Lecture 15. hemorrhagic fevers

HEMORRHAGIC FEVERS Sorokhan MD, PhD Bukovinian State Medical University Department of the infectious diseases and epidemiology

EBOLA VIRUS HEMORRHAGIC FEVER Ebola virus is one of at least 30 known viruses capable of causing viral hemorrhagic fever syndrome. All agents that cause viral hemorrhagic fever syndrome are RNA viruses with a lipid envelope, all are considered zoonoses, all damage the microvasculature, resulting in increased vascular permeability, and all are members of one of four families: Arenaviridae, Bunyaviridae, Flaviviridae, and Filoviridae.

Etiology Present nomenclature classifies the Ebola viruses into 5 separate species. The currently identified species include Sudan ebolavirus, Zaire ebolavirus, Ivory Coast ebolavirus, Reston ebolavirus, and, the most recently identified, Bundibugyo ebolavirus. Filoviruses share a characteristic filamentous form with a uniform diameter of approximately 80 nm but display great variation in length. Filaments may be straight, but they are often folded on themselves. Ebola virus has a nonsegmented negative-stranded RNA genome containing 7 structural and regulatory genes. Electron micrograph of Ebola Zaire virus.

Epidemiology Filovirus infections are characterized by transmission from an unknown host (possibly bats) to humans or nonhuman primates, presumably via direct contact with body fluids such as saliva or blood or other infected tissues. Evidence in nonhuman primates indicates that Sudan ebolavirus and Zaire ebolavirus may be transmitted by contact with mucous membranes, conjunctiva, pharynx and gastrointestinal surfaces, small breaks in the skin, and, at least experimentally, by aerosol.

Signs and symptoms Clinical course. Human infections with Ebola virus is characterized by an incubation period of 3-8 days in primary cases and slightly longer in secondary cases. However, cases with incubation periods of 19 and 21 days have been observed. The onset of clinical symptoms is sudden. Severe headache, arthralgias or myalgias, fever with or without chills, anorexia, and asthenia occur early in the disease. Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, and diarrhea, soon follow. Evidence of mucous membrane involvement includes conjunctivitis, odynophagia or dysphagia, and bleeding from multiple sites in the gastrointestinal tract. Terminally ill patients often are obtunded, anuric, tachypneic, normothermic, and in shock. Although the mechanism is unclear, hiccups have been noted in fatal cases of Ebola.

Physical examination The findings upon physical examination depend on the stage of disease in which patients present. Early in the disease, patients may present with fever, pharyngitis, and severe constitutional signs and symptoms. A maculopapular rash, more easily seen on white skin than on dark skin, may be present around day 5 of infection and is most evident on the trunk. Bilateral conjunctival injection is also common. Late in the disease, patients often develop an expressionless facies. At this point in the disease, bleeding from intravenous puncture sites and mucous membranes is common. Myocarditis and pulmonary edema also are seen in the later stages of the disease. Terminally ill patients often die tachypneic, hypotensive, anuric, and in a coma.

Differential Diagnoses The diseases most frequently confused with Ebola hemorrhagic fever are Malaria, Marburg Hemorrhagic Fever, Other Hemorrhagic Fevers, Typhoid Fever, Acute surgical abdomen versus abdominal signs of Ebola hemorrhagic fever, and Crimean-Congo hemorrhagic fever.

Laboratory Studies The early phase of infection is characterized by thrombocytopenia, leukopenia, and a pronounced lymphopenia. Neutrophilia develops after several days, as do elevations in aspartate aminotransferase and alanine aminotransferase. Bilirubin may be normal or slightly elevated. With the onset of anuria, blood urea nitrogen and serum creatinine increase. Terminally ill patients may develop a metabolic acidosis that may contribute to the observation that these patients often have tachypnea, which may be an attempt at compensatory hyperventilation. Definitive diagnosis rests on isolation of the virus in tissue culture or PCR.

Treatment There is no standard treatment for Ebola hemorrhagic fever. Treatment is primarily supportive and includes minimizing invasive procedures, balancing electrolytes (since patients are frequently dehydrated), replacing lost coagulation factors to help stop bleeding, maintaining oxygen and blood levels, and treating any complicating infections. Convalescent plasma (factors from those that have survived Ebola infection) shows promise as a treatment for the disease. Presently, no specific therapy is available that has demonstrated efficacy in the treatment of Ebola hemorrhagic fever.

Prevention In the early stages, Ebola may not be highly contagious. Contact with someone in early stages may not even transmit the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent a hazard. Due to lack of proper equipment and hygienic practices, large-scale epidemics occur mostly in poor, isolated areas without modern hospitals or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments, all that can be done is to immediately cease all needle-sharing or use without adequate sterilization procedures, isolate patients, and observe strict barrier nursing procedures with the use of a medical rated disposable face mask, gloves, goggles, and a gown at all times, strictly enforced for all medical personnel and visitors. Presently, no commercially available Ebola vaccines are available.

Complications Ocular complications: patients reported ocular pain, photophobia, increased lacrimation, and decreased visual acuity. Survivors have developed the following late manifestations: Myalgias; Asymmetric and migratory arthralgias; Headache; Fatigue; Bulimia; Amenorrhea; Hearing loss; Tinnitus; Unilateral orchitis; Suppurative parotitis. Prognosis The overall prognosis of Ebola is poor. However, patients who survive for 2 weeks often make a slow recovery.

LASSA VIRUS HEMORRHAGIC FEVER Lassa fever is an acute, often fatal viral hemorrhagic fever endemic to West Africa and characterized by high fever, headache, ulcers of the mucous membranes, and disturbances of the gastrointestinal tract. It was first described in 1969 in the town of Lassa, in Borno State , Nigeria located in the Yedseram river valley at the south end of Lake Chad . Clinical cases of the disease had been known for over a decade earlier but not connected with this viral pathogen.

Etiology Lassa fever is caused by the Lassa virus, a member of the Arenaviridae family; it is an enveloped, single-stranded, bisegmented RNA virus. L assa virus

Epidemiology Lassa virus is zoonosis and was isolated from rodents of the genus Mastomys. This is probably the most common rodent in equatorial Africa. In these rats infection is in a persistent asymptomatic state. The virus is shed in their excreta (urine and feces), which can be aerosolized. Lassa fever is common in the dry season. Mastomys rodent, natural host of Lassa virus. Image courtesy of the Centers for Disease Control and Prevention.

Epidemiology Infection in humans typically occurs via exposure to animal excrement through the respiratory or gastrointestinal tracts. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infective material. Like other hemorrhagic fevers , Lassa fever can be transmitted directly from one human to another, presenting a disease risk for healthcare workers. It can be contracted by an airborne route or with direct contact with infected human blood, urine, or semen. Transmission through breast milk has also been observed.

Pathogenesis The primary defect in patients with Lassa hemorrhagic fever is that of increased vascular permeability. Lassa fever virus has an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias. Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse.

Signs and symptoms Most infections due to the Lassa virus are mild or subclinical. Severe multisystem disease is believed to occur in 5-10% of total infections. Incubation period is 7-18 days. Illness begins insidiously with fever, weakness, malaise, joint and/or lumbar pain, cough, and severe headache. In severe cases, the other symptoms arising from the affected organs are: Gastrointestinal tract - Nausea ; Hematemesis; Hematochezia; Stomach ache ; Constipation ; Dysphagia ; Hepatitis . Cardiovascular system - Pericarditis ; Hypertension ; Hypotension ; Tachycardia . Respiratory tract - Cough ; Chest pain; Dyspnoea ; Pharyngitis ; Pleuritis . Nervous system - Encephalitis ; Meningitis ; Unilateral or bilateral hearing deficit; Seizures . Clinically, Lassa fever infections are difficult to distinguish from other viral hemorrhagic fevers such as Ebola and Marburg , and from more common febrile illnesses such as malaria .

Differential Diagnoses The diseases most frequently confused with Lassa virus hemorrhagic fever are Meningococcemia, Plague, Pneumococcemia, Filovirus infection (Ebola or Marburg), Falciparum malaria, Yellow fever, Viral hepatitis, Congo-Crimean hemorrhagic fever, Leptospirosis, and Dengue. Diagnosis The diagnosis of Lassa virus hemorrhagic fever is made using antigen and/or antibody measurements, and virus isolation.

Treatment The antiviral drug ribavirin is used in Lassa fever. Supportive care related to blood pressure monitoring/control and careful attention to fluid and electrolytic balance can be lifesaving. Medication Ribavirin (Virazole) - 2 g (30 mg/kg) IV initially; 1 g (15 mg/kg) IV q6h for 4 d; then 500 mg (7.5 mg/kg) IV q8h for 6 d. Suggested prophylactic dose: 600 mg PO qid for 10 d.

Prevention Aggressive rodent control (eg, trapping, rodent poisons) and avoidance of high-density rodent areas are the most important preventative maneuvers. Procedures to avoid rodent droppings and exposure include properly disposing of trash and clutter, properly airing out cabins and buildings prior to reoccupation, and avoiding creating dust when cleaning buildings with signs of rodent infestation.

Complications Deafness, which can be unilateral or bilateral, is observed in as many as 30% of patients. Recovery of hearing occurs in approximately 50% of patients, but the deafness can be permanent. Maternal and fetal losses during Lassa fever infection are substantial. Maternal mortality rates can approach 30% and may be reduced with abortion. Fetal loss rates are close to 90% and are not affected by the trimester of infection. Renal or hepatic failure is not observed.

Prognosis About 15%-20% of hospitalized Lassa fever patients will die from the illness. It is estimated that the overall mortality rate is 1%, however during epidemics mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother. Thanks to treatment with Ribavirin , fatality rates are continuing to decline. Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.

Lecture 15. hemorrhagic fevers

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Lecture 15. hemorrhagic fevers