Геморрагическая лихорадка Ласса: систематический обзор вновь возникающих инфекционных заболеваний

• Малик Сумира
• Дееп А.
• Бора Дж.
• Мондал С.
• Агравал С.
• Рамнивас C.
• Наг C.
• Рустаги С.
• Барман И.

Резюме

Геморрагическая лихорадка Ласса (ГЛЛ) является распространенным заболеванием, которым страдает значительная часть населения - примерно 2-3 млн человек, проживающих в регионе Западной Африки. Инфекция, источником возбудителя которой являются грызуны, поражает местное население и медицинских работников, которые представляют группу риска. В энзоотичных районах ГЛЛ представляет угрозу общественному здравоохранению, приводит к значительной заболеваемости и летальным исходам, частота которых ≥50%. Это заболевание широко распространено в Западной Африке и является одной из наиболее распространенных и опасных для жизни вирусных геморрагических лихорадок. Мониторинг и предотвращение постоянно возникающих вспышек заболевания является сложной задачей в энзоотичных регионах из-за нехватки медицинских учреждений, диагностических лабораторий и центров по уходу. Имеет значение и низкий социально-экономический уровень жизни населения.

Отсутствие осведомленности общественности и наличие экологической ниши для Mastomys natalensis - естественного хозяина и резервуара вируса Ласса поддерживает эпидемический процесс ГЛЛ. Представленный обзор посвящен ранней диагностике и лечению ГЛЛ. Отмечена необходимость в вакцинах против ГЛЛ, отсутствие которых влияет на эффективность профилактических и противоэпидемических мероприятий.

Ключевые слова:лихорадка Ласса; эпидемия; эпидемиологический анализ; патогенез; вакцина; профилактика

The Lassa virus (LASV), a well-known member of the Arenaviridae family within the virus class, is characterised by its enclosed structure and single-stranded nature. Additionally, it is classified as a bipartite virus [1]. This ribonucleic acid (RNA) virus exhibits a spherical or rounded morphology, characterised by a consistent diameter ranging from 110 to 130 nm. The observed cross-sectional structure exhibits characteristics of “sandy or grainy particles”, namely ribosomes generated from the host cell. The RNA genomes are responsible for encoding four distinct proteins. These include the precursor nucleoprotein (NP) and glycoprotein (GP) found in the smaller segment, as well as the RNA-dependent RNA-polymerase and matrix really interesting new gene (RING) zinc-finger protein present in the larger segment [1, 2]. The Lassa virus has a high degree of nucleotide variety, which is intricately associated with the clustering of strains across several geographical regions. Through extensive examinations, researchers have successfully discovered six prominent clades or lineages of Lassa mammarenavirus. These clades are categorised as Clades I to III, which are predominantly seen in Nigeria, Clade IV, prevalent in Sierra Leone, Guinea, and Liberia, Clade V, primarily observed in southern Mali, and Clade VI, an emerging lineage originating from Togo [3]. These strains possess a notable characteristic known as the capacity for temporal transformation. The ongoing Nigerian Lassa fever epidemic has led to the identification of a novel lineage, thus increasing the total number of lineages to seven [4, 5]. The considerable genetic diversity exhibited by the LASV has implications for the advancement of diagnostic molecular assays and the creation of a universally effective vaccine against Lassa illness. The inherent variety of the virus poses a significant challenge in developing a test for diagnosis or vaccination that can effectively combat its presence across diverse geographic regions, irrespective of the particular strain [5-7]. Additionally, it has the potential to impact the clinical manifestation and severity of an infection [8-13].

Mastomys natalensis, commonly referred to as the “multimammate rat”, is widely believed to serve as the animal reservoir for the LASV. The organism in question is a member of the Mastomys genus, a widely distributed rodent species that predominantly engages in reproduction within the West African region [14-16]. The rats get the virus during fetal development and maintain it persistently throughout their lifespan. Rats infected with LASV do not exhibit clinical manifestations of illness, but rather excrete the virus through their urine and fecal matter. The identification of Mastomys erythroleucus and Hylomyscus pamfi as novel rodent reservoirs has the potential to influence the dynamics of LASV transmission and the distribution of Lassa fever patients over time. This finding challenges the traditional assumption that Mastomys natalensis solely serves as the natural reservoir for the virus [16, 17].

Mode of transmission of Lassa virus

The primary or first infection in humans is induced by direct or indirect contact with rodents, namely those carrying Lassa fever [16, 18, 19]. Individuals residing in rural settings, which are commonly inhabited by Mastomys rats, have an elevated susceptibility to acquiring Lassa Hemorrhagic Fever (LHF) or Lassa Infection, particularly in areas characterised by inadequate hygiene practices or densely populated dwellings [13, 20-22]. During periods of arid climatic conditions, Mastomys rats exhibit a tendency to intrude into residential dwellings in search of sustenance. Human infection with LASV occurs through the transmission of bodily fluids, such as urine, fecal matters, blood, or tissues, from Mastomys rats harboring the pathogen. Exposure to hazardous substances, which may arise via contact with unpleasant materials, intake of contaminated food, or direct interaction with open wounds or sores, can result in the onset of infection [22-26]. The transmission of secondary infections (person-to-person) among individuals has been associated with several factors, including individuals living in homes with overcrowded conditions, families seeking care for an ill relative, and local communities engaging in funeral practices.

Pathogenesis and virulence factors

The Lassa virus is classified as an enveloped, negative-sense, single-stranded RNA virus. The genome comprises two ambisense sections, namely the large and small segments. The important region encodes both RNA polymerase (L) and a zinc-binding protein (Z), which has similarities to the matrix protein found in other RNA viruses [27]. The concise segment encompasses the genetic information for the envelope of GP and NP combination, known as GPC. A stable hairpin loop is formed by an intergenic (IGR) non-coding region, which serves to separate the coding regions of each segment [28]. The IGR is involved in the processes of viral assembly or budding, as well as structure-dependent transcription termination.

The NP, which is the principal structural protein, consists of nucleocapsid proteins that play a vital role in viral RNA replication, transcription, and the production of virions. The inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKK-e) protein is utilised to inhibit the retinoic acid-inducible gene-I (RIG-I) - like pathway of the innate immune response by its binding to the kinase domain [29]. The NP portion of the LASV genome, which has been extensively sequenced, plays a crucial role in distinguishing various strains and lineages. The envelope protein, responsible for facilitating viral attachment and cell penetration, is synthesised by the GP complex (GPC). The lipid bilayer of the mature virion undergoes proteolytic transformation mediated by the host cell’s subtilizing SKI-1/S1P, resulting in the formation of a heterotrimer. Every heterotrimer consists of a stable signal peptide (SSP) that is myristoylated, which is essential for the processing and functioning of GPC. Additionally, it contains a GP2 protein that belongs to the class-I membrane fusion category, as well as a GP1 domain responsible for receptor binding [30]. The Z protein plays a crucial role in the formation of the matrix layer of the virions, whereas the L RNA polymerase is primarily responsible for the processes of transcription and replication. The pathway of pathogenesis is briefly illustrated in Fig. 1.

Clinical features

Nevertheless, it is important to note that person-to- person transmissions can also contribute to the spread of LHF. A significant proportion of LHF cases is attributed to the transfer of the LASV from rodents to humans, which occurs through direct contact with infected animals or their excreta [31]. Although infection with LASV can result in illnesses in humans, it is widely believed that the virus causes asymptomatic infection in its natural animal reservoirs. These reservoirs include several species of multimammate rodents such as Mastomys natalensis, Mastomys erythroleucus, and Hylomyscus pamfi. Additionally, experimental infection of rodents, such as Mus musculus (house mouse) and Rattus rattus, has also been shown to result in asymptomatic infection. This observation demonstrates the longstanding coevolution between LASV and wild rodent species, which may serve as potential reservoirs for the virus [32]. In the West African region, the incidence of LHF exhibits a notable increase during dry seasons, followed by a subsequent decrease during wet seasons.

The incubation period of LHF typically spans a duration of 7 to 21 days, which is equivalent to 1-3 weeks, subsequent to the individual’s exposure to the infectious agent. Based on data provided by the World Health Organization (WHO), it has been shown that over 80% of individuals infected with LASV do not exhibit any symptoms, indicating an asymptomatic state. Conversely, a minority of around 20% of affected patients experience the onset of severe, multisystemic illnesses [33]. The clinical diagnosis of LHF can provide a significant challenge due to the often mild first signs and symptoms, which often resemble those of other enteric fevers. Individuals who are indigenous to West Africa or those who have recently visited a region where LHF is known to be prevalent, and are experiencing a fever exceeding 38 °C (100.4 °F), should be evaluated for the possibility of being afflicted with the illness if their symptoms do not show signs of improvement following the administration of antimalarial or antibiotic treatments [34]. Patients with mild LHF commonly have symptoms resembling those of influenza, including fever, fatigue, tiredness, and cephalalgia.

In the initial phases of the illness progression, individuals often experience joint stiffness, lower back pain, a dry cough, and a sore throat as common manifestations. According to research findings, a significant proportion, specifically 70%, of individuals afflicted with severe LHF experience pharyngitis, a condition characterised by the inflammation of the pharynx. This inflammation may lead to the formation of pseudo membranes on the tonsils, exhibiting areas of yellow to white discharge [34]. In a significant proportion of cases, individuals afflicted with symptomatic LHF exhibit gastrointestinal symptoms such as diarrhea, vomiting, and abdominal discomfort, with prevalence rates ranging from 50 to 70%. Following the onset of symptoms, it is common for mild illnesses to have a recovery period of approximately 8 to 10 days. Nevertheless, over a span of 6 to 10 days subsequent to contracting the virus, individuals afflicted with LHF have a rapid deterioration in their condition. The ability to predict the progression of a disease based on distinct symptomatology and levels of viremia is a plausible proposition. Patients with serum virus titers over 10³ tissue culture infectious dose (TCID50/mL) are at a significantly higher risk of experiencing a life-threatening result, with the likelihood being 21 times greater. The TCID50 refers to the viral dose required to infect 50% of the target cells in a culture of mammalian cells. Additionally, elevated levels of aspartate aminotransferase (AST), a cellular enzyme that serves as an indicator of tissue damage, are observed. The occurrence of viremia reaches its highest point between 4 to 9 days following the onset of symptoms, then decreasing as the virus exits the bloodstream, often within a three-week period from the initial manifestation of symptoms. However, individuals who exhibit severe symptoms of LHF and have high levels of viremia often do not elicit a sufficient immune response to effectively control the transmission of the virus. This ultimately results in a poor prognosis or even death.

Instances of severe LHF are often characterised by heightened vascular permeability, resulting in facial edema, pleural effusions, and pericardial effusions. Severe cases of LHF can lead to the manifestation of acute respiratory distress, characterised by the presence of laryngeal edema and fluid accumulation inside the pulmonary cavity. Mucosal hemorrhage is observed in around 15 to 20% of severe cases of LHF characterised by hypotension. Mortality is a common outcome (table 1) observed within a 14-day period subsequent to the manifestation of symptoms related to hypovolemic shock and encephalopathy. During the advanced stages of the sickness, individuals may have symptoms such as disorientation, atypical gait patterns, convulsions, loss of consciousness, and seizures. In certain cases, patients may exhibit tremors shortly before dying from the illness.

Phases or outbreaks of Lassa Fever Outbreaks in Nigeria

The Lassa virus, a zoonotic and highly lethal virus, has caused a widespread outbreak of viral hemorrhagic fever in many regions of West Africa, including Liberia, Nigeria, Guinea, and Sierra Leone [35]. The primary reservoir host for LASV is Mastomys natalensis, a species of rat known for its many mammary glands. This rodent species is widely distributed over different areas of West Africa, making it a significant source of viral transmission. The initial documented instance of LHF dates back to 1969; however, earlier research suggests that the continuous transmission of this viral pathogen to people has been occurring for over a century. Presently, the prevalence of this issue remains a substantial matter of public health in certain regions of West Africa, manifesting in around 3 million instances of infection and an estimated 67 000 fatalities on a yearly basis. The extensive genetic variability exhibited by this virus is a formidable obstacle for researchers and the medical community engaged in its detection and therapeutic intervention.

The infectious disease is currently referred to as “Lassa fever” due to the identification of its initial symptom in the geographically isolated Yedseram River valley town of Lassa, located in the northeastern region of Nigeria [36]. The very first individuals impacted were missionary nurses who contracted the infection while fulfilling their professional duties at a remote clinic inside this particular region. Tragically, these individuals ultimately died from the illness. Subsequently, a third nurse became afflicted and was promptly sent to a medical facility situated in New York City, where she successfully recuperated from the infection. The plasma containing a high concentration of antibodies derived from her body was subsequently utilised. The blood and other samples obtained from the infected nurses were analysed at the Arbovirus Research Unit located at Yale University, where the novel virus was effectively isolated. Two researchers employed at the research unit contracted the infection, resulting in one fatality and the survival of the second individual. The surviving researcher received passive immunotherapy treatment, wherein blood was administered from a nurse who had earlier overcome the infection.

Subsequent to the aforementioned period, numerous instances of LHF have occurred in various geographical areas within Nigeria, involving Jos, Onitsha, Zonkwua, Abo Mbaise, Owerri, Epkoma, and Lafiya. During the 1970s and 1980s, a comprehensive analysis was conducted to identify the primary transmission locations of LHF in Nigeria. The findings revealed that three major regions were particularly affected by this disease. These regions included the area surrounding Lassa in the north-eastern part of the country, as well as Jos located in the central region [37]. The dry season is considered the most favourable period for the transmission of LHF, typically reaching its highest incidence between the months of December and February [38]. Between 1970 and 1972, three separate epidemic outbreaks took place in various regions of Western Africa, including in Nigeria, Liberia, and Sierra Leone. Nosocomial transmission was frequently observed in the preceding two epidemics, whereas the third epidemic primarily exhibited community-based transmission [39].

In 1989, Nigeria experienced an additional occurrence of LHF. The affected individual, a 43-year-old Nigerian native who had been in the United States for eleven years at the time, contracted the infection. The individual’s maternal figure succumbed to a terrible viral illness in Nigeria, followed by the subsequent manifestation of a comparable ailment among other members of the household. In January 1989, the individual arrived in Nigeria to reunite with his family, coinciding with a period of severe illness experienced by his mother. In the month of February, the individual presented with pronounced symptoms resembling those of influenza, specifically resembling the symptoms associated with LHF. Following the individual’s demise due to additional complications, a post-mortem examination successfully detected and verified the presence of the LHF antigen. Various degrees of examinations were administered to assess and oversee interactions, with appropriate measures taken to provide care for individuals affected by these interactions.

In the years 2003 and 2004, a study was conducted in Irrua to investigate the transmission patterns of a viral sickness that had reached epidemic proportions in the Edo state of Nigeria. The inquiry was conducted within a hospital setting to gain a more comprehensive understanding of the spread of this disease [4]. The examination was conducted within the laboratory of the University of Lagos, wherein a variety of samples were analysed and tests were assessed at various levels [40]. Based on the documented results, it has been shown that approximately 6% of individuals presenting with fever have been diagnosed with a confirmed infection caused by the LASV. In a report from 2005, the Abakaliki Hospital in Ebonyi State documented four cases, consisting of one male and three females. Out of these cases, only one female patient was able to recover. In 2007, a 19-year-old female patient presented at the Jos Plateau State Hospital with the aforementioned illness, ultimately dying from it. In the year 2008, three individuals succumbed to this perilous ailment, with one individual being 37 years old and the other two individuals being 38 years old. Furthermore, a total of 30 individuals were diagnosed with the sickness, of which two were male. These two male patients were then admitted to the Jos, Plateau State Hospital for examination and treatment. Notably, one of the male patients successfully recovered from the disease.

During the period spanning from January to April 2016, Nigeria experienced a notable surge in the total count of LHF infections, with a recorded 268 cases and 147 fatalities. The transmission of the disease has been observed across 23 out of the 36 states in Nigeria [41]. In the year 2018, there was a notable increase in the incidence of LHF infections within the same geographical area. Subsequent investigations revealed that this rise in cases was multifactorial in nature and not attributable to the emergence of a new strain. As of the 42nd week of 2022, a significant proportion of the population impacted in Nigeria falls under the age range of 21 to 30 years. The incidence and documentation of incidents exhibited a progressive rise in comparison to the corresponding timeframe in 2021.

The absence of comprehensive assessment pertaining to testing procedures has resulted in a scarcity of vast and comprehensive data regarding Nigerian LHF prior to the year 2000. The prevalence of the pervasive virus in Nigeria and the lack of complete data on how the infection spreads vary widely. However, the currently available published data indicate that the outbreaks of this potentially lethal disease have been reduced in terms of scale and duration. It is anticipated that these outbreaks will manifest in a more severe form among the native populations of Nigeria and other regions in West Africa.

Factors contributing to re-emergence of Lassa Fever epidemics

Nosocomial transmission

The initial detection of the LHF outbreak occurred within several healthcare facilities, where the virus subsequently disseminated by nosocomial transmission. This incident transpired as a result of insufficient implementation of infection prevention and control protocols [42]. The transmission of the virus occurred within hospital settings and then extended to various communities as a result of inadequate precautions taken during contact with human fluids, the utilisation of a single needle in multiple patients, and substandard sanitization and sterilisation practices pertaining to medical equipment, among other factors. The insufficiency of preventive measures and control strategies for LASV infection in many nations contributes to the necessity for more funding and assistance for the public health care system.

Travel and migration

The occurrence of conflicts in Liberia, Nigeria, and Sierra Leone has prompted individuals to relocate from hazardous areas to refugee settlements. Consequently, the migrants were compelled to reside in unsanitary and overcrowded refugee communities or camps. The living conditions in the surrounds and atmosphere were highly conducive to the proliferation of LASV. The migration of substantial human populations to geographically unsuitable areas has resulted in an escalated proximity between rodents and human settlements, hence augmenting the potential for the transmission of LASV [43]. Moreover, there has been a significant increase in cross-border travel over the last decade, which has heightened the potential for the transmission of LASV infection between countries where the disease is prevalent and those where it is not [44].

Public health systems

The rapid and widespread proliferation of the fever throughout several regions in West Africa can be primarily attributed to the inadequacy of public health measures and the fragility of the public health infrastructure. The fundamental components of an ideal public health system are effective health education, a robust surveillance system, comprehensive hospital prevention and control programmes, efficient risk communication strategies, well-defined public health policies and laws, routine and supplemental immunisation programmes, and a strong epidemic readiness and response framework [45].

Climate and environment

The reproductive cycle of Mastomys natalensis rats occurs continuously throughout the year, with the highest fertility rates observed during the wet season. The proliferation of rodents is promoted by advantageous environmental conditions, including timely precipitation, extended periods of rainfall, and increased vegetation coverage. The occurrence and spread of LHF in West African countries are significantly influenced by seasonal dynamics. The Mastomys natalensis rodents exhibit a preference for grain crops commonly cultivated by subsistence farmers residing in isolated settlements in West Africa. The mice’ search for grains has resulted in frequent contact between farmers and rats, as well as exposure to their bodily fluids and excrement, which subsequently contaminates agricultural products [46].

Social factors

The dissemination of the LASV is also influenced by human activity, as has been shown. Actions including hunting and deforestation have been seen to contribute to the movement of rodents towards human houses in search of sustenance and refuge, thereby leading to the dissemination of infectious diseases. Land-use practices and demographic characteristics, such as age, profession, schooling, and sex-related exposure risk, exert an influence on LASV infections [47]. The application of herbicides on agricultural areas, the deliberate burning of grasslands for the purpose of land preparation, the intensive exploitation of soil, the cultivation of wetlands, the implementation of rodent control measures, and various other practices have all led to the frequent instances where target rodents come into close proximity with vulnerable individuals. The aforementioned interactions facilitate the transmission of LASV from reservoir hosts to human populations, resulting in subsequent infections [48].

Effects of civil war and conflicts

Sierra Leone saw a devastating ten-year civil strife from 1991 to 2002. The healthcare infrastructure was dismantled, leading to the cessation of regular training programmes for healthcare professionals. The illness monitoring system was adversely affected, resulting in either missed or delayed identification of LHF cases. The reemergence of LASV was facilitated by various factors, including the deterioration of the country’s health infrastructure, inadequate infection prevention and control measures, and insufficient disease management initiatives [43]. Lassa fever resurfaced in the nation during the post-conflict period, several years after its initial isolation [49]. The identification and eventual reappearance of LHF cases in the nation throughout the postwar era could perhaps have been impacted by the gradual improvement of the public health system. An enhanced surveillance system yields the identification of previously undetected issues. The unstable healthcare system was undermined during and after the war, despite the potential it held. The influence of conflicts on the development of (LHF) was well demonstrated during the Biafra civil war in the late 1960s. Based on the findings of the study conducted on the NP sequences of LASV, it has been seen that the diversity of the viral population in Nigeria had a decline during the period spanning from 1967 to 1970, which may be attributed to the civil war. However, subsequent analysis reveals that the diversity has since reached a stable state over the course of the previous 25 years [50]. The available data provides evidence in support of the concept that the occurrence and dissemination of Lassa illness are influenced by violence and armed conflicts.

COVID-19 pandemic influence

The epidemiological pattern of LHF from 2016 to 2022 exhibits similarities. In contrast to previous years’ peak seasons for LHF transmission in Nigeria, the COVID-19 pandemic exhibited the most notable peak in LHF incidence. The potential impact of COVID-19 infection on the host’s immune response to other viral illnesses, particularly viral hemorrhagic fevers (VHFs), could provide an explanation for this phenomenon. The principal cellular targets of the LASV are the macrophages and dendritic cells (DCs), which are classified as myeloid cells. These cells exhibit migratory behaviour towards the lymph nodes, but, during LASV infection, the virus targets DCs in a nascent and quiescent state. The differential impact of LASV and COVID-19 on the function of antigen-presenting cells (APCs) may be attributed to the absence of adaptive immune responses in severe cases of LHF. Upon first detection of a virus within the human body, the innate immune system promptly initiates a response characterised by the production of DCs to enhance the functionality of co-stimulatory molecules. Interferons (IFNs) play a crucial role in the activation of macrophages, facilitating antigen presentation and enhancing T-cell responses. The existence of many evasion methods employed by vertebrate viruses serves as compelling evidence highlighting the crucial role played by immune responses in countering viral infections [51]. As an example, the LASV effectively hampers the IFN response by impeding the detection of viral RNA, hence impeding the maturation of infected DCs. The evasion of the innate immune system by SARS-CoV-2 and its destabilising methods are believed to create opportunities for subsequent viral infections, including LASV [52]. The Factors contributing to the re-emergence of LHF epidemics are mentioned in Fig. 2.

Preventive measures (pre-clinical, clinical trials, measures and vaccines, medication, and vaccines)

Lassa fever is prevalent in the western regions of Africa, specifically Nigeria, Liberia, Guinea, and Sierra Leone [53]. The vector’s presence across the region poses a potential concern to the neighbouring countries as well. The mainstay of treatment for LHF is supportive care. Ribavirin has emerged as the most auspicious pharmaceutical agent for the therapeutic management of LHF. Ribavirin, being a guanosine analogue, has antiviral properties by exerting a virus-static effect on a wide range of viruses [54]. The methods of treatment commonly employed include convalescent plasma therapy and pharmacological interventions. The treatment of LHF is confronted with several significant problems. These challenges include the non-specific nature of illness presentation, which poses difficulties in obtaining accurate clinical diagnoses. Additionally, the disease exhibits high rates of transmissibility, further complicating treatment efforts. Moreover, there are issues related to limited accessibility to treatment options, exacerbating the overall management of the disease. Lastly, the cost of ribavirin, a commonly used antiviral medication, has been steadily increasing, posing financial burdens on healthcare systems and individuals seeking treatment. Furthermore, its implementation is restricted to a few number of specialised medical facilities. The mechanism is elucidated in Fig. 3. In order to mitigate the risk of contracting LHF, it is imperative to adhere to certain preventive measures. These measures include exercising caution in regions where the disease is prevalent by avoiding contact with rodents, as well as minimising the potential for person-to-person transmission through the maintenance of personal hygiene practices. It is imperative to implement isolation measures for those afflicted with LHF. Additionally, healthcare professionals must exercise caution while handling bodily fluids, diligently practise hand hygiene, and adhere to contact and droplet precautions [55].

The convalescent plasma treatment involves the administration of plasma obtained from a previously infected individual who has successfully recovered, to a patient who is now experiencing an active infection. All patients who received treatment within a ten-day window from the initial start of symptoms had a complete survival rate, whereas 75% of patients who received treatment beyond the ten-day mark experienced survival. In cases where viremia levels were elevated and aspartate transaminase levels above 150 IU, a therapeutic approach involving the administration of convalescent plasma alongside oral or intravenous ribavirin was employed. Favipiravir is a pharmacological compound classified as a nucleoside analogue, which functions by inhibiting the activity of RNA-dependent RNA polymerase in influenza viruses. Additionally, it demonstrated a reduction in viremia. However, it was accompanied by adverse symptoms such as nausea, transaminitis, and vomiting. Stampidine is a nucleoside derivative that is derived from stavudine (d4T). The compound exhibits preventive action in mice as a retroviral reverse transcriptase inhibitor. The substance has the ability to permeate the central nervous system (CNS), hence exerting a protective function against problems affecting the CNS [56]. However, the effectiveness of these interventions in human beings is yet to be established. Amodiaquine, niclosamide, zoniporide, arbidol, and apilimod have demonstrated potential efficacy in the inhibition of the LASV [57]. Arbidol is a pharmacological agent used for the treatment of influenza, possessing the ability to impede the fusion of the virus with host cells by targeting the GP-mediated and virus-cell fusion processes [57]. The compounds 5-ethynyl-1-b-D-ribofuranosylimidazole-4-carboxamide (EICAR) and my­cophenolic acid (MPA) are known to specifically target the depletion of guanosine-5’-triphosphate (GTP) in viral organisms. Inosine monophosphate dehydrogenase (IMPDH) inhibitors have demonstrated efficacy in suppressing the replication of LASV at significantly lower concentrations compared to ribavirin [58]. Isavuconazole, a pharmacological drug with antifungal properties, exhibits an effective concentration (EC50) of 1.2 µM. It specifically acts on the stable signal peptide (SSP)-membrane fusion component (GP2) to impede the process of cell-to-cell fusion of the virus [56].

Currently, there is a lack of an officially sanctioned pharmaceutical intervention specifically designed for the exclusive management of LHF. The repurposing of drugs that have been approved by the FDA will expedite the therapeutic approach to address LHF. Two drugs that have been found for their ability to limit the entry of the virus by inhibiting the low-pH-induced membrane fusion are lacidipine and phenothrin. Additionally, the viruses’ entry was impeded, with the interface between SSP-GP2 serving as the specific target for entry inhibition. The access is impeded, hence hindering the reproduction and early dissemination of the virus [59]. Remdesivir exhibits effective inhibitory activity against the NP of the LASV [60]. Casticinis is a botanical pharmaceutical agent that exhibits potential therapeutic properties for the treatment of LHF. Bergamottin, a plant substance, demonstrated inhibitory effects on the entrance of LASV by impeding the process of endocytic trafficking [61]. The following table 2 presents a selection of pharmaceutical substances now undergoing clinical trials.

Currently, there are 21 vaccines for LHF in the preclinical stages, with a number of these vaccines being developed using innovative technology rather than traditional approaches. Regrettably, official approval for the treatment of LHF has not been provided by any of the aforementioned entities. The vaccinations comprise inactivated or killed viruses and virus-like particles, which include DNA vaccines as well [62], adenovirus-vectored vaccines [63], recombinant vesicular measles virus [64], vaccinia virus [65], and ML29 MOPV/LASV live reassortant [66], and also the recombinant stomatitis virus expressing GP (VSV-LASV-GPC) vaccine and LASSARAB [67]. Irrespective of the NP expression, vaccines that generate the whole LASV GP have been observed to confer protection against LHF in monkeys. Conversely, immunisations that solely exhibit the NP or a single GP gene do not offer any protective effects. Cytotoxic T cells typically confer protection against LHF. Simultaneously, it is important to note that there is no discernible association between pre-existing elevated levels of high-titer antibodies specific to Lassa NP and the subsequent protection against the associated sickness. The treatment and preventative strategies are succinctly outlined in Fig. 1. The process of vaccine development for the treatment of LHF is depicted in Fig. 4.

Conclusions and future perspectives

The ongoing spread of the LASV, a contagious illness linked to socio-economic deprivation, persists as a significant threat to the well-being of the general population and places a heavy burden on marginalised communities in West Africa, including Nigeria. LHF exhibits a high prevalence within the Nigerian population and poses significant implications for public health, necessitating prompt intervention. The containment of the ongoing illness outbreak and the provision of vaccinations, the primary therapeutic intervention for LHF, necessitate international aid. This measure would contribute to the mitigation of environmental health disparities associated with the LASV. Nevertheless, research has demonstrated that vaccinations can reduce the incidence of patient morbidity associated with LHF. The continual emphasis on the advancement of more efficient vaccinations with diverse modes of action remains imperative in order to mitigate the resurgence of LHF within susceptible communities. Lassa fever is often viewed as a disease that disproportionately affects individuals living in impoverished conditions, hence exerting a substantial influence on those with limited access to resources. Consequently, the allocation of enough money towards the development of a vaccine is deemed imperative. The virus can be regarded as a disregarded and indigenous pathogen in the West African region. Nevertheless, if we consider the insights gained from the COVID-19 pandemic, it becomes evident that the future dissemination of the virus is contingent upon the actions and choices made by individuals. Hence, the phenomenon of globalization and the increasing prevalence of international travel have raised concerns over the potential weaponization of diseases. Moreover, a considerable degree of ambiguity exists concerning the influence of the environment on the transmission of this virus within the West African sub-region. Therefore, it is recommended to initiate a comprehensive public awareness campaign at the community, state, regional, zonal, and national levels in order to educate the general population about the existing and potential risk factors linked to the LASV. An operational research system is necessary to implement the “One Health” approach, which aims to comprehensively understand the spatial and geographical patterns of risk factors and phylogenetics. This understanding will guide evidence-based decision-making, facilitate the mapping of reservoirs, and enable the development of tailored and timely integrated plans and strategic interventions to address the threats of disease epidemics in Nigeria and the sub-Saharan Africa region. After all [68], the escalation of LHF cases during an epidemic can be attributed to the dearth of essential resources necessary for managing clinical complications, as well as the shortage of adequately qualified personnel. Furthermore, it is imperative to enhance investment and foster collaboration among key stakeholders and impacted communities in Nigeria, West Africa, and worldwide in order to bolster the surveillance, early warning, readiness, and response system for the LHF outbreak [69]. The propagation of the LASV has been reported to have societal effects in addition to the potential worsening of Lassa illness. In order to optimise the care of LHF, it is advisable to incorporate educational and training components within the treatment facilities. In order to effectively mitigate the occurrence of LHF outbreaks, it is imperative to enhance the surveillance of public health, expand research efforts towards the development of innovative antiviral agents and vaccines, regulate rodent populations, and enforce governmental policies that facilitate the reconstruction of public health infrastructures and the reinforcement of vulnerable healthcare systems. In order to achieve global eradication of LHF and avoid its re-emergence, it is imperative to implement international measures such as technical help, financial support, and funding across nations.

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ЛИТЕРАТУРА/References

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