Epidemiology, ecology, and clinical presentation of VHFs

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Epidemiology, ecology, and clinical presentation of VHFs

EVD is a severe illness associated with hemorrhage and high fatality rates, and is thought to be of zoonotic origin. EVD is caused by 5 species in the genus Ebolavirus in the family Filoviridae: Zaire ebolavirus (more commonly known as ebolavirus or EBOV), Sudan ebolavirus (SUDV), Taï Forest ebolavirus (TAFV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESV). A sixth species, Bomboli ebolavirus, has recently been identified in bats in Sierra Leone, but has not been associated with human infection16. These ebolavirus species have been identified in outbreaks from geographically diverse parts of sub-Saharan Africa and epidemiologically have shown differing pathogenicity17 (Figure 2). EBOV was first described in 1976 in what is now DRC18, and was responsible for the largest outbreak on record in West Africa in 2013–1619 as well as the ongoing, second-largest outbreak in DRC. SUDV has been detected only in South Sudan and Uganda, whereas BDBV has been reported in both Western Uganda and Isiro district in the neighboring eastern DRC20, 21. TAFV was reported in a single non-fatal case in West Africa in 199422. No fatal human cases have been associated with RESV, which was first isolated in the USA from monkeys imported from the Philippines23.
The early stages of EVD typically manifest as fever, headaches, and myalgia, followed by gastrointestinal symptoms such as diarrhea, vomiting, abdominal pain, and dehydration. If not identified early and properly treated, the infection can progress to a hemorrhagic phase with bleeding from multiple orifices, produce neurological symptoms, and lead to shock that is often fatal. In the West African EVD outbreak, the clinical signs reported most frequently were fever (87.1%), fatigue (76.4%), loss of appetite (64.5%), vomiting (67.6%), diarrhea (65.6%), headache (53.4%), and abdominal pain (44.3%). Specific hemorrhagic symptoms were rare, with bleeding of unexplained orgin reported in only 18.0% of cases24. During a SUDV outbreak in northern Uganda in 2000, all laboratory-confirmed cases presented as febrile, and other frequently documented symptoms were asthenia, loss of appetite, cough, nausea or vomiting, and diarrhea25. Specific symptoms do not usually present during the incubation period, which ranges between 2–21 days. Identifying suspected EVD cases depends on the clinical symptoms and epidemiological links to confirmed or probable cases.
Ebolaviruses are thought to transmit from wildlife to the human populations through direct or indirect exposure to infected bat species (Figure 3). Bats have long been the suspected reservoir of ebolaviruses, and ebolavirus RNA and anti-ebolavirus antibodies have detected in some bat species16, 26. However, until the recent identification of Bomboli ebolavirus, no ebolavirus has been directly detected or isolated from bats. Non-human primates have long been recognized as potential sources of human ebolavirus infection, but their role as potential reservoirs is not widely accepted, since they are as suceptible to ebolavirus infection as humans27-30.

Marburgvirus

MVD is caused by MARV, which, like ebolaviruses, is also included in the filovirus family. MVD has similar characteristics to EVD, and is a severe, potentially fatal illness in humans and non-human primates, characterized by hemorrhagic signs indistinguishable from EVD. The disease was first described in 1967 in the German city of Marburg, where non-human primates imported from Uganda infected laboratory and animal care workers31. The incubation period of MARV ranges from 2 to 21 days, and early symptoms of MVD include sudden fever, fatigue, headache, nausea and vomiting, diarrhea, rash, and conjunctivitis. As the disease progresses, hemorrhagic signs are also accompanied by failure of multiple organs and disseminated intravascular coagulation. During a multidistrict MVD outbreak in 2012 in Uganda, nearly all confirmed and probable cases (96%) had fever, anorexia, fatigue, headache, and vomiting32, and half of confirmed and probable patients (50%) showed hemorrhagic symptoms. MVD, like other related VHFs, first manifests with non-specific symptoms, and definitive diagnosis relies on laboratory confirmation33.
In 2007, the CDC Viral Special Pathogens Branch (VSPB) viral ecology team identified R. aegyptiacus bats as the reservoir for MARV4, 34 (Figure 4). The identification was suggested after 2 tourists were retrospectively identified as having been infected with MARV after visiting a cave located in Queen Elizabeth National Park in Uganda; this cave was populated with a large colony of R. aegyptiacus bats. Additionally, a group of miners became infected with MARV after working in a nearby artisanal mine, which also hosted a large R. aegyptiacus fruit bat colony26.

Crimean-Congo hemorrhagic fever virus

Crimean-Congo hemorrhagic fever (CCHF) is an ancient viral disease, with human cases probably occurring as far back as the 12th century in present-day Tajikistan and other parts of central Asia. CCHFV was formally recognized in 1944 during an outbreak in the Crimean Peninsula35, 36. After the causative agent of this outbreak was characterized, it was later found to be related to a virus isolated from a febrile patient in the Kisangani area of the DRC in 195637, 38, leading to the combined name Crimean-Congo hemorrhagic fever virus. CCHFV is the most widely geographically distributed tick-borne disease in the world, affecting both animals and humans mainly in Eastern Europe, Asia, Middle East, and Africa39 (Figure 5). In animals, infection is mainly asymptomatic, while in humans, it can manifest as an acute and highly infectious VHF that readily transmits to close contacts, with a case fatality rate of over 50% in hospitalized patients40, 41.
CCHFV is an enveloped, negative-sense RNA virus in the Bunyavirales order, family Nairoviridae, and genus Orthonairovirus. It is maintained in nature by tick vectors, principally Hyalomma species, through tick-to-tick enzootic and vertebrate-mediated epizootic cycles (Figure 6). Virus spillovers to humans usually occur through tick bites and direct contact with viremic animals and other infectious biological materials42, 43. Persons most at risk for CCHFV infection include individuals working in agricultural fields and abattoirs, and herdsmen who may be exposed to ticks as well as infectious animal products like milk and meat. Secondary transmissions are also common among medical staff, other hospital patients, and close contact family members and relatives who are exposed through infectious blood or other body fluids of acutely sick patients.
Whereas CCHF is well studied in Europe and now increasingly in Asia44, its epidemiology in sub-Saharan Africa is much less defined45, with most available country information dependent on serological and vector presence46, 47. Given its widely believed potential to cause a future large public health emergency, it was recently listed by WHO as a top priority emerging disease requiring accelerated efforts in surveillance, research, and diagnostics development48.

Epidemiology and ecology of RVF

RVF is caused by RVFV, a virus in the Bunyavirales order, family Phenuiviridae, genus Phlebovirus. It is an emerging epidemic disease of humans and livestock, and an important endemic problem in sub-Saharan Africa49. RVFV is transmitted to livestock and humans by the bite of infected mosquitoes or exposure to tissues or blood of infected animals50. Interepidemic virus maintenance is thought to occur either transovarially in Aedes species mosquitoes, or through cycling of low-level transmission between mosquitoes and domestic livestock or wild ungulates51. After periods of heavy rainfall, Aedes mosquitoes rapidly emerge, resulting in extensive amplification of the virus through infection of livestock50.
Clinical presentation of RVF in animals varies depending on the species and ranges in severity. Livestock, particularly cattle, sheep, and goats, are highly susceptible to RVFV and present with symptoms of fever, loss of appetite, weakness, low milk production, nasal discharge, vomiting, and diarrhea. During large epizootics, “abortion storms,” particularly in sheep and cattle, have been recorded. High newborn mortality (80–100%) and adult mortality (5–20%) may also occur51. Humans infected with RVFV can present with varying degrees of symptomatology ranging from asymptomatic or mild, self-limited febrile illness, to with severe jaundice, rhinitis, encephalitis, and hemorrhagic manifestations in a small number of cases (<8%). Retinal degeneration (5–10% of cases), hemorrhagic fever (<1%), or encephalitis (<1%) may also develop8, 52 53. Laboratory findings in patients with RVF can include leukopenia, thrombocytopenia, and elevated liver enzymes. About 1% of RVF cases progress to hemorrhagic disease. The overall fatality rate is estimated to be 0.5–1%, but in the 2006–2007 outbreak in Kenya, the case fatality rate was reported to be as high as 29%54.
Although low-level RVFV activity most likely occurs throughout enzootic regions each year, the emergence of RVFV in large epidemic and/or epizootic cycles is typically associated with unusually heavy rainfall and the emergence of the natural reservoir host, which is thought to be primarily transovarially infected Aedes spp. floodwater mosquitoes55 (Figure 7). During large epidemics56 and epizootics, the high numbers of infected individuals can greatly strain the capacity of the public health and veterinary infrastructure to provide rapid real-time diagnostic testing and basic medical care for infected individuals or animals.
The ability of RVFV to cross international and natural boundaries is well documented. In 1977, it was first recorded north of the Sahara Desert in Egypt, and resulted in a massive epizootic and epidemic in that country, during which more than 200,000 people were estimated to have been infected. In 1979, RVFV was identified for the first time outside of continental Africa on the island of Madagascar57. Later, in 2000, the virus was isolated for the first time outside of Africa across the Red Sea in Saudi Arabia and Yemen58 (Figure 8). The potential of further introductions of RVFV into previously unaffected countries via infected livestock importation, mosquito translocation, human travel, or intentional release highlights the need for continued surveillance, prevention, and intervention measures.

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Genetic analysis of RVFV in Africa and the Arabian Peninsula

RVFV is an enveloped, single-stranded, negative-sense RNA virus consisting of 3 RNA segments varying in size: large (L), medium (M), and small (S). The tripartite, negative-sense, single-stranded RNA genome of RVFV virus contains the small ambisense segment (S segment) encoding the nucleoprotein and the nonstructural proteins, the medium segment (M segment) encoding the polyglycoprotein precursors, and the large segment (L segment) containing the virus RNA-dependent RNA polymerase73. The S segment encodes the nucleoprotein (NP) in the antigenomic sense and the nonstructural (NSs) protein in the genomic sense74. The M segment encodes several viral proteins in a single open reading frame, including the 14 kDa NSm, 2 major envelope surface glycoproteins (Gn and Gc), and a 78 kDa fusion protein of NSm and Gn. The NSm proteins are non-essential for in vitro virus growth75, but contribute to virulence in the mammalian host76. The first confirmed RVF outbreak outside Africa was reported in September 2000 in the Arabian Peninsula. By February 2001, a total of 884 hospitalized patients were identified in Saudi Arabia, with 124 deaths. In Yemen, 1,087 cases were estimated to have occurred, with 121 deaths69. Laboratory diagnosis of RVFV infections included genetic detection of the virus and characterization of clinical specimens by RT-PCR, in addition to serological tests and virus isolation. Genetic analysis of selected regions of RVFV S, M, and L RNA genome segments indicated little genetic variation among the viruses associated with disease. The Saudi Arabia and Yemen RVFV isolates were almost identical to those associated with earlier RVF epidemics in East Africa, indicating that genetic re-assortment did not play an important role in the emergence of this virus on the Arabian Peninsula. The genetic analysis of RVFV identified in Saudi Aribia and Yemen will be described in further detail below in Objective 1.
In late autumn of 2006, following unusually heavy rainfall, reports of human and animal illness consistent with RVF emerged across semiarid regions of the Garissa District of northeastern Kenya and southern Somalia74. A total of 3,250 specimens from a variety of animal species, including domesticated livestock (cattle, sheep, goats, and camels) and wildlife, collected from a total of 55 of 71 Kenyan administrative districts, were tested by molecular and serologic assays. Evidence of RVFV infection was found in 9.2% of animals tested and across 23 districts, reflecting the large number of affected livestock and the geographic extent of the outbreak. The complete S, M, and/or L genome segment sequences were obtained from a total of 33 wild-type virus isolates collected from throughout Africa and Saudi Arabia between 1944 and 2000. Extensive genomic analyses demonstrated the concurrent circulation of multiple virus lineages, gene segment re-assortment, and the common ancestry of the 2006–2007 outbreak viruses with those from the 1997–1998 East African RVF outbreak. Complete genome sequencing of multiple isolates of RVFV revealed that the overall virus genomic diversity is low (~5%) at the nucleotide level77. These findings impacted further studies of basic RVFV ecology and the design of broad-based surveillance and diagnostic methods to detect a diverse array of RVFVs, and will be described in further detail below in Objective 2.

VHF surveillance system in Uganda

Uganda has reported more VHF outbreaks than any other country in Sub-Saharan Africa, including 5 EVD outbreaks, 4 MVD outbreaks, and multiple outbreaks of CCHF and RVF. The first EVD outbreak in Uganda (which has remained the most significant EVD outbreak ever recorded in that country) occurred in 2000 in the districts of Gulu, Masindi, and Mbarara and involved 425 cases with 224 deaths (CFR 53%)78. Since then, 4 additional EVD outbreaks have occurred in Uganda, including in Bundibugyo District in 2007 (147 cases, 37 deaths)20, in Luweero District in 2011 (1 case, 1 death)10 and in 2012 (7 cases, 4 deaths)12, and in Kibaale District in 2012 (24 cases, 17 deaths). The outbreak in Bundibugyo District was attributed to a new strain of Ebolavirus, later named BDBV79; this strain subsequently caused an outbreak in Isiro, DRC, in 2012 (72 cases, 31 deaths21).
Four MVD outbreaks have been recorded in Uganda. The first occurred in 2007, and involved 3 cases and 1 death80. In a 2012 outbreak, the total count of confirmed and probable MVD cases was 26, of which 15 (58%) were fatal32. The outbreak in 2012 started in Ibanda District and subsequently spread to at least 3 other districts. In 2014, Uganda reported a single MVD case from Mpigi District, and in 2017, 4 confirmed cases of MVD were identified in Kween District in eastern Uganda.
In addition to EVD and MVD, since 2013, multiple sporadic outbreaks of CCHF and RVF have been and continue to be detected and confirmed in multiple districts across Uganda.
The purpose of any effective public health surveillance system is to enable the prompt recognition of and inform rapid and appropriate responses to disease outbreaks. Important trends or new potential disease threats must be quickly recognized. Additionally, hypotheses regarding causes of re-emergence or changing patterns of the hemorrhagic diseases and allocation of resources for continued surveillance and research into VHFs can lead to improved planning, development, and policies for mitigating VHF impact. Thus, development and maintenance of routine and enhanced VHF surveillance is critical, especially in Uganda, to detect, confirm, and rapidly respond to any possible threat of VHF.

Table of contents :

Acknowledgements
Résumé de these
List of Figures and Tables
List of Acronyms
1 Introduction and Objectives
2 Background
2.1 Epidemiology, ecology, and clinical presentation of VHFs
2.1.1 Ebolaviruses
2.1.2 Marburgvirus
2.1.3 Crimean-Congo hemorrhagic fever virus
2.1.4 Rift Valley fever virus
2.2 VHF surveillance system in Uganda
2.3 RVFV Emergence in Uganda
3 Methods and Results
3.1 Objective 1
3.2 Objective 2
3.3 Objective 3
3.4 Objective 4
3.5 Objective 5
3.6 Objective 6
3.6.1 Objective 6 Part 1
3.6.2 Objective 6 Part 2
3.6.3 Objective 6 Part 3
4 Discussion
5 Conclusions and Perspectives
6 Personal Perspective
7 References
8 Manuscripts

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