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Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013&ndash, 2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.

Ebola virus disease (EVD) is a serious global health concern because case fatality rates are approximately 50% due to recent widespread outbreaks in Africa. Well-defined nonhuman primate (NHP) models for different routes of Ebola virus exposure are needed to test the efficacy of candidate countermeasures. In this natural history study, four rhesus macaques were challenged via aerosol with a target titer of 1000 plaque-forming units per milliliter of Ebola virus. The course of disease was split into the following stages for descriptive purposes: subclinical, clinical, and decompensated. During the subclinical stage, high levels of venous partial pressure of carbon dioxide led to respiratory acidemia in three of four of the NHPs, and all developed lymphopenia. During the clinical stage, all animals had fever, viremia, and respiratory alkalosis. The decompensatory stage involved coagulopathy, cytokine storm, and liver and renal injury. These events were followed by hypotension, elevated lactate, metabolic acidemia, shock and mortality similar to historic intramuscular challenge studies. Viral loads in the lungs of aerosol-exposed animals were not distinctly different compared to previous intramuscularly challenged studies. Differences in the aerosol model, compared to intramuscular model, include an extended subclinical stage, shortened clinical stage, and general decompensated stage. Therefore, the shortened timeframe for clinical detection of the aerosol-induced disease can impair timely therapeutic administration. In summary, this nonhuman primate model of aerosol-induced EVD characterizes early disease markers and additional details to enable countermeasure development.

In the 2014&ndash, 2016 West Africa Ebola Virus (EBOV) outbreak, there was a significant concern raised about the potential for secondary bacterial infection originating from the gastrointestinal tract, which led to the empiric treatment of many patients with antibiotics. This retrospective pathology case series summarizes the gastrointestinal pathology observed in control animals in the rhesus EBOV-Kikwit intramuscular 1000 plaque forming unit infection model. All 31 Non-human primates (NHPs) exhibited lymphoid depletion of gut-associated lymphoid tissue (GALT) but the severity and the specific location of the depletion varied. Mesenteric lymphoid depletion and necrosis were present in 87% (27/31) of NHPs. There was mucosal barrier disruption of the intestinal tract with mucosal necrosis and/or ulceration most notably in the duodenum (16%), cecum (16%), and colon (29%). In the intestinal tract, hemorrhage was noted most frequently in the duodenum (52%) and colon (45%). There were focal areas of bacterial submucosal invasion in the gastrointestinal (GI) tract in 9/31 (29%) of NHPs. Only 2/31 (6%) had evidence of pancreatic necrosis. One NHP (3%) experienced jejunal intussusception which may have been directly related to EBOV. Immunofluorescence assays demonstrated EBOV antigen in CD68+ macrophage/monocytes and endothelial cells in areas of GI vascular injury or necrosis.

Background: \ud The frequency of asymptomatic infection with Ebola virus is unclear: previous estimates vary and there is no standard test. Asymptomatic infection with Ebola virus could contribute to population immunity, reducing spread. If people with asymptomatic infection are infectious it could explain re-emergences of Ebola virus disease (EVD) without known contact.\ud \ud Methods: \ud We validated a new oral fluid anti-glycoprotein IgG capture assay among survivors from Kerry Town Ebola Treatment Centre and controls from communities unaffected by EVD in Sierra Leone. We then assessed the seroprevalence of antibodies to Ebola virus in a cross-sectional study of household contacts of the survivors. All household members were interviewed. Two reactive tests were required for a positive result, with a third test to resolve any discrepancies.\ud \ud Findings: \ud The assay had a specificity of 100% (95% CI 98·9–100; 339 of 339 controls tested negative) and sensitivity of 95·9% (89·8–98·9; 93 of 97 PCR-confirmed survivors tested positive). Of household contacts not diagnosed with EVD, 47·6% (229 of 481) had high level exposure (direct contact with a corpse, body fluids, or a case with diarrhoea, vomiting, or bleeding). Among the contacts, 12·0% (95% CI 6·1–20·4; 11 of 92) with symptoms at the time other household members had EVD, and 2·6% (1·2–4·7; 10 of 388) with no symptoms tested positive. Among asymptomatic contacts, seropositivity was weakly correlated with exposure level.\ud \ud Interpretation: \ud This new highly specific and sensitive assay showed asymptomatic infection with Ebola virus was uncommon despite high exposure. The low prevalence suggests asymptomatic infection contributes little to herd immunity in Ebola, and even if infectious, would account for few transmissions.\ud \ud Funding: \ud Wellcome Trust ERAES Programme, Save the Children.

Recent experimentation with the variants of the Ebola virus that differ in the glycoprotein’s poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. In order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permitted us to intramuscularly challenge statistically significant numbers of naïve and vaccinated cynomolgus macaques with either a 7U or 8U variant of the Ebola virus, Kikwit isolate. In naïve animals, no difference in survivorship was observed, however, there was a significant delay in the disease course between the two groups. Significant differences were also observed in time-of-fever, serum chemistry, and hematology. In vaccinated animals, there was no statistical difference in survivorship between either challenge groups, with two succumbing in the 7U group compared to 1 in the 8U challenge group. In summary, survivorship was not affected, but the Ebola virus disease course in nonhuman primates is temporally influenced by glycoprotein poly-U editing site populations.

Objective This article looks at lessons learned from the 1995 Kikwit Ebola outbreak and suggests how modern hospitals should apply these lessons to the next lethal viral epidemic that occurs. Method The 1995 Kikwit Ebola outbreak in the Democratic Republic of the Congo (formally Zaire) is one of the most well studied epidemics to have occurred to date. Many of the lessons learned from identifying, containing and treating that epidemic are applicable to future viral outbreaks, natural disasters and bioterrorist attacks. This is due to Ebola's highly contagious nature and high mortality rate. Results When an outbreak occurs, it often produces fear in the community and causes the basic practice of medicine to be altered. Changes seen at Kikwit included limited physical examinations, hesitance to give intravenous medications and closure of supporting hospital facilities. The Kikwit Ebola outbreak also provided beneficial psychological insight into how patients, staff and the general community respond to a biological crisis and how this will affect physicians working in an epidemic. Conclusions General lessons from the outbreak include the importance of having simple, well-defined triage procedures; staff who are flexible and able to adapt to situations with unknowns; and the need to protect staff physically and emotionally to ensure a sustained effort to provide care.

The Ebola epidemic in Kikwit, Democratic Republic of the Congo, was recognized because of a nosocomial outbreak in Kikwit General Hospital. Initially, a diagnosis of shigella infection was suspected because many patients presented with bloody diarrhea. On 4 May 1995, blood samples from 14 acutely ill patients were sent to the Centers for Disease Control and Prevention (Atlanta), and on 9 May, a diagnosis of Ebola hemorrhagic fever was confirmed. The major disease control measures that were undertaken were the isolation of patients in a quarantine ward at Kikwit General Hospital, the distribution of protective equipment to health care workers and family members caring for Ebola patients, the use of barrier nursing techniques, the distribution of health education material, active and passive case finding, and the burying of the deceased in plastic bags by a trained team of Red Cross volunteers who wore gloves and protective clothing.

Le plateau du Kwango (Congo-Kinshasa ) est l'objet de phénomènes érosifs actuels particulièrement spectaculaires. Ceux-ci se traduisent par de profondes griffures d'érosion, par l'enfoncement rapide des cours d'eau (ce qui détermine des terrasses) consécutif à une forte érosion régressive et par le développement de gigantesques cirques d'érosion. Ces derniers évoluent essentiellement par soutirage et recul des sources au niveau de leur soubassement, plus ou moins imperméable. L'explication de cette érosion exacerbée fait appel à la conjonction d'un léger soulèvement tectonique et d'un abaissement conséquent du niveau de base régional suite à la rupture du seuil d'Inkisi ayant contenu un grand lac dans la Cuvette Centrale congolaise il y a environ 10 000 ans. Cette érosion est particulièrement catastrophique lorsqu'elle se manifeste en milieu fortement urbanisé comme à Kikwit., Salomon Jean-Noël. Les phénomènes d'érosion accélérée du Plateau du Kwango (République Démocratique du Congo). In: Travaux du Laboratoire de Géographie Physique Appliquée, n°16, Février 1998 1997. pp. 45-63.

From May to July 1995, a serologic and interview survey was conducted to describe Ebola hemorrhagic fever (EHF) among personnel working in 5 hospitals and 26 health care centers in and around Kikwit, Democratic Republic of the Congo. Job-specific attack rates estimated for Kikwit General Hospital, the epicenter of the EHF epidemic, were 31% for physicians, 11% for technicians/room attendants, 10% for nurses, and 4% for other workers. Among 402 workers who did not meet the EHF case definition, 12 had borderline positive antibody test results; subsequent specimens from 4 of these tested negative. Although an old infection with persistent Ebola antibody production or a recent atypical or asymptomatic infection cannot be ruled out, if they occur at all, they appear to be rare. This survey demonstrated that opportunities for transmission of Ebola virus to personnel in health facilities existed in Kikwit because blood and body fluid precautions were not being universally followed.

Between 6 and 22 June 1995, 8 patients in Kikwit, Democratic Republic of the Congo, who met the case definition used in Kikwit for Ebola (EBO) hemorrhagic fever, were transfused with blood donated by 5 convalescent patients. The donated blood contained IgG EBO antibodies but no EBO antigen. EBO antigens were detected in all the transfusion recipients just before transfusion. The 8 transfused patients had clinical symptoms similar to those of other EBO patients seen during the epidemic. All were seriously ill with severe asthenia, 4 presented with hemorrhagic manifestations, and 2 became comatose as their disease progressed. Only 1 transfused patient (12.5%) died; this number is significantly lower than the overall case fatality rate (80%) for the EBO epidemic in Kikwit and than the rates for other EBO epidemics. The reason for this low fatality rate remains to be explained. The transfused patients did receive better care than those in the initial phase of the epidemic. Plans should be made to prepare for a more thorough evaluation of passive immune therapy during a new EBO outbreak.

In contrast with procedures in previous Ebola outbreaks, patient care during the 1995 outbreak in Kikwit, Democratic Republic of the Congo, was centralized for a large number of patients. On 4 May, before the diagnosis of Ebola hemorrhagic fever (EHF) was confirmed by the Centers for Disease Control and Prevention, an isolation ward was created at Kikwit General Hospital. On 11 May, an international scientific and technical committee established as a priority the improvement of hygienic conditions in the hospital and the protection of health care workers and family members; to this end, protective equipment was distributed and barrier-nursing techniques were implemented. For patients living far from Kikwit, home care was organized. Initially, hospitalized patients were given only oral treatments; however, toward the end of the epidemic, infusions and better nutritional support were given, and 8 patients received blood from convalescent EHF patients. Only 1 of the transfusion patients died (12.5%). It is expected that with improved medical care, the case fatality rate of EHF could be reduced.

Urbanization, considered theoretically a driving force for development, is existing in an embryonic form in the South-West of Zaïre, and particularly in the Kwilu sub-region. In that region, Kikwit city was detached since 1972 to constitute an urban sub-region, endowed wich administrative autonomy. This incomplete urbanization, with remaining strong rural characteristics, induces new needs, but does not succeed in fulfilling them correctly, especially on two levels : -that of the urban equipments ; -that of the supplying of the populations with consumables, and especially foodstuffs. The secondary urban centers or («semi-urban centers»), which are less than 10 in the Kwilu sub-region (having around 10 000 and 45 000 inhabitants) and the «medium» sized urban center Kikwit (around 200 000 inhabitants) are no longer villages, although they retain some rural characteristics, as for example a majoritarian «village style» housing. Examples of underequipment are numerous in the emerging but already debased urban structure in the Kwilu region : underequipment in administrative buildings, in health centers and school buildings, insufficiency or failure of elementary urban equipments such as water supply, electricity supply, refuse collection, fighting against erosion. In the meantime, the only existing factories (oil factories) are declining. The supplying of the urban populations with foodstuffs especially, contributes to the decline of the standards of living of the towns populations who most of times have no job, or if they have, earn wages in constant regression because of inflation. The following difficulties can be noticed : -growth of price of the local products, which must be fetched or bought farther and farther ; -increase of the use of foreign foodstuffs and of their price (imported products or substituting to local ones : bread, beer, sea fish - fresh or salted - etc.), the prices of which follow the inflation ; -difficulties more and more important to buy land suitable for cultivation, and risks to see them damaged or urbanized ; -impossibility to find substitutive employments for the non-working rural people living in town ; -and weakening of the purchasing power of the workers and employees. This situation should induce a study of the supplying of Kikwit in current consumption commodities, arid especially of how the household consumption is organised. Such a study would probably show that the chronic under-nourishment is gradually growing worse for the urban people in the Kwilu region, in Kikwit particularly, which would not indeed be the sign that development is going on., L'urbanisation, moteur théorique du «développement», existe de façon embryonnaire dans le sud-ouest du Zaïre, en particulier dans la sous-région du Kwilu, dont la ville de Kikwit a été détachée depuis 1972 pour constituer une sous-région urbaine administrativement indépendante. Cette urbanisation incomplète et fortement teintée de ruralité provoque des besoins nouveaux sans parvenir à les satisfaire correctement, en particulier sur deux plans : -celui des équipements urbains ; -celui de l'approvisionnement des populations en produits de consommation courante, notamment alimentaires. Les centres urbains secondaires (ou «semi-urbains»), moins d'une dizaine dans la sous-région du Kwilu (entre 10 000 et 45 000 habitants), ainsi que la ville «moyenne» de Kikwit (environ 200 000 habitants) ne sont plus des villages, malgré des occupations rurales et un habitat de style villageois encore largement dominants., Codou Alain,Mutungu Kuleta,Gahanga Gushimana. Urbanisation et difficultés de développement à Kikwit et au Kwilu (région du Bandundu-Zaïre). In: Urbanisation et développement dans les pays tropicaux. Bordeaux : Presses Universitaires de Bordeaux, 1991. pp. 45-54. (Espaces tropicaux, 4)

Fifteen (14%) of 105 women with Ebola hemorrhagic fever hospitalized in the isolation unit of the Kikwit General Hospital (Democratic Republic of the Congo) were pregnant. In 10 women (66%) the pregnancy ended with an abortion. In 3 of them, a curettage was performed, and all 3 received a blood transfusion from an apparently healthy person. One woman was prematurely delivered of a stillbirth. Four pregnant women died during the third trimester of their pregnancy. All women presented with severe bleeding. Only 1 survived; she had a curettage because of an incomplete abortion after 8 months of amenorrhea. The mortality among pregnant women with Ebola hemorrhagic fever (95.5%) was slightly but not significantly higher than the overall mortality observed during the Ebola epidemic in Kikwit (77%; 245/316 infected persons).

Three (15%) of 20 survivors of the 1995 Ebola outbreak in the Democratic Republic of the Congo enrolled in a follow-up study and 1 other survivor developed ocular manifestations after being asymptomatic for 1 month. Patients complained of ocular pain, photophobia, hyperlacrimation, and loss of visual acuity. Ocular examination revealed uveitis in all 4 patients. All patients improved with a topical treatment of 1% atropine and steroids.