths.
Table 1. Information for Lassa virus (LASV) strains examined in animal models *.

Strain

Lineage

Lethal/Fatal

Host

Isolation Country

Isolation Year

Reference

Josiah

IV

Yes

Human

Sierra Leone

1976

[6]

AV

V

Yes

Human

Ghana/Ivory Coast

2000

[6]

Ba366

IV

No

Mastomysnatalensis

Guinea

2003

[6]

LF2384

IV

Yes

Human

Sierra Leone

2012

[6,8]

[6][8]

LF2450

IV

No

Human

Sierra Leone

2012

[6,8]

[6][8]

Soromba-R

V

No

Mastomysnatalensis

Soromba, Mali

2009

[6]

Pinneo

I

No

Human

Lassa, Nigeria

1969

[6]

NJ2015

IV

Yes

Human

Liberia

2015

[9]
* Only strains mentioned here that have known isolation information are listed in this table.
There are no FDA-approved vaccines against LASV. Current clinical treatments are limited to an off-label use of ribavirin [2,14][2][14]. However, ribavirin treatment is expensive and only effective if administered within the first six days after the onset of symptoms [15]. When considering the high rate of misdiagnosis of LF for other endemic infections, such as typhoid or falciparum malaria [1[1][2][16][17],2,16,17], this time frame for effective LF treatment is extremely challenging [16]. Moreover, ribavirin has a high rate of side effects, such as hemolysis, that often require further medical intervention [15].

2. Lassa Fever Symptoms and Pathogenesis

LF symptoms typically appear 1–3 weeks post-infection [2]. Eighty percent of cases are asymptomatic or present with mild, non-specific febrile symptoms such as fever, sore throat, headache, and general malaise, that may be misdiagnosed as typhoid, malaria, or appendicitis [1,2,16,17][1][2][16][17]. The other 20% of cases progress to much more severe symptomology [2]. These clinical manifestations include diarrhea, hemorrhage, disorientation, respiratory distress, abdominal pain, vomiting, facial edema, and severe pharyngitis [1,2][1][2]. Neurological signs such as hearing loss, encephalitis, and tremors also occur [2]. Of note, this hearing loss manifests as sudden-onset sensorineural hearing loss (SNHL) in approximately one-third of patients and is irreversible in two-thirds of those cases [10,18,19][10][18][19]. Infections during pregnancy have a greater risk of death as well as spontaneous abortion [20]. Death will typically occur due to multiorgan failure approximately two weeks post-onset of symptoms [2]. The long-term sequelae, such as SNHL, are generating a huge socioeconomic burden across Western Africa, where stigmatization and isolation lead to increased rates of depression and unemployment [21]. Aid programs in Nigeria alone can cost upwards of $43 million each year [18].
Clinical laboratory findings include thrombocytopenia, leucopenia with lymphopenia, elevated blood urea and proteinuria [22]. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, and creatine phosphokinase (CPK) concentrations are also elevated in patient’s serum [17], often with a higher AST level than ALT level, suggesting that the transaminases in serum are not solely derived from damaged liver, but may also be from other tissues [23]. High viral titers are measured in the spleen, lung, liver, kidney, heart, mammary gland, and placenta [17]. The level of viremia has been correlated with the severity of disease outcome.
Current knowledge on the pathology of Lassa fever is still limited due to civil unrest and social taboos and customs when dealing with the deceased in endemic areas [22]. The knowledge on pathology of LF in humans is still largely lacking.  Available pathologic analysis of clinical cases indicates lesions in the spleen, liver, and adrenal glands [17]. Histologic analysis of the liver indicates significant eosinophilic necrosis and parenchymal cell necrosis with an infiltration of eosinophils in the sinusoids [1,17,24][1][17][24]. Spleen samples indicate a presence of eosinophilic necrosis, lymphoid depletion, atrophied white pulp, and fibrin deposits with an infiltration of lymphocytes and mononuclear cells [1,17,24][1][17][24]. Adrenal gland samples indicate multifocal adrenocortical cellular necrosis, often associated with inflammation [17]. Less frequent findings include petechiae of the gastrointestinal tract, interstitial nephritis, renal tubular injury, lymph node sinus histiocytosis, mild interstitial pneumonia, renal edema and hemorrhage, as well as mild interstitial mononuclear myocarditis [1,17,24][1][17][24]. No alterations are detected in placental, mammary, uterine, ovarian, pancreatic, central nervous system (CNS), or brain samples [17]. These observations were made from a study performed in 1982. Studies with non-human primates have provided valuable information regarding the pathogenesis of LASV infection. As there is a limitation in study with non-human primates (NHPs), a small animal model that can resemble pathological changes in LF patients is desired.

References

  1. Günther, S.; Lenz, O. Lassa fever. Br. Med. J. 1972, 4, 253–254. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1788780/ (accessed on 14 June 2019).
  2. Centers for Disease Control and Prevention. Lassa Fever. 2019. Available online: https://www.cdc.gov/vhf/lassa/index.html (accessed on 15 June 2019).
  3. Frame, J.D.; Baldwin, J.M., Jr.; Gocke, D.J.; Troup, J.M. Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. Am. J. Trop. Med. Hyg. 1970, 19, 670–676.
  4. Olayemi, A.; Oyeyiola, A.; Obadare, A.; Igbokwe, J.; Adesina, A.S.; Onwe, F.; Ukwaja, K.N.; Ajayi, N.A.; Rieger, T.; Gunther, S.; et al. Widespread arenavirus occurrence and seroprevalence in small mammals, Nigeria. Parasit Vectors 2018, 11, 416.
  5. Andersen, K.G.; Shapiro, B.J.; Matranga, C.B.; Sealfon, R.; Lin, A.E.; Moses, L.M.; Folarin, O.A.; Goba, A.; Odia, I.; Ehiane, P.E.; et al. Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus. Cell 2015, 162, 738–750.
  6. Manning, J.T.; Forrester, N.; Paessler, S. Lassa virus isolates from Mali and the Ivory Coast represent an emerging fifth lineage. Front. Microbiol. 2015, 6, 1037.
  7. Ehichioya, D.U.; Dellicour, S.; Pahlmann, M.; Rieger, T.; Oestereich, L.; Becker-Ziaja, B.; Cadar, D.; Ighodalo, Y.; Olokor, T.; Omomoh, E.; et al. Phylogeography of Lassa Virus in Nigeria. J. Virol. 2019, 93.
  8. Yun, N.E.; Ronca, S.; Tamura, A.; Koma, T.; Seregin, A.V.; Dineley, K.T.; Miller, M.; Cook, R.; Shimizu, N.; Walker, A.G.; et al. Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection. J. Virol. 2015, 90, 2920–2927.
  9. Welch, S.R.; Scholte, F.E.M.; Albariño, C.G.; Kainulainen, M.H.; Coleman-McCray, J.D.; Guerrero, L.W.; Chakrabarti, A.K.; Klena, J.D.; Nichol, S.T.; Spengler, J.R.; et al. The S Genome Segment Is Sufficient to Maintain Pathogenicity in Intra-Clade Lassa Virus Reassortants in a Guinea Pig Model. Front. Cell. Infect. Microbiol. 2018, 8, 240.
  10. Ibekwe, T.S.; Okokhere, P.O.; Asogun, D.; Blackie, F.F.; Nwegbu, M.M.; Wahab, K.W.; Omilabu, S.A.; Akpede, G.O. Early-onset sensorineural hearing loss in Lassa fever. Eur. Arch. Otorhinolaryngol. 2011, 268, 197–201.
  11. Dan-Nwafor, C.C.; Furuse, Y.; Ilori, E.A.; Ipadeola, O.; Akabike, K.O.; Ahumibe, A.; Ukponu, W.; Bakare, L.; Okwor, T.J.; Joseph, G.; et al. Measures to control protracted large Lassa fever outbreak in Nigeria, 1 January to 28 April 2019. Euro. Surveill. 2019, 24.
  12. World Health Organization. On the Frontlines of the Fight against Lassa Fever in Nigeria. 2018. Available online: http://www.who.int/features/2018/lassa-fever-nigeria/en/ (accessed on 15 June 2019).
  13. Nigeria Centers for Disease Control. 2018 Lassa Fever Outbreak in Nigeria. 2018. Available online: https://ncdc.gov.ng/themes/common/files/sitreps/00235292b8a3f55c01f9ea2eb15c8d3a.pdf (accessed on 15 June 2019).
  14. World Health Organization. Emergencies Preparedness, Response Lassa Fever. 2019. Available online: https://www.who.int/csr/don/archive/disease/lassa_fever/en/ (accessed on 16 June 2019).
  15. McCormick, J.B.; King, I.J.; Webb, P.A.; Scribner, C.L.; Craven, R.B.; Johnson, K.M.; Elliott, L.H.; Belmont-Williams, R. Lassa fever. Effective therapy with ribavirin. N. Engl. J. Med. 1986, 314, 20–26.
  16. Mustapha, A. Lassa fever: Unveiling the misery of the Nigerian health worker. Ann. Nigerian. Med. 2017, 11, 1–5.
  17. Walker, D.H.; McCormick, J.B.; Johnson, K.M.; Webb, P.A.; Komba-Kono, G.; Elliott, L.H.; Gardner, J.J. Pathologic and virologic study of fatal Lassa fever in man. Am. J. Pathol. 1982, 107, 349–356.
  18. Mateer, E.J.; Huang, C.; Shehu, N.Y.; Paessler, S. Lassa fever-induced sensorineural hearing loss: A neglected public health and social burden. PLoS Negl. Trop. Dis. 2018, 12, e0006187.
  19. Cummins, D.; McCormick, J.B.; Bennett, D.; Samba, J.A.; Farrar, B.; Machin, S.J.; Fisher-Hoch, S.P. Acute sensorineural deafness in Lassa fever. JAMA 1990, 264, 2093–2096.
  20. Price, M.E.; Fisher-Hoch, S.P.; Craven, R.B.; McCormick, J.B. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ 1988, 297, 584–587.
  21. Dunmade, A.D.; Segun-Busari, S.; Olajide, T.G.; Ologe, F.E. Profound bilateral sensorineural hearing loss in nigerian children: Any shift in etiology? J. Deaf Stud. Deaf Educ. 2007, 12, 112–118.
  22. Khan, S.H.; Goba, A.; Chu, M.; Roth, C.; Healing, T.; Marx, A.; Fair, J.; Guttieri, M.C.; Ferro, P.; Imes, T.; et al. New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral. Res. 2008, 78, 103–115.
  23. Johnson, K.M.; McCormick, J.B.; Webb, P.A.; Smith, E.S.; Elliott, L.H.; King, I.J. Clinical virology of Lassa fever in hospitalized patients. J. Infect. Dis. 1987, 155, 456–464.
  24. Winn, W.C., Jr.; Walker, D.H. The pathology of human Lassa fever. Bull. World Health Organ. 1975, 52, 535–545.
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