Le Infezioni in Medicina, n. 3 , 332-345, 2020 332 REVIEWS Past and current advances in Marburg virus disease: a review Ameema Asad1, Alifiya Aamir1, Nazuk Eraj Qureshi1, Simran Bhimani1, Nadia Nazir Jatoi1, Simran Batra1, Rohan Kumar Ochani1, Muhammad Khalid Abbasi2, Muhammad Ali Tariq3, Mufaddal Najmuddin Diwan1 1Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan; 2Department of Internal Medicine, Ziauddin Medical University, Karachi, Pakistan; 3Department of Internal Medicine, Dow International Medical College, DUHS, Karachi, Pakistan SUMMARY Marburg Virus (MARV), along with the Ebola virus, populated by the bats, are at an increased risk of con- belongs to the family of Filovirus and is cause of a lethal tracting the illness. The incubation period ranges from and severely affecting hemorrhagic fever. The Mar- 2-21 days and the clinical outcome can be broken down burgvirus genus includes two viruses: MARV and into three phases: initial generalized phase (day 1-4), Ravn. MARV has been recognized as one of utmost im- early organ phase (day 5 to 13) and either a late organ/ portance by the World Health Organization (WHO). convalescence phase (day 13 onwards). The case fatality rate of the virus ranges from 24.0 to Furthermore, the treatment of MARD is solely based 88.0% which demonstrates its lethal nature and the on supportive care. Much has been investigated in need for its widespread information. over the past half-century of the initial infection but The first case of the Marburgvirus disease (MARD) only a few treatment options show promising results. was reported in 1967 when lab personnel working In addition, special precaution is advised whilst han- with African green monkeys got infected in Germany dling the patient or the biospecimens. Disease-modify- and Serbia simultaneously. Following the initial case, ing agents and inhibitors of viral replications show many more outbreaks occurred around the world such constructive outcomes. as Uganda, Angola, Congo, Kenya and even in the It is crucial to identify the host of the virus and educate United States in 2008. It was soon found out that the the populations that are greatly at risk of the disease. MARV was a zoonotic virus and mainly contracted While much is being investigated to devise a vaccine, it from animal-to-human contact and further transmitted is important to educate Health Care Workers (HCWs) via human-to-human contact. The Egyptian fruit bat and close contacts facing the illness. Stopping the trans- (Rousettus aegyptiacus) is known to be one of the signif- mission remains the best measure that can be taken. icant sources of the infection and tourists visiting caves inhabited by these bats or workers accessing mines, Keywords: Marburg virus, Ebola virus n INTRODUCTION cludes a single species, Marburg marburgvirus, which is represented by two distinct viruses, arburg virus (MARV) is one of two viruses MARV and Ravn virus (RAVV) [1]. Both the Mof the Filovirus family in the order of Mon- EBOV and MARV genomes are about 19,000 nu- onegavirales which, along with Ebola virus cleotides long and are transcribed into eight ma- (EBOV), can cause a severe and fatal Marburg jor sub-genomic messenger RNAs (mRNAs), en- disease (MARD). The genus Marburgvirus in- coding for seven structural proteins [2]. Both vi- ruses are classified as category A pathogens by the Centers for Disease Control and Prevention Corresponding author (CDC) and select agents, with Marburg being Simran Batra rated as a Risk Group 4 Pathogen (requiring bi- E-mail: [email protected] osafety level 4-equivalent containment) by the Past, current and advances in Marburg virus disease 333 World Health Organization (WHO) [3]. The Hence, rare diseases with the possibility of fre- morphological traits of MARV when studied un- quent outbreaks must be addressed, so more clin- der a transmission electron microscope showed ical trials must be conducted to make a treatment pleomorphism, with filamentous, rod-shaped, regimen for such life-threatening diseases. There- cobra-like, spherical, and branch-shaped parti- fore, we wrote this comprehensive review of viral cles of uniform diameter but different lengths pathogenesis, clinical manifestation, manage- [4]. MARV was first discovered in 1967, when ment, and the advances made in efforts to combat outbreaks of hemorrhagic fever occurred simul- such a disease. taneously in laboratories in Marburg and Frank- furt in Germany, and Belgrade in Yugoslavia n METHODS (now Serbia). A total of 31 people became ill, in- cluding 25 laboratory workers, and medical per- A literature search was conducted using PubMed sonnel and a family member who had cared for and Google Scholar from their inception to No- them [5]. vember 2019 for this review. In order to refine the MARV is a zoonotic (animal-borne) virus and its search, the following keywords were incorporated: reservoir is the Egyptian fruit bat (Rousettus ae- (Marburg virus) AND (“epidemiology” OR “virol- gyptiacus) [6]. Previous literature shows that ma- ogy” OR “pathogenesis” OR “vector” OR “trans- jority of the primary infections of natural MARV mission” OR “reservoir” OR “symptom” OR “di- disease outbreaks so far have been linked to hu- agnosis” OR “management” OR “treatment” OR man entry into caves inhabited by bats (e.g., cave “vaccination” OR “prevention”). Any articles that visitors, mine workers) [7]. After an initial zo- were found in languages other than English were onotic transmission from an infected animal to a excluded. human occurs, the transmission is then ampli- The initial search included 2245 articles. 578 du- fied through close human-to-human contact. plicates found between Google Scholar and Pu- This can be through direct contact with bodily bMed were excluded. A total of 1667 titles and fluids and through contact with contaminated abstracts were scanned, of which 156 studies were fomites (objects or materials that are likely to found relevant. A further 14 exclusions were carry infection) [8]. made as full texts were not available for these. 142 Its clinical manifestations include abrupt onset of full texts were then retrieved, and a further 84 ex- high fever, severe headache and severe malaise clusions were made as the studies were beyond followed by severe watery diarrhea, abdominal the scope of this review. A total of 58 studies were pain with cramping, nausea and vomiting. Many included in this final review. patients develop severe hemorrhagic manifesta- tions later as the disease progresses. Both the Filo- Epidemiology viridae are associated with high case fatality rates The first outbreak of the MARD was reported in (CFR). WHO reports that the CFR of EBV ranges 1967 when the laboratory personnel working with from 25.0 to 90.0% while that of MARV ranges grivets (chlorocebusaethiops) which are green Afri- from 24 to 88% [9]. As of March 2018, there have can monkeys, brought in from Uganda, got infect- been thirteen outbreaks of MARV disease, most ed in Germany and Serbia (former Yugoslavia). occurring in sub-Saharan Africa; the largest of The grivets were reported to have been infected which occurred in Angola during 2004-2005 and with MARV and the personnel mainly contracted had a case-fatality rate of 90% [10, 11]. In lieu of the disease due to the direct handling of the tissue MARV posing a potential and severe threat to and organs of these infected wild animals [12, 13]. public health and safety, systemic surveillance is A total of 31 patients [25 primary, six secondary required to overcome its recurrence and rising infections] developed a severe illness which then mortality rates. resulted in seven of the patients dying of the dis- Considering the regular epidemics and a very re- ease [14]. Following the initial outbreak, more cas- cent pandemic, it is important to highlight the es emerged. Some of these cases supported noso- burden even of the rare diseases, primarily dis- comial transmission whilst only one case was re- eases such as MARD, which do not have a defini- ported that showed seminal transmission. A tive treatment with a high case-fatality rate. woman was reportedly infected from her hus- 334 A. Asad, A. Aamir, N.E. Qureshi, et al. band’s semen, who was already infected for al- sporadic cases supported the theory that there most three months [12]. were repeated infections. This was further con- In 1975, in Zimbabwe/South Africa three new firmed when 9 genetically different virus strains cases were reported. Amongst them was the in- were found out to be the source of transmissions dex patient who was on a visit to the Senoia caves of the disease during the outbreak. Furthermore, in Rhodesia (now Zimbabwe) with other tourists it became apparent that there had been cases in slept in places where insectivorous bats resided association with the mine in 1987 that were unre- [13, 15]. Their itinerary was a leading evidence for ported. These cases were previously called as bridging direct contact of bats and their discharge ‘hemorrhagic syndrome’ of Durba [7, 21]. Accord- as the cause of contraction of the disease [12]. ing to Languon S. et al., gold mine workers had In 1980, another outbreak was reported in Kenya. exposure to the fauna littered near the mine. The The infected patient was known to have visited mine had variety of animals such as rodents, bats, many small forested areas on multiple occasions frogs, shrews, cockroaches, and mouth flies; how- and fed the forests’ mammals and birds. Prior to ever, there was no report of direct exposure or in- the development of the illness, the patient had sect bites in the mine to the infected individuals also visited the Kitum cave with a huge popula- [12, 21]. Moreover, the work environment of the tion of bats live at Mount Elgon National park.