Ebola Virus Disease. What the physician needs to know. (Overview, Transmission and Clinical Features)

Transcription

1 Ebola Virus Disease What the physician needs to know (Overview, Transmission and Clinical Features) Sources: Centers for Disease Control and Prevention (CDC) guidelines ( and WHO guidelines for Ebola Virus Disease ( with contributions from Dr. Asha Abraham, Professor and Dr. Shoba Mammen, Assoc. Prof., Dept. of Virology, CMC Vellore BACKGROUND Ebola Virus Disease (formerly called Ebola Hemorrhagic Fever) is an acute, serious, infectious illness which is often fatal (average case fatality rate of around 50%) if untreated. It is caused by the Ebola virus that belongs to the family Filoviridae. There are 5 species that have been identified: Zaire, Bundibugyo, Sudan, Reston and Taï Forest. The virus causing the 2014 West African outbreak belongs to the Zaire species. These viruses are classified as Biosafety Level 4 or Risk Group 4 pathogens since they cause severe human disease have no specific antiviral therapy and for which specific preventive interventions are not available. This group of pathogens poses a serious hazard to workers and presents a high risk of spreading to the community. Ebola virus disease (EVD) was reported first in 1976 when there were 2 simultaneous outbreaks, one in Sudan, and the other in Democratic Republic of Congo. The latter occurred in a village near the Ebola River, from which the disease takes its name. Since then there have been multiple outbreaks, but the current outbreak in West Africa is the largest and most complex. There have been more cases and deaths in this outbreak than all others combined. The most severely affected countries are Guinea, Sierra Leone and Liberia. Researchers from the New England Journal of Medicine have traced the current outbreak to a two year old toddler who died in December 2013 in Meliandou, a small village in south-eastern Guinea. The disease has since then spread to other African countries like Mali, Senegal and Nigeria. Cases have been reported in Spain, United Kingdom and USA. On August 8, 2014, the WHO Director-General declared this outbreak a Public Health Emergency of International Concern. The human cost of EVD The current outbreak in West Africa, which began in March 2014, has exacted a significant toll in terms of human lives, suffering and economic devastation as the most affected countries also happen to be some of the poorest countries in the world. These countries -Guinea, Sierra Leone and Liberia have very weak health systems and lack adequate human and infrastructural resources, having only recently emerged from long periods of civil war and instability. Statistics in the most affected countries (Case counts from updated last on7 th Jan 2015) The number of cases has stabilized in Liberia, but is still No. of Deaths cases Guinea Sierra Leone Liberia CMI 13:1 3 Total Jan 2015

2 rising in Guinea and Sierra Leone. The economic cost of EVD The economic damage wreaked by the EVD on the West African countries has been estimated by the World Bank considering two scenarios: a low impact one in which the disease is rapidly contained and a high impact one in which it is contained only slowly. The estimated economic cost under these two scenarios ranges from $1.6 billion to $25 billion over time. By way of comparison, the economy of Liberia produces a little less than $2 billion a year and that of Sierra Leone under $5 billion a year. The human and economic devastation along with the nature of the illness (its staggeringly high case-fatality rate, highly infectious nature and the fact that there is no cure) have ensured that it has captured international headlines. Several international organizations have joined together to contain this outbreak and experimental therapies are being developed. Some of these therapies have shown promise and the race is on to produce a vaccine. Key facts The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission. The average EVD case fatality rate is around 50%. Ebola only spreads when the patient is sick and manifests symptoms. Early supportive care with rehydration, symptomatic treatment improves survival. There is as yet no licensed treatment or vaccine but a range of blood, immunological and drug therapies are under development. TRANSMISSION OF EBOLA VIRUS Natural reservoir: The natural reservoir of EBOV is not completely understood. Fruit bats of the Pteropodidae family are thought to be the natural Ebola virus hosts. Infection in humans occurs through contact with infected animals such as fruit bats or primates (apes and monkeys). Human to human transmission: Ebola then spreads through human-tohuman transmission via direct contact (through broken skin or mucous membranes) with the blood, secretions, organs or other bodily fluids of infected people, and with surfaces and materials (e.g. bedding, clothing) contaminated with these CMI 13:1 4 Jan 2015

3 fluids. The virus is present in high quantity in blood, body fluids, and excreta of symptomatic EVD-infected patients. Modes of human-to-human transmission Direct contact (through broken skin or unprotected mucous membranes) with an EVD-infected patient s blood or body fluids Sharps injury (with EVD-contaminated needle or other sharp) Direct contact with the corpse of a person who died of EVD Indirect contact with an EVD-infected patient s blood or body fluids via a contaminated object (soiled linens or used utensils) Ebola is generally not spread through air, water or by food. There is no evidence that mosquitoes or other insects can transmit EBOV. Health-care workers are particularly vulnerable while treating patients with suspected or confirmed EVD when infection control precautions are not strictly practiced. Burial ceremonies in which mourners have direct contact with the body of the deceased person can also play a role in the transmission of Ebola. People remain infectious as long as their blood and body fluids, including semen and breast milk, contain the virus. Men who have recovered from the disease can still transmit the virus through their semen for up to 7 weeks after recovery from illness. Key facts - Transmission of EVD Infected persons are not contagious until onset of symptoms Infectiousness of body fluids (e.g., viral load) increases as patient becomes more ill Remains from deceased infected persons are highly infectious Gg Human-to-human transmission of Ebola virus via inhalation (aerosols) has not been demonstrated CMI 13:1 5 Jan 2015

4 PREVENTION AND CONTROL Community involvement is vital for successfully controlling outbreaks. Raising awareness of risk factors for Ebola infection and protective measures that individuals can take is an effective way to reduce human transmission. Risk reduction should focus on several factors: 1. Reducing the risk of wildlife-to-human transmission 2. Reducing the risk of human-to-human transmission from direct or close contact with people with Ebola symptoms, particularly with their bodily fluids. 3.Outbreak containment measures including prompt and safe burial of the dead, identifying people who may have been in contact with someone infected with Ebola, monitoring the health of contacts for 21 days, the importance of separating the healthy from the sick to prevent further spread, the importance of good hygiene and maintaining a clean environment. Keys to good outbreak control * Proper case management * Surveillance and contact tracing * Good laboratory service, * Safe burials and * Social mobilisation. Direct entry into tissues: Ebola virus infects many different cell types (usually macrophages and dendritic cells first) after entering the body. The virus then replicates within these cells, causing their necrosis and the release of large numbers of new viral particles into extracellular fluid. Host inflammatory response: In addition to causing extensive tissue damage, Ebola virus also induces a systemic inflammatory syndrome by inducing the release of cytokines, chemokines, and other proinflammatory mediators from macrophages and other cells. This inflammatory response results in a cascade of dysfunction in other systems and is responsible for many of the clinical features. Immune dysregulation: The infection results in the failure of adaptive immunity by disabling antigen-specific immune responses. There is PATHOGENESIS: There are two viral glycoprotein groups one group binds to and disintegrates sentinel cells. The other group shuts down the immune system s ability to produce interferons which act as potent virus killers. impairment of dendritic cell function and lymphocyte apoptosis. This may explain how the virus is able to cause a severe, frequently fatal illness. Hypovolemia and vascular collapse: Two factors may be involved in the development of hypovolemia and vascular collapse (1) fluid depletion due to vomiting and diarrhea, which can result in acute volume depletion and (2) circulating cytokines that are a part of the inflammatory host response. The gastrointestinal dysfunction and diffuse vascular leak ultimately leads to multi-organ failure. Disseminated intravascular coagulation (DIC) and coagulopathy: The coagulation defects seen in Ebola virus disease develop rapidly and are often severe. They appear to be induced indirectly, through the host inflammatory response. CMI 13:1 6 Jan 2015

5 CASE DEFINITIONS: Person Under Investigation (PUI) A person who has both consistent signs or symptoms and risk factors as follows: 1. Elevated body temperature or subjective fever or symptoms, including severe headache, fatigue, muscle pain, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage; AND 2. An epidemiological risk factor within the 21 days before the onset of symptoms. (For epidemiological risk factors, refer CDC guidelines Confirmed Case Laboratory-confirmed diagnostic evidence of Ebola virus infection. CLINICAL PRESENTATION Signs and symptoms: Symptoms of Ebola Virus Disease may appear anywhere from 2 to 21 days after exposure to Ebola, but the average is 8 to 10 days. Initial: Fever, chills, myalgia, malaise, anorexia Recovery from Ebola depends on good supportive After 5 days: GI symptoms, such as nausea, clinical care and the patient s immune response. vomiting, watery diarrhea, abdominal pain People who recover from Ebola infection develop Other: Headache, conjunctivitis, hiccups, rash, chest antibodies that last for at least 10 years. pain, shortness of breath, confusion, seizures Hemorrhagic symptoms (bleeding and bruising) in Early Clinical Presentation 18% of cases. Onset of disease: The onset is acute - typically 8 Ebola can spread to others only after the person 10 days after exposure (range 2 21 days) becomes sick i.e., after symptoms appear. Once people recover from Ebola, they can no longer spread the virus to the community. CMI 13:1 7 Jan 2015

6 Box 1: Clinical Features by organ systems Clinical Course Nonspecific early symptoms may progress to: Hypovolemic shock and multi-organ failure Hemorrhagic disease Death Non-fatal cases typically improve 6 11 days after symptoms onset. Fatal disease is usually associated with more severe early symptoms. Fatality rates of 70% have been reported in rural Africa. Intensive care, especially early intravenous and electrolyte management, may increase the survival rate. LABORATORY FINDINGS Thrombocytopenia (50, ,000 / ml range) Leukopenia followed by neutrophilia Transaminase elevation: elevation serum aspartate amino-transferase (AST) > alanine transferase (ALT) Electrolyte abnormalities Coagulation: PT and PTT prolonged Renal: proteinuria, increased creatinine Time line of infection Diagnostic tests available Within a few days of start of symptoms Antigen capture enzyme linked immunosorbent assay testing Later in disease course or after recovery IgM (as early as 6 days) and IgG antibodies Retrospectively in deceased patients Immunohistochemistry testing PCR Virus isolation CLINICAL CASE MANAGEMENT There is no specific curative therapy. Management is supportive, but has to be aggressive. Supportive care includes management of the following: 1. Hypovolemia and sepsis Aggressive intravenous fluid resuscitation Hemodynamic support and critical care management if necessary 2. Electrolyte and acid-base abnormalities Aggressive electrolyte repletion Correction of acid-base derangements CMI 13:1 8 Jan 2015

7 3. Symptomatic management of fever and gastrointestinal symptoms Avoid NSAIDS (they can worsen bleeding) Multisystem organ failure can develop and may require Oxygenation and mechanical ventilation Correction of severe coagulopathy Renal replacement therapy INVESTIGATIONAL THERAPIES There are at present, no approved Ebola-specific prophylaxis or treatment. Ribavirin has no in-vitro or in-vivo effect on Ebola virus. Treatment options in development with limited human clinical trial data include: Convalescent serum (serum from infected persons who have survived the infection) Therapeutic agents Two antiviral agents, favipiravir and brincidofovir have anti-ebola virus activity and have been used with patients with Ebola. Ebola specific agents in development include Zmapp (a combination of human monoclonal antibodies), TKM-Ebola (a short interfering RNA molecule), phosphorodiamidate morpholino oligomers and BCX4430 (a nucleoside analogue). Zmapp (produced in tobacco plants) is a cocktail of three monoclonal CLINICAL MANAGEMENT SUPPORTIVE BUT AGGRESSIVE Ebola Virus Disease antibodies targeting the Ebola virus surface lipoprotein and had been successfully tried in patients with Ebola. Vaccines in clinical trial Chimpanzee-derived adenovirus with an Ebola virus gene inserted Attenuated vesicular stomatitis virus with an Ebola virus gene inserted Prognosis and recovery: There is a high case fatality rate. The case-fatality rate in the 2014 Ebola outbreak is around 50-71%. Casefatality rate is much lower if there is access to intensive care. Patients who survive often have signs of clinical improvement by the second week of illness Recovery is associated with the development of virus-specific antibodies. Antibody with neutralizing activity against Ebola persists greater than 12 years after infection. Prolonged convalescence Includes arthralgia, myalgia, abdominal pain, extreme fatigue, and anorexia- many symptoms resolve by 21 months Significant arthralgia and myalgia may persist for >21 months Skin sloughing and hair loss has also been reported. The Ebola outbreak in West Africa is unlike anything since the emergence of HIV/Aids, according to Thomas Frieden, director of the CDC, Atlanta. It is a highly infectious disease and because of this, health care workers dressed in space-suit-like coverings have to take pains to make sure there is absolutely no skin contact with the patients they are caring for. Burial of the deceased also has to be a strictly sanitized no-touch affair. Perhaps it is this aspect of the disease- the fact that it deprives the sufferer of human touch, that makes it particularly miserable and poignant. Kent Brantly, an American physician who contracted the illness while taking care of patients called it a terrible, dignity-stripping disease. Several international organizations like the WHO, CDC and the MSF (Medecins Sans Frontieres) as well as other smaller groups have joined in the fight against this deadly illness and have made significant progress in containing its spread. Because of its low reproductive rate, the epidemic had been thankfully slow-growing and although a measure of control has been obtained, it is far from finished. CMI 13:1 9 Jan 2015