42 Ebola Virus Disease

Textbooks on tropical diseases in Africa are well out of date. With the recognition of new and deadly viral infections - Lassa, Marburg, Ebola, Congo- Crimean Hemorrhagic Fever, Rift Valley Fever, and AIDS - the classical descriptions of major diseases such as malaria and yellow fever must be thor­oughly revised, and to the roster of more minor ail­ments can be added dengue, Chikungunya, O’Nyong Nyong, West Nile fever, and others.

It is when the patient does not respond to the antimalarial therapy exhibited that other possible diagnoses are considered. In addition to the viral possibilities, the list should also include influenza, typhoid fever, various rickettsioses, leptospiral infec­tions, bacterial and viral enteropathogenic agents - indeed the range of infections capable of inducing a febrile response.

After the appearance of the Marburg virus in 1967 and the Lassa virus in 1969 had given a jolt to complacency, the Ebola virus in 1976 provoked a convulsive shudder. The Ebola story began with al­most simultaneous outbreaks of a deadly infection in the Maridi region of southern Sudan and in the Bumba Zone of the equator region of north central Zaire, neighboring on the Sudan, and in towns along the course of the Ebola River. The Sudan and Zaire foci are about 150 kilometers distant from each other, and people are continually passing back and forth between these regions.

Epidemiology, Distribution, and Incidence The epidemic of a highly fatal disease (later named Ebola virus disease) began in June 1976, with an index case in Nzara, southern Sudan, among work­ers in a cotton factory. This patient went to a large hospital in Maridi, where the disease spread rapidly among hospital patients and staff. The epidemic ran its course by November 1976. There were 148 deaths in 284 detected cases (52 percent mortality). In 1979 a further outbreak occurred in southern Sudan, with fewer cases and a small number of deaths.

The epidemic in Zaire was traced to an index case seen on September 1, 1976. The individual in ques­tion had received an intravenous injection of chloroquine for presumptive malaria with fever at the outpatient clinic of Yambuku Mission Hospital, Bumba District. He recovered, but within a week a large epidemic of fever began in hospital patients and staff. A total of 318 cases occurred, with 288 deaths (90.5 percent mortality). A number of inpa­tients and members of the hospital staff, physicians, and attendants also died. The epidemic had termi­nated by November 5, 1976. The diagnosis of the first epidemiological team sent to the area was “a fulminating epidemic of typhoid fever in a non­vaccinated population.” Fatalities, however, oc­curred in a hospital in Kinshasa in the cases of three nurses who had been transferred from the infected area, and it became clear, as investigations contin­ued, that passage of the virus from human to human had occurred through the medium of contaminated needles and syringes.

The epidemics in the Sudan and Zaire terminated as abruptly as they had started. However, in 1979 another hospital-centered outbreak occurred in Tan- dala, Zaire, 300 kilometers distant from the original Bumba outbreak. In total, 33 patients were diag­nosed, of whom 22 died (66 percent mortality). Through the 1980s no further outbreaks have been reported in Sudan or Zaire or elsewhere in Africa, with the exception of a probable case from Kenya reported in 1983.

Complacency was shattered in the United States and internationally in early November 1989 when an epidemic, confirmed to be caused by Ebola virus, erupted in a shipment of 100 Macaca Cynomolgus monkeys originating in the Philippines and shipped to a laboratory in Virginia, in the United States, via Amsterdam and J. F. Kennedy airports. Sixty of the 100 monkeys died. A second shipment received 2 to 3 weeks later in Virginia had two infected monkeys therein.

Extensive epidemiological explorations interna­tionally have focused on this frightening episode. No human cases have been reported. At the time of writing (February 14,1990), no satisfactory explana­tions have been advanced. All exposed individuals are being monitored.

This demonstration of the danger of transmission of virus by use and reuse of inadequately sterilized needles and syringes has important implications for medical practice, not just in underdeveloped coun­tries but also in developed cultures because of AIDS. Excessive parenteral administration of many drugs, which could be equally efficacious given by mouth, constitutes bad medical practice. Parenteral adminis­tration of drugs in medical emergencies is under­standable and desirable. But such a practice for the “typical” patients seen at the clinic for undiagnosed fevers that are not immediately life-threatening is indefensible.

Unsophisticated patients unfortunately cherish an intuitive feeling that drugs, from vitamin prepa­rations up the scale to specific therapeutic agents, are much more effective when given intradermally, subcutaneously, intramuscularly, or intravenously. Indeed, patients often demand parenteral adminis­tration of drugs and think poorly of a physician who does not oblige them. This view unfortunately is not discouraged by some practitioners of the medical arts, both licensed and unlicensed, and the practice also greatly increases the bill for pharmaceuticals benefiting drug companies and pharmacists. The poorer countries can ill afford the increased cost.

Epidemiologists have been active in trying to trace the origins of the Ebola virus and the distribu­tion of the infection throughout Africa, locate host vertebrates other than humans, as well as Ieam methods of transmission to humans and the ways the virus is maintained and propagated in nature. Table VIII.42.1 summarizes these data. Although it may appear that much has been done, actually ef­forts have been limited to a handful of dedicated investigators, and to a scattered, spotty sampling of the vast expanse of Africa south of the Sahara.

Primates have been sampled (see Table VIII.42.1) and have revealed no involvement, or at best mini­mal involvement. In connection with the 1979 Tandala, Zaire, outbreak is the unexpected finding of guinea pig immunes. Guinea pigs are South American rodents, inquilines in human habitations in the high Andes. The inhabitants raise them for pets and for food. They were introduced to Africa decades ago and in some regions have established themselves as inquilines in houses. In this respect, their behavior resembles that of the abundant multimammate rat (Mastomys natalensis'), already known to be involved in Lassa virus maintenance and spread to human beings. Guinea pig immune rates as high as 26.1 percent were found in these animals in some houses in Tandala. Study of the background of those who were positive, however, failed to indicate guinea pig-to-guinea pig transmis­sion, guinea pig-to-human spread, or human-to- guinea pig spread.

Table VIII.42.1. Ebola serosurυeys

Etiology

The Ebola agent was demonstrated by electron mi­croscopy to consist of long filamentous rods, some­times branched, often intertwined.

The infectious virus particle is inactivated by ul­traviolet (UV)-irradiation, gamma-ray irradiation, 1 percent formalin, beta-propiolactone, and lipid sol­vents. The particles closely resemble those of the Marburg agent, but there are some distinguishing characteristics. The Ebola agent, for example, has more branching than the Marburg agent. Oligonucle­otide patterns are distinctive. Seven nucleoproteins have been described. Serologically no relationship has been demonstrated, either to Marburg or to Lassa or to any other of a long list of arbo and nonarbo viruses. Another distinguishing characteris­tic of Ebola-Sudan and Ebola-Zaire is pathogenic­ity. Both cause excessive mortality, but mortality is lower for the Sudan strain than for the Zaire strain. Cercopithecus monkeys infected with and recovered from Ebola-Sudan virus, and therefore resistant to superinfection by the homologous virus, nonetheless succumbed when inoculated with Ebola-Zaire virus. A new family, Filoviridae, has been created for the agents Marburg and Ebola. As of 1988, no further agents have been proposed.

Clinical Manifestations

Onset of illness was usually sudden, with progres­sively more severe frontal headache of a type fre­quently seen with P. falciparum malaria infection, spreading Occipitally. Fever and weakness were al­ways present. Myalgia appeared early. Arthralgia of the large joints was very common from the onset. Severe generalized disease followed in a matter of a day or two. Patients were lethargic, their faces ex­pressionless with deep set eyes. Loss of appetite, sometimes accompanied by vomiting and rapid weight loss, was a nearly constant feature. In 2 to 3 days, gastrointestinal symptoms developed, fre­quently accompanied by cramping.

In later stages, particularly in patients with hem­orrhagic manifestations, red blood was seen in the stools. Vomiting was common, being seen in nearly half of the patients with hemorrhagic signs; vomitus was often of red blood or changed blood (cf. the Vomitusniger of yellow fever). Other common mani­festations included sore throat and dysphagia, fis­sures and open sores on the lips, conjunctivitis some­times accompanied by subconjunctival bleeding, and coughing. Jaundice occurred in some. Pancreatitis (clinical diagnosis) was also seen frequently, and abortion occurred in 23 percent of 82 infected preg­nant women. Hemorrhagic manifestations, seen in many patients and in over half of those who died, probably resulted from disseminated intravascular coagulation. Death occurred as early as the fourth day, but more usually on the fifth or sixth day and in occasional cases as late as the twentieth day.

Pathology and Diagnosis

Very few specimens were obtained for histological study. In three adequately preserved liver specimens available, fatty changes and necrosis of hepatocytes and Kupffer cells were noted, necrosis being of the focal type, distributed throughout the liver lobules. Intact cells with hyalinized cytoplasm and ghostlike nuclei (Councilman bodies of yellow fever fame) were seen, as were large amounts of karyorrhectic debris. Inflammatory changes were minimal in the liver and other organs.

Comparisons were made with Marburg disease, for which there was a large amount of pathological material available, both from human beings and from experimental animals. Here, in addition to the focal necrotic centers in the liver, was evidence of hemorrhagic diathesis in many organs and of pan­encephalitis in the brain, with glial nodule forma­tion, perivascular lymphocyte cuffing, and intersti­tial edema.

Several pathologists deemed the differential diag­nosis of Ebola infection to be extremely difficult in settings where there might be malaria, Lassa fever, Marburg disease, yellow fever, Congo-Crimean hem­orrhagic fever, typhoid fever, infectious hepatitis,

leptospirosis, brucellosis, and other fevers. Some other pathologists felt the lesions observed to be adequately specific to permit an Ebola diagnosis.

Clinical pathological data are extremely limited. A few white blood cell counts were normal to slightly elevated. No differential counts were made. Pro­teinuria occurred frequently.

Treatment and Prevention

Plasmapheresis with plasma from recovered pa­tients has been tried as treatment. Interpretation of limited trials (at the tail end of the epidemics) indi­cates little hope of an effective therapy. No drugs have been effective. A hospital staff member attend­ing an Ebola patient (from Africa) in a hospital in England became ill and soon was gravely ill. Inter­feron and immune plasma were both given and the patient recovered. A possible vaccine remains a dream.

Interestingly, 11 of 11 blood donors for plasma­pheresis had microfilariae, although no protozoa, in their blood. It should be emphasized that most of the Ebola patients who came to a clinic or a hospital had had several days of treatment with an antimalarial drug, often followed by typhoid treatment or antibiot­ics of whatever kind available. Malarial parasites could hardly be expected to be found under such circumstances.

Wilbur G. Downs

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