- freely available
Viruses 2012, 4(9), 1668-1686; doi:10.3390/v4091668
Published: 21 September 2012
Abstract: Filovirus infection presents many unique challenges to patient management. Currently no approved treatments are available, and the recommendations for supportive care are not evidence based. The austere clinical settings in which patients often present and the sporadic and at times explosive nature of filovirus outbreaks have effectively limited the information available to evaluate potential management strategies. This review will summarize the management approaches used in filovirus outbreaks and provide recommendations for collecting the information necessary for evaluating and potentially improving patient outcomes in the future.
In humans, filovirus infection results in a spectrum of illness, but most recognized infections present as severe acute febrile illness with a high proportion of fatalities. The typical clinical presentation consists of acute onset of a non-specific febrile illness, including chills, headache, myalgia, nausea/vomiting, and diarrhea. A faint rash develops in 25-52% of patients in the first week . Minor hemorrhagic manifestations are noted in some patients after a few days of illness (e.g., conjunctival hemorrhage, petechiae, ecchymoses, bleeding from puncture sites). In many instances, a biphasic pattern can occur, with a brief remission followed by a recurrence of fever and more severe late stage disease. In later stages of the severe forms of illness, patients demonstrate hypotension, shock, mucosal hemorrhages (typically from the gastrointestinal tract) and multi-organ system (particularly renal) failure [2,3]. Although autopsies demonstrate multifocal necrosis, they have generally not identified specific pathological lesions responsible for death . Nevertheless, severe cases are frequently fatal, with ultimate demise attributed to the systemic effects of a septic shock-like syndrome. No licensed or approved specific medical countermeasures exist, making supportive care the cornerstone of patient management.
Provision of supportive care, as well as detailed documentation of the care given, is challenging in austere settings in which most large filovirus outbreaks occur. Laboratory equipment, supplies (particularly personal protective equipment), and adequate infrastructure are often lacking. Healthcare worker attrition and abandonment of suspected cases can result from actual infection or fear of infection, perceived inability to affect the clinical course, and community stigmatism. In some outbreaks, communities hide sick patients and dead bodies , thus, forcing efforts to focus on community surveillance.
In this review, we summarize the management approaches documented in published outbreak reports, conference proceedings, journal articles, and a recently published compendium of the filovirus literature . We highlight gaps in knowledge of clinical management of filovirus patients and areas where our current outbreak response strategies could be enhanced to improve patient care.
2. Results and Discussion
There have been 34 recognized filovirus outbreaks, including sporadic cases and laboratory accidents, since 1967. Perhaps not surprisingly, the most detailed information on the clinical management of filovirus-infected patients came from outbreaks or cases occurring in developed countries. In general, the clinical care provided to filovirus patients has varied widely, primarily due to resource constraints of many outbreak settings.
2.1. Supportive Care Provided in Filovirus Outbreaks
The clinical presentation of filovirus-infected patients is difficult to distinguish from other infections, especially early in the clinical course. Given that laboratory diagnostic capabilities were often limited in outbreak settings, patient care typically followed the routine approach to severe febrile illness in the tropics, beginning with antibiotics and antimalarial drugs [Table 1]. In many cases, antibiotics were also used to prevent and/or treat secondary bacterial infections. Acyclovir was used in one patient in the 1976 Zaire outbreak, and ribavirin was given to one patient in Russia. No other employments of antiviral drugs were documented. Analgesics, antipyretics, and antiemetic drugs were typically available and administered as needed. Unfortunately, many patients did not receive any further care. Other symptomatic treatments occasionally available included antidiarrheal drugs, sedatives, and antipsychotic drugs to reduce anxiety and agitation.
Oral rehydration was routinely encouraged, but at times not administered partially due to the close proximity required to prop up a severely ill patient so they could drink . Oral rehydration was typically preferred to administration of IV fluids, partially due to the perceived risk of transmission associated with the use of needles as well as resource constraints. Fluid and electrolyte monitoring and supplementation were universally applied to patients in well-equipped hospitals, but these measures were not routinely available during most outbreaks. Intravenous (IV) fluids were first used in a developing country setting in the 1976 outbreak in Zaire for the treatment of three nuns . The first large filovirus outbreak in Africa in which IV fluids were routinely used was in Kikwit, Zaire (now Democratic Republic of the Congo) in 1995, but such fluids were used only in the last few weeks of the outbreak (approximately 25 patients) . Hartmann’s solution and lactated Ringer’s solution have been used, but in most reports, the type of IV fluid administered was not specified. Pressor agents (epinephrine) were occasionally administered to prevent shock.
Various blood products, clotting factors, inhibitors of fibrinolysis (ε-aminocaproic acid) and regulators of coagulation were administered to counteract hemorrhage. Transfusion of blood components included whole blood, packed red blood cells, fresh frozen plasma, and platelets. Clotting factors and other regulators of coagulation administered included fibrinogen, and prothrombin, proconvertin, Stuart-factor and antihemophilic globulin B, and vitamin K. In contrast, anticoagulants (heparin) and rheologic agents (pentoxyfylline) were given in some patients to prevent thrombosis and disseminated intravascular coagulation.
Attempts at passive immunotherapy included use of convalescent blood, plasma or serum. Convalescent sera was first administered to four patients during the 1967 Marburg virus disease outbreak in Frankfurt, West Germany (now Germany)  and in Belgrade, Yugoslavia (now Serbia) . Gamma globulin infusions were used in 1 patient in Yambuku, Zaire  and interferon in one patient in the UK in 1976 [9,10,12,13] and one patient in Russia in 2004 . Polyoxidonium, an immunomodulator, was also given to the patient in Russia .
Support for organ failure, including dialysis, hemofiltration, intubation, and mechanical ventilation was only available for a small number of patients in developed-country settings.
2.2. Treatment Efficacy
None of the supportive care strategies used in the field were prospectively evaluated to determine treatment efficacy. Transfusion of blood from convalescent patients was highlighted as potentially useful in Kikwit, Zaire when only one of eight patients receiving a transfusion died . However, these patients received substantially better care than those in the early stages of the epidemic, and treatment started relatively late in the disease course, indicating that selection bias may have contributed to the positive results [15,16]. Ebola convalescent serum had been administered to three additional patients in two separate outbreaks, all of which survived [6,12]. Five patients in four separate outbreaks received IV heparin; two of the five patients survived [8,14,17,18]. Dehydration was noted in several outbreaks as potentially contributing to the high mortality, but as with other therapies, the effect of IV fluid administration has not been rigorously evaluated.
|Table 1. Clinical Management Approaches Used in Filovirus Disease Outbreaks.|
|Year||Virus||Location(s)||No. Cases, No. Deaths(Percent)||Clinical Management||Ref*|
|1967||MARV||Marburg & Frankfurt, West Germany (Germany); Belgrade, Yugoslavia(Serbia)||31, 7 (22.6%)||[10,11,19,20,21]|
|1975||MARV||Rhodesia (Zimbabwe), transfer to Johannesburg, South Africa||3, 1 (33.3%)||[17,22]|
|1976||EBOV||Yambuku, Zaire (DRC)||318, 280 (88.1%)||[8,22,23,24,25]|
|1976||SUDV||Nzara, Sudan (South Sudan)||284, 151 (53.2%)||[26,27,28]|
|1976||SUDV (maybe EBOV?)||U.K.||1, 0 (0%)||[12,13]|
|1977||EBOV||Tandala, Zaire (DRC)||1, 1 (100%)||♦ No information found on clinical management|||
|1979||SUDV||Nzara, Sudan (South Sudan)||34, 22 (64.7%)||♦ No information found on clinical management||[30,31,32]|
|1980||MARV||Kenya||2, 1 (50%)|||
|1987||RAVV||Kenya||1, 1 (100%)|||
|1988||MARV||Koltsovo, Soviet Union (Russia)||1-2, 1-2 (50%-100%)||♦ No information found on clinical management||[34,35]|
|1990||MARV||Koltsovo, Soviet Union(Russia)||1, 0 (0%)||♦ Extracorporeal hemo-sorbent and hemodialysis||[36,37]|
|1994||TAFV||Côte d'Ivoire||1, 0 (0%)|||
|1994-95||EBOV||Mékouka, Gabon||52, 32 (61.5%)||♦ No information found on clinical management||[39,40,41,42,43]|
|1995||EBOV||Kikwit, Zaire (DRC)||317, 245 (77.3%)||[2,3,9,15,16,44]|
|1996||EBOV||Mayibout (2), Gabon (2 secondary cases in South Africa)||31, 21 (67.7%)||[9,45,46]|
|1996||EBOV||Russia||1, 1 (100%)||♦ No information found on clinical management|||
|1996-97||EBOV||Booué, Gabon||62, 46 (74.2%)|||
|1998-2000||MARVand RAVV||Durba and Watsa, DRC||154, 128 (83.1%)||[9,49,50]|
|2000-01||SUDV||Gulu and Masindi, Uganda||425, 224 (52.7%)|||
|2001-02||EBOV||Mékambo, Gabon, Mbomo, Kéllé, RC||124, 97 (78.2%)||[51,52,53,54,55,56,57,58,59,60,61,62]|
|2002||EBOV||Gabon and RC||11, 10 (90.9%)||♦ No information found on clinical management||[53,59,63]|
|2002-03||EBOV||Kéllé and Mbomo, RC||143, 128 (90%)||♦ No information found on clinical management||[58,64,65,66,67,68,69,70,71]|
|2003-04||EBOV||Mbomo, RC||35, 29 (82.9%)||♦ Symptomatic oral treatments for dehydration and fever||[72,73]|
|2004||EBOV||Koltsovo, Russia||1, 1 (100%)||[6,14]|
|2004||SUDV||Yambio, Sudan(South Sudan)||17, 7 (41.2%)||♦ No information found on clinical management||[74,75,76,77]|
|2004-05||MARV||Uíge, Angola||374, 329 (88.0%)||[5,78]|
|2005||EBOV||Etoumbi, RC||11, 9 (81.8%)||♦ No information found on clinical management||[79,80]|
|2007||MARV and RAVV||Kamwenge, Uganda||4, 2 (50.0%)||♦ No information found on clinical management||[81,82,83,84]|
|2007||EBOV||Luebo, DRC||264, 187 (70.8%)||♦ No information found on clinical management||[85,86,87,88]|
|2007||BDBV||Bundibugyo, Uganda||131, 42 (37%)||[89,90]|
|2008ŧ||MARV||Uganda (transferred to USA)||1, 0 (0%)|||
|2008||MARV||Uganda (transferred to Netherlands)||1, 1 (100%)|||
|2008-09||EBOV||Mweka and Luebo, DRC||32, 15 (46.9%)||♦ No information found on clinical management||[86,93,94,95]|
|2011||SUDV||Uganda||1, 1 (100%)||♦ No information found on clinical management|||
*The references refer to articles where information on management was obtained. If no information on management was found, the references refer to articles that were reviewed. ŧ Patient was retrospectively diagnosed with MARV by repeat convalescent serology and detection of MARV RNA in archived convalescent serum. Notes: The most current filovirus taxonomy and nomenclature is used in the table [97,98,99]. The recent outbreaks in Uganda (July 2012) and DRC (August 2012) are not included as no information is yet available on patient care. MARV=Marburg virus, RAVV=Ravn virus, EBOV=Ebola virus, SUDV=Sudan virus, TAFV= Taï Forest virus, BDBV=Bundibugyo virus, PPSB=prothrombin, proconvertin, Stuart-factor and antihaemophilic globulin B, PTT=partial thromboplastin time, IV=intravenous, IM=intramuscular, RBC=red blood cells, DRC=Democratic Republic of the Congo, RC=Republic of the Congo, USA=United States of America
2.3. Clinical Documentation and Dissemination
No information on clinical management was found for 13 of the 34 outbreaks. Of those outbreaks that documented and published information on patient management, the description of the exact treatment regimen(s) was often vague. Patient management reportedly improved over time in many outbreaks [9,26,78]. In particular, Guimard et al. reported the patient care separately by phase of the outbreak in Kikwit, Zaire  in order to reflect this change.
3. Experimental Section
We searched PubMed for articles relating to each filovirus disease outbreak individually, as well as for articles on treatment for filovirus infections (“Ebola AND treatment”, “Marburg AND treatment”, and “filovirus AND treatment”, species filter: Humans). We obtained additional references from a recent compendium of filovirus literature , as well as a recent review of the clinical and laboratory features of filovirus infection . In total, we reviewed over 200 journal articles, outbreak reports, and conference proceedings [100,101,102,103,104]. Articles in German or French were screened using an online translation tool (Google Translate); a native speaker screened two articles in Russian [14,47].
4. Recommendations and Conclusions
Although there have been many advances in our understanding of the pathophysiology of filovirus infections and progress towards development of vaccines and therapeutics, insufficient attention has been paid to evaluating and improving the supportive care of filovirus patients. The contrast in the case-fatality observed in patients with access to modern hospital facilities versus those in resource-constrained settings has been previously noted, causing many to speculate that substantial improvements in survival could be made through enhanced supportive care [105,106]. Several management strategies have been attempted in outbreak settings, as summarized in this review, but none of the strategies have been implemented or documented to permit evaluation of the treatment efficacy. As noted by Colebunders et al., improvements in clinical documentation are required for basic evaluation of supportive treatment . In the absence of a clinical trial, accurate collection and timely publication of observational data on patient demographics, clinical signs and symptoms, treatment, and clinical outcome are crucial.
Barring the development of an effective drug or vaccine, clearly the most critical need in the improvement of filovirus infection management are scientifically collected data to validate clinical interventions and provide a foundation for evidence-based guidance. As the pathologic process of filovirus infection resembles that of severe sepsis and septic shock, a reasonable management strategy is aggressive supportive care using standard protocols for severe sepsis [105,106,107]. The efficacy of early goal-directed therapy (EGDT) and the related Surviving Sepsis Campaign management protocols has been well established in highly-resourced medical facilities across a broad range of common pathogens [108,109,110,111]. Nevertheless, the applicability of these approaches has yet to be tested or validated with more exotic diseases (including filovirus infections) commonly presenting as severe sepsis in tropical or under-developed regions. In addition, although theoretically possible, such approaches have not been proven to be feasible in medical facilities in resource-limited settings [112,113].
EGDT requires early fluid resuscitation within the first 6 hours of presentation; most algorithms include an initial bolus of 20-40 ml/kg of crystalloid solution followed by frequent volume boluses sufficient to meet specific goal targets with respect to indices such as central venous pressure (CVP), mean arterial pressure, and mixed venous oxygen saturation (SvO2). The rationale for this approach in severely septic patients was summarized in a meta-analysis . Significant mortality benefit was seen in studies where hemodynamic optimization in critically ill patients was initiated before the development of organ failure when compared to those studies that achieved optimization after the occurrence of organ failure. Notably, fluid resuscitation alone can help to reduce the global tissue hypoxia that is central to the development of multi-organ dysfunction by increasing the cardiac output and improving oxygen delivery to the tissues . While fluid resuscitation alone, as dictated by EGDT, may have benefit, the Surviving Sepsis Campaign created management protocols that are a group of interventions related to a disease that, when implemented together, result in better outcomes than when implemented individually . The synergistic effect of appropriate therapies given together at the appropriate time may alter the pathophysiologic course of disease enough to improve the outcome. Finally, it should be noted that some experts argue that aggressive fluid resuscitation generally attributed to EGDT are actually contraindicated in the management of filoviruses, given the associated endothelial dysfunction and theoretical risk of pulmonary edema.
Evaluation of enhanced supportive care and development of tailored protocols for management of filovirus infections should be priorities in the response to future outbreaks. The challenges inherent in this task are considerable, but not insurmountable. Strategies for conducting clinical research in filovirus disease outbreak settings have been proposed, including establishment of a collaborative platform for development and approval of research protocols in advance of an outbreak [106,107]. Furthermore, the research capacity required to conduct clinical trials to evaluate sepsis management strategies in austere settings, namely the availability of institutional review boards, community outreach programs, trained personnel, clinical supplies, and laboratory diagnostics, could be adapted to filovirus disease outbreak settings. Provision of enhanced supportive care, accurate clinical documentation, and rigorous evaluation of innovative treatment strategies may improve patient outcomes in future filovirus disease outbreaks.
We sincerely thank Laura Bollinger for her thorough review and thoughtful suggestions. We greatly appreciate Dr. Pavlo Fedorenko for his assistance with the Russian language articles.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
- Kortepeter, M.G.; Bausch, D.G.; Bray, M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J. Infect. Dis. 2011, 204 Suppl 3, S810–S816, doi:10.1093/infdis/jir299.
- Ndambi, R.; Akamituna, P.; Bonnet, M.J.; Tukadila, A.M.; Muyembe-Tamfum, J.J.; Colebunders, R. Epidemiologic and clinical aspects of the Ebola virus epidemic in Mosango, Democratic Republic of the Congo, 1995. J. Infect. Dis. 1999, 179 Suppl 1, S8–S10. 21984739
- Bwaka, M.A.; Bonnet, M.J.; Calain, P.; Colebunders, R.; De Roo, A.; Guimard, Y.; Katwiki, K.R.; Kibadi, K.; Kipasa, M.A.; Kuvula, K.J. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J. Infect. Dis. 1999, 179 Suppl 1, S1–S7, doi:10.1086/314568.
- Zaki, S.R.; Goldsmith, C.S. Pathologic features of filovirus infections in humans. Curr. Top. Microbiol. Immunol. 1999, 235, 97–116. 9893381
- Ndayimirije, N.; Kindhauser, M.K. Marburg hemorrhagic fever in Angola--fighting fear and a lethal pathogen. N. Engl. J. Med. 2005, 352, 2155–2157, doi:10.1056/NEJMp058115.
- Kuhn, J.H. Filoviruses. A compendium of 40 years of epidemiological, clinical, and laboratory studies; Calisher, C.H., Ed.; Springer Wien: New York, NY, USA, 2008.
- Borchert, M.; Mutyamba, I.; Van Kerkhove, M.D.; Lutwama, J.; Luwaga, H.; Bisoborwa, G.; Turyagaruka, J.; Pirard, P.; Ndayimirije, N.; Roddy, P.; Van Der Stuyft, P. Ebola haemorrhagic fever outbreak in Masindi District, Uganda: outbreak description and lessons learned. BMC Infect. Dis. 2011, 11, 357, doi:10.1186/1471-2334-11-357.
- Isaäcson, M.; Sureau, P.; Courteille, G.; Pattyn, S.R. Clinical aspects of Ebola virus disease at the Ngaliema hospital, Kinshasa, Zaire, 1976. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier / North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June 2012).
- Guimard, Y.; Bwaka, M.A.; Colebunders, R.; Calain, P.; Massamba, M.; De Roo, A.; Mupapa, K.D.; Kibadi, K.; Kuvula, K.J.; Ndaberey, D.E. Organization of Patient Care during the Ebola Hemorrhagic Fever Epidemic in Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 1999, 179 Suppl 1, S268–S273. 21984739
- Stille, W.; Böhle, E. Clinical course and prognosis of Marburg virus (‘Green-Monkey’) disease. In Marburg virus disease; Martini, G.A., Siegert, R., Eds.; Springer Verlag: New York, 1971; pp. 10–18.
- Todorovitch, K.; Mocitch, M.; Klasnja, R. Clinical picture of two patients infected by the Marburg vervet virus. In Marburg virus disease; Martini, G.A., Siegert, R., Eds.; Springer Verlag: New York, NY, USA, 1971; pp. 19–23.
- Emond, R.T.; Evans, B.; Bowen, E.T.; Lloyd, G. A case of Ebola virus infection. Br. Med. J. 1977, 2, 541–544, doi:10.1136/bmj.2.6086.541. 890413
- Emond, R.T. Isolation, monitoring and treatment of a case of Ebola virus infection. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier / North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June,2012).
- Akinfeyeva, L.A.; Aksyonova, O.I.; Vasilyevich, I.V.; Ginko, Z.I.; Zarkov, K.A.; Zubavichene, N.M.; Katkova, L.R.; Kuzovlev, O.P.; Kuzubov, V.I.; Lokteva, L.I.; Ryabchikova, Ye.I. A case of Ebola hemorrhagic fever. Infektsionnye Bolezni (Moscow) 2005, 3, 85–88.
- Mupapa, K.; Massamba, M.; Kibadi, K.; Kuvula, K.; Bwaka, A.; Kipasa, M.; Colebunders, R.; Muyembe-Tamfum. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. J. Infect. Dis. 1999, 179 Suppl 1, S18–S23. 21984739
- Sadek, R.F.; Khan, A.S.; Stevens, G.; Peters, C.J.; Ksiazek, T.G. Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995: Determinants of survival. J. Infect. Dis. 1999, 179 Suppl 1, S24–S27. 21984739
- Gear, J.S.; Cassel, G.A.; Gear, A.J.; Trappler, B.; Clausen, L.; Meyers, A.M.; Kew, M.C.; Bothwell, T.H.; Sher, R.; Miller, G.B.; et al. Outbreake of Marburg virus disease in Johannesburg. Br. Med. J. 1975, 4, 489–493, doi:10.1136/bmj.4.5995.489. 811315
- Johnson, E.D.; Johnson, B.K.; Silverstein, D.; Tukei, P.; Geisbert, T.W.; Sanchez, A.N.; Jahrling, P.B. Characterization of a new Marburg virus isolated from a 1987 fatal case in Kenya. Arch. Virol. Suppl. 1996, 11, 101–114. 8800792
- Martini, G.A. Marburg virus disease. Postgrad. Med. J. 1973, 49, 542–546, doi:10.1136/pgmj.49.574.542.
- Martini, G.A.; Siegert, R. Marburg virus disease. Springer Verlag: New York, NY. USA, 1971.
- Martini, G.A. Marburg virus disease. Clinical syndrome. In Marburg virus disease; Martini, G.A., Siegert, R., Eds.; Springer Verlag: New York, NY, USA, 1971. 10-181-9.
- Isaäcson, M. The Memoirs of Margaretha Isaacson. Annals ACTM. 2008, 9, 43–50.
- Sureau, P.; Piot, P.; Breman, G.; Ruppol, F.; Masamba, M.; Berquist, H.; Heymann, D.; Kintoki, V.; Koth, M.; Mandiangu, M.; et al. Containment and surveillance of an epidemic of Ebola virus infection in Yambuku area, Zaire, 1976. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier /North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June,2012).
- Breman, J.G.; Piot, P.; Johnson, K.M.; White, M.K.; Mbuyi, M.; Sureau, P.H.; Heymann, D.L.; Van Nieuwenhove, S.; McCormick, J.B.; Ruppol, J.P.; et al. The Epidemiology of Ebola Haemorrhagic Fever in Zaire,1976. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier /North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June, 2012).
- Ebola haemorrhagic fever in Zaire, 1976. Bull. World Health Organ. 1978, 56, 271–293. 307456
- Smith, D.H.; Francis, D.P.; Simpson, D.I.H. African haemorrhagic fever in the southern Sudan, 1976. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier /North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June, 2012).
- El Tahir, B.M. The haemorrhagic fever outbreak in Maridi, Western Equatoria, southern Sudan. Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier /North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June, 2012).
- Ebola haemorrhagic fever in Sudan, 1976. Bull. World Health Organ. 1978, 56, 247–270. 307455
- Heymann, D.L.; Weisfeld, J.S.; Webb, P.A.; Johnson, K.M.; Cairns, T.; Berquist, H. Ebola hemorrhagic fever: Tandala, Zaire, 1977-1978. J. Infect. Dis. 1980, 142, 372–376, doi:10.1093/infdis/142.3.372.
- Baron, R.C.; McCormick, J.B.; Zubeir, O.A. Ebola virus disease in southern Sudan: hospital dissemination and intrafamilial spread. Bull. World Health Organ. 1983, 61, 997–1003. 6370486
- World Health Organization. Viral haemorrhagic fever: Sudan. Wkly. Epidemiol. Rec. 1979, 54, 319.
- World Health Organization. Viral haemorrhagic fever surveillance: Sudan. Wkly. Epidemiol. Rec. 1979, 54, 342–343.
- Smith, D.H.; Johnson, B.K.; Isaacson, M.; Swanapoel, R.; Johnson, K.M.; Killey, M.; Bagshawe, A.; Siongok, T.; Keruga, W.K. Marburg-virus disease in Kenya. Lancet 1982, 1, 816–820. 6122054
- Alibek, K.; Handelman, S. Biohazard. The chilling true story of the largest covert biological weapons program in the world - told from inside by the man who ran it; Random House: New York, New York, NY, USA, 1999.
- Leitenberg, M.; Zilinskas, R.; Kuhn, J. The Soviet Biological Weapons Program. A History; Harvard University Press: Cambridge, MA, USA, 2012.
- Mehedi, M.; Groseth, A.; Feldmann, H.; Ebihara, H. Clinical aspects of Marburg hemorrhagic fever. Future Virol. 2011, 6, 1091–1106, doi:10.2217/fvl.11.79.
- Nikiforov, V.V.; Turovskiĭ, IuI.; Kalinin, P.P.; Akinfeeva, L.A.; Katkova, L.R.; Barmin, V.S.; Riabchikova, E.I.; Popkova, N.I.; Shestopalov, A.M.; Nazarov, V.P.; et al. A case of a laboratory infection with Marburg fever. Zh. Mikrobiol. Epidemiol. Immunobiol. 1994, 104–106.
- Formenty, P.; Hatz, C.; Le Guenno, B.; Stoll, A.; Rogenmoser, P.; Widmer, A. Human infection due to Ebola virus, subtype Côte d’Ivoire: clinical and biologic presentation. J. Infect. Dis. 1999, 179 Suppl 1, S48–S53, doi:10.1086/514285. 9988164
- Volchkov, V.; Volchkova, V.; Eckel, C.; Klenk, H.D.; Bouloy, M.; LeGuenno, B.; Feldmann, H. Emergence of subtype Zaire Ebola virus in Gabon. Virology. 1997, 232, 139–144, doi:10.1006/viro.1997.8529.
- Amblard, J.; Obiang, P.; Edzang, S.; Prehaud, C.; Bouloy, M.; Guenno, B.L. Identification of the Ebola virus in Gabon in 1994. Lancet 1997, 349, 181–182. 9111553
- Georges, A.J.; Leroy, E.M.; Renaut, A.A.; Benissan, C.T.; Nabias, R.J.; Ngoc, M.T.; Obiang, P.I.; Lepage, J.P.M.; Bertherat, E.J.; Benoni, D.D.; et al. Ebola Hemorrhagic Fever Outbreaks in Gabon, 1994–1997: Epidemiologic and Health Control Issues. J. Infect. Dis. 1999, 179 Suppl 1, S65–S75. 21984739
- Bertherat, E.; Renaut, A.; Nabias, R.; Dubreuil, G.; Georges-Courbot, M.C. Leptospirosis and Ebola virus infection in five gold-panning villages in northeastern Gabon. Am. J. Trop. Med. Hyg. 1999, 60, 610–615. 10348236
- Arthur, R.R. Ebola in Africa--discoveries in the past decade. Euro Surveill. 2002, 7, 33–36. 12631942
- Colebunders, R.; Sleurs, H.; Pirard, P.; Borchert, M.; Libande, M.; Mustin, J.P.; Tshomba, A.; Kinuani, L.; Olinda, L.A.; Tshioko, F.; Muyembe-Tamfum, J. Organisation of health care during an outbreak of Marburg haemorrhagic fever in the Democratic Republic of Congo, 1999. J. Infect. 2004, 48, 347–353, doi:10.1016/S0163-4453(03)00122-1.
- Richards, G.A.; Murphy, S.; Jobson, R.; Mer, M.; Zinman, C.; Taylor, R.; Swanepoel, R.; Duse, A.; Sharp, G.; De La Rey, I.C.; Kassianides, C. Unexpected Ebola virus in a tertiary setting: clinical and epidemiologic aspects. Crit. Care Med. 2000, 28, 240–244, doi:10.1097/00003246-200001000-00041.
- Baize, S.; Leroy, E.M.; Georges-Courbot, M.C.; Capron, M.; Lansoud-Soukate, J.; Debre, P.; Fisher-Hoch, S.P.; McCormick, J.B.; Georges, A.J. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat. Med. 1999, 5, 423–426, doi:10.1038/7422.
- Borisevich, I.V.; Markin, V.A.; Firsova, I.V.; Yevseyev, A.A.; Khamitov, R.A.; Maksimov, V.A. Hemorrhagic (Marburg, Ebola, Lassa and Bolivian) fevers: epidemiology, clinical pictures, and treatment. Voprosy Virusologii (Moscow). 2006, 51, 8–16.
- Baize, S.; Leroy, E.M.; Georges, A.J.; Capron, M.; Bedjabaga, I.; Lansoud-Soukate, J.; Mavoungou, E. Inflammatory responses in Ebola virus-infected patients. Clin. Exp. Immunol. 2002, 128, 163–168, doi:10.1046/j.1365-2249.2002.01800.x.
- Bausch, D.G.; Nichol, S.T.; Muyembe-Tamfum, J.; Borchert, M.; Rollin, P.E.; Sleurs, H.; Campbell, P.; Tshioko, F.K.; Roth, C.; Colebunders, R.; et al. Marburg hemorrhagic fever associated with multiple genetic lineages of virus. N. Engl. J. Med. 2006, 355, 909–919, doi:10.1056/NEJMoa051465.
- Colebunders, R.; Tshomba, A.; Van Kerkhove, M.D.; Bausch, D.G.; Campbell, P.; Libande, M.; Pirard, P.; Tshioko, F.; Mardel, S.; Mulangu, S.; et al. Marburg hemorrhagic fever in Durba and Watsa, Democratic Republic of the Congo: Clinical documentation, features of illness, and treatment. J. Infect. Dis. 2007, 196, S148–S153, doi:10.1086/520543.
- Leroy, E.M.; Souquière, S.; Rouquet, P.; Drevet, D. Re-emergence of Ebola haemorrhagic fever in Gabon. Lancet 2002, 359, 712. 11879900
- Nkoghe, D.; Formenty, P.; Leroy, E.M.; Nnegue, S.; Edou, S.Y.O.; Ba, J.I.; Allarangar, Y.; Cabore, J.; Bachy, C.; Andraghetti, R.; et al. Multiple Ebola virus haemorrhagic fever outbreaks in Gabon, from October 2001 to April 2002. Bull. Soc. Pathol. Exot. 2005, 98, 224–229.
- World Health Organization. Outbreak(s) of Ebola haemorrhagic fever, Congo and Gabon, October 2001-July 2002. Wkly. Epidemiol. Rec. 2003, 78, 223–228. 15571171
- Das, P. Infectious disease surveillance update. Lancet Infect. Dis. 2002, 2, 69. 11901651
- Das, P. Infectious disease surveillance update. Lancet Infect. Dis. 2002, 2, 391. 12127346
- Das, P. Infectious disease surveillance update. Lancet Infect. Dis. 2002, 2, 133, doi:10.1016/S1473-3099(02)00218-9. 11944179
- Milleliri, J.M.; Tévi-Benissan, C.; Baize, S.; Leroy, E.; Georges-Courbot, M.C. Les épidémies de fièvre hémorragique due au virus Ebola au Gabon (1994-2002). Bull. Soc. Pathol. Exot. 2004, 97, 199–205. 15462203
- Pourrut, X.; Kumulungui, B.; Wittmann, T.; Moussavou, G.; Delicat, A.; Yaba, P.; Nkoghe, D.; Gonzalex, J.P.; Leroy, E.M. The natural history of Ebola virus in Africa. Microbes Infect. 2005, 7, 1005–1014, doi:10.1016/j.micinf.2005.04.006. 16002313
- World Health Organization. Outbreak News - Suspected acute haemorrhagic fever syndrome, Democratic Republic of Congo. Wkly. Epidemiol. Rec. 2002, 77, 229.
- Nkoghe, D.; Nnegue, S.; Mve, M.T.; Formenty, P.; Thompson, G.; Ba, I.J.; Nkoumou, O.M.; Leroy, E. Isolated case of haemorrhagic fever observed in Gabon during the 2002 outbreak of Ebola but distant from epidemic zones. Med. Trop. (Mars) 2005, 65, 349–354.
- Georges-Courbot, M.C.; Leroy, E.; Zeller, H. Ebola: un virus endemique en Afrique Centrale? Med. Trop. (Mars) 2002, 62, 295–300.
- Nkoghé, D.; Formenty, P.; Nnegue, S.; Mve, M.T.; Hypolite, I.; Leonard, P.; Leroy, E. Practical guidelines for the management of Ebola infected patients in the field. Med. Trop. (Mars) 2004, 64, 199–204.
- World Health Organization. Outbreak News - Suspected acute haemorrhagic fever syndrome, Gabon. Wkly. Epidemiol. Rec. 2002, 77, 213.
- Das, P. Infectious disease surveillance update. Lancet Infect. Dis 2003, 3, 267, doi:10.1016/S1473-3099(03)00633-9.
- Das, P. Infectious disease surveillance update. Lancet Infect. Dis 2003, 3, 323, doi:10.1016/S1473-3099(03)00646-7.
- Hewlett, B.L.; Hewlett, B.S. Providing care and facing death: nursing during Ebola outbreaks in central Africa. J Transcult Nurs. 2005, 16, 289–297, doi:10.1177/1043659605278935.
- Formenty, P.; Roth, C.; Thompson, G. Global resources mobilized to help Congo - combating Ebola epidemic in Congo. Action Against Infection - A newsletter for WHO and its partners. 2003, 4, 3.
- Frankish, H. Death toll continues to climb in Congo Ebola outbreak. Lancet. 2003, 361, 1020. 12660066
- Revol, D. Dedicated to the cause - Ebola outbreak in Congo. Red Cross Red Crescent. 2003, 2, 14–15.
- World Health Organization. Outbreak News - Suspected acute haemorrhagic fever syndrome, Congo. Wkly. Epidemiol. Rec. 2003, 78, 41–48.
- World Health Organization. Outbreak(s) of Ebola haemorrhagic fever in the Republic of the Congo, January-April 2003. Wkly. Epidemiol. Rec 2003, 78, 285–290. 14509121
- Boumandouki, P.; Formenty, P.; Epelboin, A.; Campbell, P.; Atsangandoko, C.; Allarangar, Y.; Leroy, E.M.; Kone, M.L.; Molamou, A.; Dinga-Longa, O.; et al. Clinical management of patients and deceased during the Ebola outbreak from October to December 2003 in Republic of Congo. Bull. Soc. Pathol. Exot. 2005, 98, 218–223. 16267964
- World Health Organization. Ebola virus hemorrhagic fever: the Congo over-comes the third epidemic with acceptable delays. La Missive de l’OMS-Congo (Brazzaville), Available online: http://www.who.int/csr/disease/ebola/en/ebolacongofr.pdf (accessed on 20 June 2012).
- Cooke, F. ProMED Update for IJID 8/5. Int. J. Infect. 2004, 8, 257–258.
- Social mobilization to fight Ebola in Yambio, southerm Sudan. Action Against Infection - A newsletter for WHO and its partners 2004, 4, 2.
- Moszynski, P. Crisis in western Sudan is delaying help for south of country. BMJ. 2004, 328, 1456, doi:10.1136/bmj.328.7454.1456-c.
- Thill, M.; Tolou, H. Fièvre hémorragique à virus Ebola: Nouvel opus meurtrier au Soudan. Med. Trop. (Mars). 2004, 64, 331.
- J Jeffs, B.; Roddy, P.; Weatherill, D.; de la Rosa, O.; Dorion, C.; Iscla, M.; Grovas, I.; Palma, P.P.; Villa, L.; Bernal, O.; Rodrigues-Martinez, J.; Barcelo, B.; Pou, D.; Borchert, M. The Médecins Sans Frontières Intervention in the Marburg Hemorrhagic Fever Epidemic, Uige, Angola, 2005. I. Lessons Learned in the Hospital. J. Infect. Dis. 2007, 196 Suppl 2, S154–S161. 23169974
- Nkoghe, D.; Kone, M.L.; Yada, A.; Leroy, E. A limited outbreak of Ebola haemorrhagic fever in Etoumbi, Republic of Congo, 2005. Trans. R. Soc. Trop. Med. Hyg. 2011, 105, 466–472, doi:10.1016/j.trstmh.2011.04.011.
- World Health Organization. Ebola haemorrhagic fever, Congo. Wkly. Epidemiol. Rec. 2005, 80, 178.
- Adjemian, J.; Farnon, E.C.; Tschioko, F.; Wamala, J.F.; Byaruhanga, E.; Bwire, G.S.; Kansiime, E.; Kagirita, A.; Ahimbisibwe, S.; Katunguka, F.; et al. Outbreak of Marburg hemorrhagic fever among miners in Kamwenge and Ibanda Districts, Uganda, 2007. J. Infect. Dis. 2011, 204 Suppl 3, S796–S799, doi:10.1093/infdis/jir312.
- Outbreak of Marburg haemorrhagic fever: Uganda, June-August 2007. Wkly. Epidemiol. Rec. 2007, 82, 381–384. 17966467
- Marburg haemorrhagic fever, Uganda--update. Wkly. Epidemiol. Rec. 2007, 82, 317. 17844635
- Outbreak news. Marburg haemorrhagic fever, Uganda. Wkly. Epidemiol. Rec. 2007, 82, 297–298. 17703537
- Leroy, E.M.; Epelboin, A.; Mondonge, V.; Pourrut, X.; Gonzalez, J.P.; Muyembe-Tamfum, J.; Formenty, P. Human Ebola outbreak resulting from direct exposure to fruit bats in Luebo, Democratic Republic of Congo, 2007. Vector Borne Zoonotic Dis. 2009, 9, 723–728, doi:10.1089/vbz.2008.0167.
- Grard, G.; Biek, R.; Tamfum, J.J.; Fair, J.; Wolfe, N.; Formenty, P.; Paweska, J.; Leroy, E. Emergence of divergent Zaire ebola virus strains in Democratic Republic of the Congo in 2007 and 2008. J. Infect. Dis. 2011, 204 Suppl 3, S776–S784. 23293361
- Outbreak news. Ebola virus haemorrhagic fever, Democratic Republic of the Congo. Wkly. Epidemiol. Rec. 2007, 82, 329. 17886402
- Outbreak news. Ebola virus haemorrhagic fever, Democratic Republic of the Congo--update. Wkly. Epidemiol. Rec. 2007, 82, 345–346. 17918654
- MacNeil, A.; Farnon, E.C.; Morgan, O.W.; Gould, P.; Boehmer, T.K.; Blaney, D.D.; Wiersma, P.; Tappero, J.W.; Nichol, S.T.; Ksiazek, T.G.; Rollin, P.E. Filovirus outbreak detection and surveillance: lessons from Bundibugyo. J. Infect. Dis. 2011, 204 Suppl 3, S761–S767. 23293361
- Wamala, J.F.; Lukwago, L.; Malimbo, M.; Nguku, P.; Yoti, Z.; Musenero, M.; Amone, J.; Mbabazi, W.; Nanyunja, M.; Zaramba, S.; et al. Ebola Hemorrhagic Fever Associated with Novel Virus Strain, Uganda, 2007–2008. Emerg. Infect. Dis. 2010, 16, 1087–1092, doi:10.3201/eid1607.091525.
- Imported case of Marburg hemorrhagic fever - Colorado, 2008. MMWR Morb.Mortal. Wkly. Rep. 2009, 58, 1377–1381. 20019654
- van Paassen, J.; Bauer, M.P.; Arbous, M.S.; Visser, L.G.; Schmidt-Chanasit, J.; Schilling, S.; Olschlager, S.; Rieger, T.; Emmerich, P.; Schmetz, C.; et al. Acute liver failure, multiorgan failure, cerebral oedema, and activation of proangiogenic and antiangiogenic factors in a case of Marburg haemorrhagic fever. Lancet Infect. Dis. 2012, 8, 635–642.
- World Health Organization. Ebola haemorrhagic fever in the Democratic Republic of the Congo. Global Alert and Response, 2008. Available online: http://www.who.int/csr/don/2008_12_26a/en/index.html (accessed on 27 June 2012).
- World Health Organization. Ebola haemorrhagic fever in the Democratic Republic of the Congo - update. Global Alert and Response, 2009. Available online: http://www.who.int/csr/don/2009_01_02/en/index.html (accessed on 27 June 2012).
- World Health Organization. End of Ebola outbreak in the Democratic Republic of the Congo. Global Alert and Response, 2009. Available online: http://www.who.int/csr/don/2009_02_17/en/index.html (accessed on 27 June 2012).
- Outbreak news. Ebola, Uganda. Wkly. Epidemiol. Rec. 2011, 86, 221. 21661270
- Kuhn, J.H.; Becker, S.; Ebihara, H.; Geisbert, T.W.; Johnson, K.M.; Kawaoka, Y.; Lipkin, W.I.; Negredo, A.I.; Netesov, S.V.; Nichol, S.T.; Palacios, G.; Peters, C.J.; Tenorio, A.; Volchkov, V.E.; Jahrling, P.B. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch. Virol. 2010, 155, 2083–2103, doi:10.1007/s00705-010-0814-x. 21046175
- Kuhn, J.H.; Becker, S.; Ebihara, H.; Geisbert, T.W.; Jahrling, P.B.; Kawaoka, Y.; Netesov, S.V.; Nichol, S.T.; Peters, C.J.; Volchkov, V.E.; Ksiazek, T.G. Family - Filoviridae. In Virus Taxonomy - Ninth Report of the International Committee on Taxonomy of Viruses; King, A.M.Q., Adams, M.J., Carstens, E.B., Lefkowitz, E.J., Eds.; Elsevier/Academic Press: London, United Kingdom, 2011; pp. 665–671.
- Adams, M.J.; Carstens, E.B. Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses. Arch. Virol. 2012, 157, 1411–1422, doi:10.1007/s00705-012-1299-6.
- Proceedings of an International Colloquium on Ebola Virus Infection and Other Haemorrhagic Fevers; Elsevier /North-Holland Biomedical Press: Amsterdam, The Netherlands, 1978. Available online: http://www.enivd.de/EBOLA/ebola-02.htm#P3_30 (accessed on 22 June, 2012).
- Breman, J.G.; van der Groen, G.; Peters, C.J.; Heymann, D.L. International Colloquium on Ebola Virus Research: summary report. J. Infect. Dis. 1997, 176, 1058–1063, doi:10.1086/516543. 9333167
- Klenk, H.D.; Feldmann, H. Symposium on Marburg and Ebola viruses. Virus Res. 2001, 80, 117–123, doi:10.1016/S0168-1702(01)00258-1.
- Feldmann, H.; Geisbert, T.; Kawaoka, Y. Filoviruses: recent advances and future challenges. J. Infect. Dis. 2007, 196 Suppl 2, S129–S130, doi:10.1086/520550.
- Proceedings of the 5th International Symposium on Filoviruses, April 18-21, 2010, Tokyo, Japan. J. Infect. Dis. 2011, 204 Suppl 3, S757–S1097, doi:10.1093/infdis/jir296. 22175070
- Bausch, D.G.; Feldmann, H.; Geisbert, T.W.; Bray, M.; Sprecher, A.G.; Boumandouki, P.; Rollin, P.E.; Roth, C. Outbreaks of filovirus hemorrhagic fever: Time to refocus on the patient. J. Infect. Dis. 2007, 196 Suppl 2, S136–S141, doi:10.1086/520542.
- Roddy, P.; Colebunders, R.; Jeffs, B.; Palma, P.P.; Van Herp, M.; Borchert, M. Filovirus hemorrhagic fever outbreak case management: A review of current and future treatment options. J. Infect. Dis. 2011, 204, S791–S795, doi:10.1093/infdis/jir297.
- Bausch, D.G.; Sprecher, A.G.; Jeffs, B.; Boumandouki, P. Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions. Antiviral Res. 2008, 78, 150–161, doi:10.1016/j.antiviral.2008.01.152.
- Levy, M.M.; Dellinger, R.P.; Townsend, S.R.; Linde-Zwirble, W.T.; Marshall, J.C.; Bion, J.; Schorr, C.; Artigas, A.; Ramsay, G.; Beale, R.; et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010, 36, 222–231, doi:10.1007/s00134-009-1738-3. 20069275
- Castellanos-Ortega, A.; Suberviola, B.; Garcia-Astudillo, L.A.; Holanda, M.S.; Ortiz, F.; Llorca, J.; Delgado-Rodriguez, M. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Crit. Care Med. 2010, 38, 1036–1043, doi:10.1097/CCM.0b013e3181d455b6.
- Rivers, E.; Nguyen, B.; Havstad, S.; Ressler, J.; Muzzin, A.; Knoblich, B.; Peterson, E.; Tomlanovich, M. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 2001, 345, 1368–1377, doi:10.1056/NEJMoa010307.
- Cardoso, T.; Carneiro, A.H.; Ribeiro, O.; Teixeira-Pinto, A.; Costa-Pereira, A. Reducing mortality in severe sepsis with the implementation of a core 6-hour bundle: results from the Portuguese community-acquired sepsis study (SACiUCI study). CritCare. 2010, 14, R83.
- Jacob, S.T.; Moore, C.C.; Banura, P.; Pinkerton, R.; Meya, D.; Opendi, P.; Reynolds, S.J. Severe sepsis in two Ugandan hospitals: A prospective observational study of management and outcomes in a predominantly HIV-1 infected population. PLoSOne 2009, 4(11).
- Baelani, I.; Jochberger, S.; Laimer, T.; Otieno, D.; Kabutu, J.; Wilson, I.; Baker, T.; Dunser, M.W. Availability of critical care resources to treat patients with severe sepsis or septic shock in Africa: a self-reported, continent-wide survey of anaesthesia providers. Crit Care 2011, 15, R10. 21219619
- Kern, J.W.; Shoemaker, W.C. Meta-analysis of hemodynamic optimization in high-risk patients. Crit. Care Med. 2002, 30, 1686–1692, doi:10.1097/00003246-200208000-00002.
- Haupt, M.T.; Gilbert, E.M.; Carlson, R.W. Fluid loading increases oxygen consumption in septic patients with lactic acidosis. Am. Rev. Respir. Dis. 1985, 131, 912–916. 4003944
- Dellinger, R.P.; Levy, M.M.; Carlet, J.M.; Bion, J.; Parker, M.M.; Jaeschke, R.; Reinhart, K.; Angus, D.C.; Brun-Buisson, C.; Beale, R.; et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 2008, 36, 296–327. 18158437
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).