Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study.

BACKGROUND: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. METHODS: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. FINDINGS: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50). INTERPRETATION: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. FUNDING: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.

Remote-Controlled and Pulse Pressure-Guided Fluid Treatment for Adult Patients with Viral Hemorrhagic Fevers.

Circulatory shock, caused by severe intravascular volume depletion resulting from gastrointestinal losses and profound capillary leak, is a common clinical feature of viral hemorrhagic fevers, including Ebola virus disease, Marburg hemorrhagic fever, and Lassa fever. These conditions are associated with high case fatality rates, and they carry a significant risk of infection for treating personnel. Optimized fluid therapy is the cornerstone of management of these diseases, but there are few data on the extent of fluid losses and the severity of the capillary leak in patients with VHFs, and no specific guidelines for fluid resuscitation and hemodynamic monitoring exist. We propose an innovative approach for monitoring VHF patients, in particular suited for low-resource settings, facilitating optimizing fluid therapy through remote-controlled and pulse pressure-guided fluid resuscitation. This strategy would increase the capacity for adequate supportive care, while decreasing the risk for virus transmission to health personnel.

Antibody therapy for Lassa fever.

Serum from convalescent Lassa fever patients was previously shown to be ineffective as a source of protective antibodies in some early studies. Subsequently, monoclonal antibodies (MAbs) to the Lassa virus (LASV) glycoprotein produced by memory B cells of West African patients who survived Lassa fever were identified. Development of MAbs as potential Lassa immunotherapeutics was facilitated by structural studies and mutational analyses that identified protective epitopes on the prefusion form of the LASV glycoprotein. Human mAbs were screened for reactivity to different neutralizing epitopes, potency, and broad reactivity against multiple lineages of LASV. MAbs were downselected in a guinea pig model of Lassa fever. A cocktail of three human MAbs designated Arevirumab-3 rescued 100% of Cynomolgus macaques at advanced stages of disease more than a week post-infection. Antibody therapeutics may be further developed in clinical trials in endemic areas potentially offering a key treatment option for Lassa fever.

A short history of Lassa fever: the first 10-15 years after discovery.

This brief review is focused on the events surrounding the initial discovery of a new viral hemorrhagic fever in 1969 and the subsequent 10-15 years during which a substantial understanding of the disease was gained. In 1969, a series of sequential life-threating or fatal infections occurred among health care workers in Nigeria and the laboratory scientist who isolated and characterized the causative agent. The agent, Lassa virus was named after the geographical location of the first recognized human case. The new virus was shown to be related to lymphocytic choriomeningitis and to previously unclassified neotropical viruses, including Argentine and Bolivian hemorrhagic fevers, and a new taxonomic grouping, the Arenaviruses, was proposed. In 1970-72, three further epidemics occurred in Nigeria, Liberia and Sierra Leone, the first two involved nosocomial transmission, and the third was a community-based outbreak, during which the rodent reservoir host was identified. In 1976, a long-term research project commenced in Sierra Leone, which produced a rich body of data from prospectively designed studies on the clinical features, transmission, and treatment of the disease.

Report of a fatal case of Lassa fever in Parakou in 2018: clinical, therapeutic and diagnostic aspects.

BACKGROUND: Lassa fever is one of the most lethal neglected tropical diseases in West Africa. It is a serious public health problem in this region of Africa where it is endemic in several countries. However, it remains a very little known disease by healthcare workers. The lack of specificity of its clinical manifestations makes its diagnosis difficult even in an epidemic context. CASE PRESENTATION: We report here a confirmed case of Lassa fever whose diagnosis could not be suspected until 11 days after the symptomatology began. This case was recognized as a suspected case of Lassa fever in the Internal Medicine Department of the Regional and Teaching Hospital of Borgou due to the persistence of the fever and the worsening of the patient's clinical condition despite triple antibiotic therapy in general and especially due to the appearance of hemorrhages. Confirmation of the presence of Lassa fever virus by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) assay on blood sample was obtained after his death despite late initiation of Ribavirin treatment. CONCLUSION: This case challenges Benin's health authorities on the need to facilitate access to diagnosis of viral hemorrhagic fevers and to train caregivers at all levels of the health system for better management of these diseases.

Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study.

BACKGROUND: Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause differences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever. METHODS: We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality. FINDINGS: Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1·4 times increase in mortality risk for each 10 years of age (p=0·00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0·00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4·63 [SD 1·04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8·6 for patients without clinical history of fluid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1·3; p=0·046), aspartate aminotransferase (OR 1·5; p=0·075), and potassium (OR 3·6; p=0·0024) were independent predictors of death. INTERPRETATION: Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might significantly reduce mortality. FUNDING: German Research Foundation, German Center for Infection Research, Howard Hughes Medical Institute, US National Institutes of Health, and World Bank.

Management of a Lassa fever outbreak, Rhineland-Palatinate, Germany, 2016.

Due to rapid diagnosis and isolation of imported cases, community outbreaks of viral haemorrhagic fevers (VHF) are considered unlikely in industrialised countries. In March 2016, the first documented locally acquired case of Lassa fever (LF) outside Africa occurred, demonstrating the disease's potential as a cross-border health threat. We describe the management surrounding this case of LF in Rhineland-Palatinate - the German federal state where secondary transmission occurred. Twelve days after having been exposed to the corpse of a LF case imported from Togo, a symptomatic undertaker tested positive for Lassa virus RNA. Potential contacts were traced, categorised based on exposure risk, and monitored. Overall, we identified 21 contact persons with legal residency in Rhineland-Palatinate: seven related to the index case, 13 to the secondary case, and one related to both. The secondary case received treatment and recovered. Five contacts were quarantined and one was temporarily banned from work. No further transmission occurred. Based on the experience gained during the outbreak and a review of national and international guidelines, we conclude that exposure risk attributable to corpses may currently be underestimated, and we present suggestions that may help to improve the anti-epidemic response to imported VHF cases in industrialised countries.

Differential Immune Responses to New World and Old World Mammalian Arenaviruses.

Some New World (NW) and Old World (OW) mammalian arenaviruses are emerging, zoonotic viruses that can cause lethal hemorrhagic fever (HF) infections in humans. While these are closely related RNA viruses, the infected hosts appear to mount different types of immune responses against them. Lassa virus (LASV) infection, for example, results in suppressed immune function in progressive disease stage, whereas patients infected with Junín virus (JUNV) develop overt pro-inflammatory cytokine production. These viruses have also evolved different molecular strategies to evade host immune recognition and activation. This paper summarizes current progress in understanding the differential immune responses to pathogenic arenaviruses and how the information can be exploited toward the development of vaccines against them.

Research efforts to control highly pathogenic arenaviruses: a summary of the progress and gaps.

Significant progress has been made in the past 10 years in unraveling the molecular biology of highly pathogenic arenaviruses that are endemic in several West African countries (Lassa fever virus) and in some regions of South America (Argentine and Bolivian hemorrhagic fever viruses). While this has resulted in proof-of-concept studies of novel vaccine candidates in non-human primates and in the discovery of several novel antiviral small molecule drug candidates, none of them has been tested in the clinic to date. The recent Ebola outbreak in West Africa has demonstrated very clearly that there is an urgent need to develop the prophylactic and therapeutic armamentarium against viral hemorrhagic fever viruses as part of a global preparedness for future epidemics. As it pertains to this goal, the present article summarizes the current knowledge of highly pathogenic arenaviruses and identifies opportunities for translational research.

Diagnostic proficiency and reporting of Lassa fever by physicians in Osun State of Nigeria.

BACKGROUND: Lassa fever is highly contagious and commonly results in death. It is therefore necessary to diagnose and report any suspected case of Lassa fever to facilitate preventive strategies. This study assessed the preparedness of physicians in the diagnosis and reporting of Lassa fever. METHODS: The study design was descriptive cross-sectional. The consenting medical doctors completed a self-administered questionnaire on the diagnosis and reporting of Lassa fever. Descriptive and inferential statistics were used in data analyses. RESULTS: One hundred seventy-five physicians participated in the study. The mean age was 41.5 ± 10.9 years (range, 24-75 years). Most of the physicians were male (78.9%) and had practiced medicine ≥ 20 years (51.5%). Most of the physicians had a good knowledge regarding the diagnosis and reporting of Lassa fever; however, none of the physicians had ever diagnosed or reported a suspected case. Predictors of good knowledge include male sex, not practicing at a secondary health care level and post graduation year more than 20 years. CONCLUSION: There is disparity in knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. Thus, it is necessary to improve the knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever.

Lassa fever: the challenges of curtailing a deadly disease.

Today Lassa fever is mainly a disease of the developing world, however several imported cases have been reported in different parts of the world and there are growing concerns of the potentials of Lassa fever Virus as a biological weapon. Yet no tangible solution to this problem has been developed nearly half a decade after its identification. Hence, the paper is aimed at appraising the problems associated with LAF illness; the challenges in curbing the epidemic and recommendations on important focal points. A Review based on the documents from the EFAS conference 2011 and literature search on PubMed, Scopus and Science direct. The retrieval of relevant papers was via the University of British Columbia and University of Toronto Libraries. The two major search engines returned 61 and 920 articles respectively. Out of these, the final 26 articles that met the criteria were selected. Relevant information on epidemiology, burden of management and control were obtained. Prompt and effective containment of the Lassa fever disease in Lassa village four decades ago could have saved the West African sub-region and indeed the entire globe from the devastating effect and threats posed by this illness. That was a hard lesson calling for much more proactive measures towards the eradication of the illness at primary, secondary and tertiary levels of health care.

[An update on Lassa virus]. / Le virus lassa, état des lieux.

Lassa virus, the etiologic agent of Lassa hemorrhagic fever, infects 100,000 to 300,000 people every year in West Africa with an overall mortality rate ranging from 1 to 2%. It was discovered in 1969 and remains a significant public health risk in endemic areas. Because airborne transmission is possible and mortality can be high under certain conditions, Lassa virus has been classified as a category A bioterrorism agent. Early diagnosis is difficult due to insidious non-specific onset and to the great genetic divergence of the virus that makes RT-PCR assays unreliable. The lack of proper diagnostic tools promotes nosocomial infection and diminishes the efficacy of treatment. Recently, numerous advances have been made in the development of both diagnostic and vaccination techniques. The purpose of this review is to present an update on that research as well as the current epidemiology of Lassa virus.

Lassa virus infection in Nigeria: clinical perspective overview.

Lassa fever is a severe, often fatal, hemorrhagic fever caused by Lassa virus, an Arenavirus that can be transmitted to humans from asymptomatically infected multimammate rats. The speculation is that Lassa viral infection may affect between 2 to 3 million people each year in certain portions of the West African region, causing a mortality of about 10000 during the same period. Lassa fever is one of the endemic zoonosis in Nigeria with a high probability for nosocomial transmission due to several health care sector challenges. Although treatment is available for Lassa fever, early diagnosis is still difficult in almost all Nigerian health care institutions. The intention of this clinical overview is to: (1) summarize the pertinent literature for clinicians in primary, secondary, and tertiary health care centers; and (2) suggest a need to use the information from basic research and laboratory diagnosis to incorporate international best practices into public health and clinical practice guidelines.