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Pitfalls in Screening for Ebola Virus Disease: The Variable Febrile and Human Subjective Response

  • Hale O'mana'o Biomedical Research


ABSTRACT The Ebolavirus outbreak of 2014 in West Africa is unprecedented. As of the most recent situation report from the World Health Organization on November 11, 2014, there have been 14,098 suspected, probable and confirmed cases with 5160 deaths reported globally in this Public Health Emergency of International Concern. 5 cases outside the continent of Africa have been reported. Entry and exit screening for EVD (Ebola Virus Disease) of individuals originating from known outbreak regions currently include the presence of fever or additional symptoms consistent with EVD. Despite these efforts, the rate of transmission [R(t)] remains at 1.4 to 1.7, transnational cases are increasing, and a resurgence of the outbreak in Mali has recently been reported. This perspective article discusses the pitfalls associated with the determination of fever in the screening process as well as the difficulties with individual, subjective self-reporting of symptoms. Keywords EVD Screening Ebolavirus Ebola Virus Disease EVD Ebola fever Ebola Hemorrhagic Fever Ebola outbreak 2014 Screening for EVD EVD Exit Screening EVD Entry Screening Asymptomatic EVD Denial of Disease in EVD Fever determination in EVD
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In November 1994 after 15 years of epidemiologic silence, Ebola virus reemerged in Africa and, for the first time, in West Africa. In Côte d'Ivoire, a 34-year-old female ethologist was infected while conducting a necropsy on a wild chimpanzee. Eight days later, the patient developed a syndrome that did not respond to antimalarial drugs and was characterized by high fever, headache, chills, myalgia, and cough. The patient had abdominal pain, diarrhea, vomiting, and a macular rash, and was repatriated to Switzerland. The patient suffered from prostration and weight loss but recovered without sequelae. Laboratory findings included aspartate aminotransferase and alanine aminotransferase activity highly elevated, thrombocytopenia, lymphopenia, and, subsequently, neutrophilia. A new subtype of Ebola was isolated from the patient's blood on days 4 and 8. No serologic conversion was detected among contact persons in Côte d'Ivoire (n = 22) or Switzerland (n = 52), suggesting that infection-control precautions were satisfactory.
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The largest outbreak on record of Ebola hemorrhagic fever (EHF) occurred in Uganda from August 2000 to January 2001. The outbreak was centered in the Gulu district of northern Uganda, with secondary transmission to other districts. After the initial diagnosis of Sudan ebolavirus by the National Institute for Virology in Johannesburg, South Africa, a temporary diagnostic laboratory was established within the Gulu district at St. Mary's Lacor Hospital. The laboratory used antigen capture and reverse transcription-PCR (RT-PCR) to diagnose Sudan ebolavirus infection in suspect patients. The RT-PCR and antigen-capture diagnostic assays proved very effective for detecting ebolavirus in patient serum, plasma, and whole blood. In samples collected very early in the course of infection, the RT-PCR assay could detect ebolavirus 24 to 48 h prior to detection by antigen capture. More than 1,000 blood samples were collected, with multiple samples obtained from many patients throughout the course of infection. Real-time quantitative RT-PCR was used to determine the viral load in multiple samples from patients with fatal and nonfatal cases, and these data were correlated with the disease outcome. RNA copy levels in patients who died averaged 2 log(10) higher than those in patients who survived. Using clinical material from multiple EHF patients, we sequenced the variable region of the glycoprotein. This Sudan ebolavirus strain was not derived from either the earlier Boniface (1976) or Maleo (1979) strain, but it shares a common ancestor with both. Furthermore, both sequence and epidemiologic data are consistent with the outbreak having originated from a single introduction into the human population.
The filoviruses Marburg and Ebola cause severe hemorrhagic fever (HF) in humans. Beginning with the 1967 Marburg outbreak, 30 epidemics, isolated cases, and accidental laboratory infections have been described in the medical literature. We reviewed those reports to determine the basic clinical and laboratory features of filoviral HF. The most detailed information was found in descriptions of patients treated in industrialized countries; except for the 2000 outbreak of Ebola Sudan HF in Uganda, reports of epidemics in central Africa provided little controlled or objective clinical data. Other than the case fatality rate, there were no clear differences in the features of the various filovirus infections. This compilation will be of value to medical workers responding to epidemics and to investigators attempting to develop animal models of filoviral HF. By identifying key unanswered questions and gaps in clinical data, it will help guide clinical research in future outbreaks.
In November 1976 an investigator at the Microbiological Research Establishment accidentally inoculated himself while processing material from patients in Africa who had been suffering from a haemorrhagic fever of unknown cause. He developed an illness closely resembling Marburg disease, and a virus was isolated from his blood that resembled Marburg virus but was distinct serologically. The course of the illness was mild and may have been modified by treatment with human interferon and convalescent serum. Convalescence was protracted; there was evidence of bone-marrow depression and virus was excreted in low titre for some weeks. Recovery was complete. Infection was contained by barrier-nursing techniques using a negative-pressure plastic isolator and infection did not spread to attendant staff or to the community.
The potential of aerogenic infection by Ebola virus was established by using a head-only exposure aerosol system. Virus-containing droplets of 0.8-1.2 microns were generated and administered into the respiratory tract of rhesus monkeys via inhalation. Inhalation of viral doses as low as 400 plaque-forming units of virus caused a rapidly fatal disease in 4-5 days. The illness was clinically identical to that reported for parenteral virus inoculation, except for the occurrence of subcutaneous and venipuncture site bleeding and serosanguineous nasal discharge. Immunocytochemistry revealed cell-associated Ebola virus antigens present in airway epithelium, alveolar pneumocytes, and macrophages in the lung and pulmonary lymph nodes; extracellular antigen was present on mucosal surfaces of the nose, oropharynx and airways. Aggregates of characteristic filamentous virus were present within type I pneumocytes, macrophages, and air spaces of the lung by electron microscopy. Demonstration of fatal aerosol transmission of this virus in monkeys reinforces the importance of taking appropriate precautions to prevent its potential aerosol transmission to humans.
Ebola virus infection is largely restricted to central Africa (Gabon, the Democratic Republic of the Congo, and Sudan) and is associated with an overwhelming haemorrhagic fever characterised by pyrexia, headache, joint and muscle pains, vomiting and diarrhoea, conjunctivitis, and bleeding. The haemorrhage of Ebola infection seems to be caused by adhesion of viral particles to the endothelial lining of blood vessels via a specialised glycoprotein,1 the result being infection of, replication in, and damage to, the endothelial cells.2 The disease is usually fatal.3
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