In this learning unit, we are going to discuss the clinical presentation of Ebola virus disease patients. The learning objectives are to quickly recap the essential modes of infection and to discuss the incubation period. We will discuss main clinical signs and symptoms and laboratory findings in Ebola virus disease patients, and we will briefly look at outcomes and characteristics of patients during this current West African epidemic. To recapitulate, the primary transmission in an epidemic is zoonotic. We discussed that extensively in a previous learning unit. Subsequent transmission occurs from person to person through contact of or through contact with infected bodily fluids with mucous surfaces or broken skin. Infectious bodily fluids are blood, faeces, vomit, urine, saliva, breast milk, semen, and sweat, with other words, virtually every bodily fluids, and the first three being considered as the possibly most infectious. The incubation time varies. It's usually considered to be fairly short. We assume that the majority of patients who are infected and who become diseased develop symptoms within six to 12 days following exposure, but the range is considered to be from two to 21 days. However, recent modelling from the current outbreak suggests that a small proportion of patients may have an extended incubation period, and extended would then mean probably maybe four, five days longer actually. Signs and symptoms are unspecific in the beginning, which makes it so difficult to tell Ebola virus disease apart from other hemorrhagic fevers or from other viral diseases with the same symptoms, and also to differentiate them from virtually almost all febrile conditions which one may pick up in a tropical setting. The onset of symptoms is usually abrupt. It is nonspecific, flu-like fever. A profound weakness, malaise, myalgia may be the lead symptoms in the beginning. Gastrointestinal symptoms may develop swiftly and ensue, which is at least in the current outbreak predominately watery diarrhea, high-volume watery diarrhea, vomiting, abdominal pain. Diffuse, erythematous, non-pruritic, maculopapular rashes may evolve. Actually is not seen very frequently, and also more difficult to detect on a dark skin. Relative bradycardia may be encountered. Hemorrhages occur in many, many forms, internal and external hemorrhages, but only in a minority of patients, and this became very, very clear during the actual outbreak where only a tiny fraction of all patients with severe disease, two to three percent, maybe develop some sort of bleeding in the end stage of the disease. Laboratory findings as well are puzzlingly difficult to disentangle or to differentiate from many other tropical diseases. Mild leukopenia may be seen or thrombopenia may be encountered. Multifocal hepatic necrosis may lead to a transaminitis. There are multiple coagulation abnormalities such as prolonged bleeding time, elevated D-dimers, and renal failure may develop in patients when they progress to more severe disease with the usual markers, creatinin and urea, being elevated. What we should say at this stage again is not every individual, of course, which gets infected will progress to disease at all. There is certainly a so far ill-described or not clearly defined proportion of individual infected who will not progress to disease, who will not exhibit any signs of infections, and it will properly in the wake of the current outbreak, there will be certainly seroprevalence studies which will shed more light on the proportion of patients who will never develop disease signs, and of course then, consequently, also not progress to more severe disease. The differential diagnosis of Ebola virus disease is really broad. Why is it so broad? Because the signs and symptoms, at least at the beginning of the disease, are very unspecific, could be described as a flu-like illness, which is a feature which is shared with, as I said before, the majority of infectious diseases. The differential diagnosis has to be constructed from the clinical presentation and epidemiological characteristics. For West and Central Africa, the main differentials will always include malaria in the first place, but also the other viral haemorrhagic fevers. There is a whole range of bacterial infections which may mimic Ebola virus disease, as well as they may complicate Ebola virus disease in later stages. Bacterial sepsis, typhoid fever, leptospirosis, the rickettsioses may form important differential diagnosis. Parasitological diseases, other than malaria, may be amoebiasis, may be in certain areas, African trypanosomiasis, and then, of course, there are other viral afflictions, and a flu-like infectious agent and the whole range of the viral hepatitis may form an important differential diagnosis. As I mentioned before, there are other viral haemorrhagic fevers which may also be present in the area of an outbreak. At present, for example, Lassa fever is an important differential diagnosis in the area of the current outbreak. Complications and outcome. If an individual which falls ill does not progress to severe disease, then an average rule of thumb is that a majority of patients will show signs of improvement between six and 11 days. Of course, this has to be handled flexibly as well. In individuals who progress to more severe disease, death ensues usually are most frequently within a period of six to 16 days after onset of symptoms. Complications in an individual which becomes diseased are multitude with regard to GI symptoms. Dehydration, of course, is very important, if not most important, and of course, with dehydration come electrolyte dysbalances which may lead to cardiac arrhythmias. There are coagulation abnormalities. Major bleeding is a nano to rarity, but not encountered as frequently as the old term haemorrhagic fevers would suggest. Actually, we discussed that before. Renal failure, multifocal hepatitis may ensue in patients who are severely ill. The fatality rates, actually, they vary. In the beginning of an outbreak, we usually encounter higher fatality rates. At the end of an outbreak, this is usually then brought down a bit. In the beginning of this extra outbreak, the death rates exceeded 70 percent. Now, towards what may constitute the end of the outbreak in retrospect, we are down to a mortality rate between 40 to 50 percent, which is still very high. As I said before, the Zaire Ebola virus is known to be the most virulent one and usually claims the highest death toll amongst all the various Ebola viruses. Now, what did we learn about clinical characteristics from the current massive large-scale outbreak? First of all, and one cannot say this too frequently, the haemorrhagic events occur only in a minority of patients. Or at least to be a bit more cautious, we may say that in the current outbreak, in minority of patients, severe haemorrhages, internally or externally, were witnessed actually, and the estimates run at least below five percent. GI symptoms including massive watery diarrhea and vomiting are very common and seem to be associated with fatal outcomes actually. Early oral rehydration may improve outcomes. If people are unable to take oral rehydrations, actually, wherever this is possible, early intravenous rehydration seems to be a key measure to keep patients alive, to see them through the organ complication phase. Case fatality rates seem to be comparable to previous epidemics, and patients younger than 21 years old seem to have a better survival chance compared to older individuals. Probably, we have to exclude very young children from this age range calculation. Diagnostics. Ebola virus disease is confirmed by detection of viral antigens or RNA from bodily fluids. Of course, also the visualization by electron microscopy and cell cultivation methods are possible, but the current gold standard of the diagnosis is RT-PCR, and rapid diagnostic tests are under development. Serology by means of an immunoassay and ELISA is well possible and also helpful, but the RT-PCR is the current gold standard at least up to the time now actually. Negative tests for more than 72 hours after symptom onset excludes Ebola as a causative agent if the methodology is good actually, if we are talking about RT-PCR. However, to gain confidence and to gain security, these tests should be repeated, particularly when patients are symptomatic actually. Two negative tests separated by at least 48 hours in patients whose symptoms have resolved can be considered as providing enough safety to discharge patients from an isolation area actually. I would like to conclude with a referral to the rapidly growing body of knowledge, particularly gained from this current outbreaks, by pointing at our list of references, which is, of course, still in a stage of rapid growth. Thank you very much.
