Clinical presentation and management of severe Ebola virus disease.

ANNALSATS Articles in Press. Published on 04-November-2014 as 10.1513/AnnalsATS.201410-481PS

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Clinical Presentation and Management of Severe Ebola Virus Disease T. Eoin West1,2 and Amélie von Saint André-von Arnim2,3 1

Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA 2

International Respiratory and Severe Illness Center, University of Washington, Seattle, WA, USA 3

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

Correspondence:

Phone: Fax: Email:

T. Eoin West Harborview Medical Center Box 359640 325 9th Avenue Seattle, WA 98104-2499 USA 206-897-5271 206-897-5392 [email protected]

Support: None Running Head: Presentation and Management of Severe Ebola Infection Key Words: Ebola Virus Disease, Critical Illness, Intensive Care, Disease Outbreaks, Infection Control Word Count: 5139 Abstract: 298 words

Copyright © 2014 by the American Thoracic Society


Abstract Clinicians caring for patients infected with Ebola virus must be familiar not only with screening and infection control measures, but also with management of severe disease. By integrating experience from several Ebola epidemics with best practices for managing critical illness, this report focuses on the clinical presentation and management of severely ill infants, children, and adults with Ebola virus disease. Fever, fatigue, vomiting, diarrhea, and anorexia are the most common symptoms of the 2014 West African outbreak. Profound fluid losses from the gastrointestinal tract result in volume depletion, metabolic abnormalities (including hyponatremia, hypokalemia, and hypocalcemia), shock, and organ failure. Overt hemorrhage occurs rarely. The case fatality rate in West Africa is at least 70% and individuals with respiratory, neurological, or hemorrhagic symptoms have a higher risk of death. There is no proven anti-viral agent to treat Ebola virus disease, although several experimental treatments may be considered. Even in the absence of anti-viral therapies, intensive supportive care has the potential to markedly blunt the high case fatality rate reported to date. Optimal treatment requires conscientious correction of fluid and electrolyte losses. Additional management considerations include searching for co-infection or superinfection, treatment of shock (with intravenous fluids and vasoactive agents), acute kidney injury (with renal replacement therapy), and respiratory failure (with invasive mechanical ventilation), provision of nutrition support, pain and anxiety control, psychosocial support, and use of strategies to reduce complications of critical illness. Cardiopulmonary resuscitation may be appropriate in certain circumstances but extracorporeal life support is not indicated. Among other ethical issues, patients’ medical needs must be carefully weighed against healthcare worker safety and infection control concerns. However, meticulous attention to use of personal protective equipment and strict adherence to infection


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control protocols should permit the safe provision of intensive treatment to severely ill patients with Ebola virus disease.



The 2014 Ebola outbreak in West Africa was described by the director general of the World Health Organization on October 13, 2014 as “unquestionably the most severe acute public health emergency in modern times” (1). Originating in December 2013 in Guinea, followed by spread in subsequent months to Liberia and Sierra Leone, the infection has since been exported further around the region (to Nigeria, Senegal, and Mali) and to Europe and North America (2, 3). Prevention and infection control have dominated recent discussions about the disease, but – other than typically brief mentions of supportive care – relatively little has been promulgated about clinical management of infection.

As estimates of total potential cases range from thousands into the millions of persons (4, 5) and the historical average case fatality rate of Ebola virus disease exceeds 50% (6), it is essential that all healthcare providers who care for severely ill patients be prepared to encounter and treat patients with this infection. Moreover, there is evidence that high quality supportive care may reduce mortality in Ebola (5, 7) and in other filovirus infections (8, 9). There are now sufficient cumulative data from the current outbreak to provide specific clinical contrasts with reports of previous outbreaks. The objective of this report is therefore to describe the pathophysiology, clinical presentation, diagnosis and management of infants, children, and adults with severe Ebola virus infection for providers in adequately resourced environments, considering the paramount importance of safety of healthcare workers and prevention of further spread of infection.

The information presented in this review was collated from US Centers from Disease Control and Prevention (CDC) and World Health Organization (WHO) documents, press releases,


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guidelines from organizations and professional societies, and the published literature. Terms used for searching PubMed and Google Scholar included “Ebola and treatment,” “Ebola and management,” and “Ebola and critical care.” Published articles that addressed clinical presentation and management of Ebola infection were selected and reviewed for relevance to this review. Recommendations on management were developed by integrating data from these sources and established best practices in critical care.

Pathophysiology Ebola, a zoonotic filovirus comprised of enveloped, non-segmented, negative-stranded RNA, enters the human host via mucosal surfaces or percutaneously (9, 10). Following infection, the virus disseminates readily throughout the body via replication in monocytes, macrophages, and dendritic cells followed by transfer through lymphatic vessels to regional lymph nodes, and continued spread to the blood stream, liver, and spleen (9). Unlike endothelial cells and hepatocytes, lymphocytes are not infected but are depleted by apoptosis (11-13). The virus circumvents the immune response by blockade of the type I interferon response, avoidance of antibody neutralization due to glycosylation, and other measures (14). Subsequent uncontrolled viral replication – up to 1010 RNA copies per milliliter of serum at the height of illness (15) – results in excessive pro-inflammatory responses, dysregulation of the coagulation cascade, and often death. Release of tissue factor from infected monocytes and macrophages or reduction of protein C levels may precipitate the coagulation abnormalities observed. In autopsy studies, multiple foci of hemorrhage are common on gross examination. Histologically, extensive hepatocellular necrosis, depletion of lymphocytes in the spleen, thymus and lymph nodes, and



widespread non-specific organ damage, is characteristic (16). Adrenal necrosis is also reported (9).

Clinical Presentation The incubation period for Ebola infection is two to 21 days, although most cases manifest within two weeks following exposure (5, 6). Symptoms, signs, and laboratory test abnormalities commonly observed in patients with Ebola virus disease are summarized in Table 1.

Symptoms, Signs, and Clinical Course The most common symptoms in the present outbreak are fever (87%), fatigue (76%), vomiting (68%), diarrhea (66%), loss of appetite (65%), headache (53%), abdominal pain (44%) and myalgias (39%) (5). Symptoms may begin abruptly and progress from non-specific (fever, fatigue, headache, myalgias, and malaise) to include abdominal pain, nausea, high volume vomiting, and diarrhea (17). Hiccups are uncommon but well described in the present and previous outbreaks (5, 18).

On examination, a characteristic finding in Ebola infection is elevated temperature, but this can oscillate markedly (18). Pulse-temperature dissociation has been observed on occasion early in the evolution of disease in prior outbreaks and was recently reported in the present epidemic (18, 19). A maculopapular rash (that may subsequently desquamate) has also been described, but is sometimes hard to identify in dark-skinned patients (17, 18). In the current outbreak, rash has not been a prominent feature (5). Some patients manifest mucosal hemorrhage and oozing from puncture sites; gastrointestinal hemorrhage also occurs and can be massive. However,


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hemorrhage has been reported in fewer than 50% of cases previously (9). In the current outbreak only 19% of patients have symptoms of unexplained bleeding, and overt bleeding at presentation seems to be much less frequent (5, 19). While disseminated intravascular coagulation may occur in more severe cases, the new term Ebola virus disease rather than Ebola hemorrhagic fever reflects the reduced frequency of hemorrhagic complications observed overall (9, 20).

Alterations in mental status, perhaps due to encephalitis, metabolic derangements, or sepsisinduced encephalopathy, can accompany the syndrome of Ebola virus disease (21, 22)(S. Jacob, personal communication). In infants and children, fever, respiratory symptoms (e.g. cough and dyspnea), and gastrointestinal symptoms were described as common in a prior Ebola outbreak, while only 16% had hemorrhage, and central nervous system signs were rare (23).

A dominant gastrointestinal syndrome may result in fluid losses of up to 10 liters per day in adult patients (7, 24) (S. Jacob, personal communication). This, in concert with septic physiology, can result in shock and organ failure such as acute kidney injury and respiratory failure that may require dialysis and mechanical ventilation (7, 25, 26). In advanced disease there can be seizures and coma. Pregnant women infected with Ebola may be at higher risk for severe illness and have increased rates of spontaneous abortion and pregnancy-associated hemorrhage (27, 28).

Clinical Laboratory Studies Laboratory findings, as described in previous outbreaks (18), may include the following: Leukopenia (with an increased proportion of neutrophils) may be seen initially, with a subsequent leukocytosis and atypical lymphocytosis. Marked anemia is rare but



thrombocytopenia is a characteristic feature. Elevations in transaminases (AST>ALT) are also common in past outbreaks and have recently been described in the present epidemic (18, 19). Additional reports on the current epidemic indicate that electrolytes, including sodium, potassium and calcium, may be markedly abnormal after severe vomiting and diarrhea (19, 20, 24). As disease progresses over several days, shock and severe metabolic disturbances lead to organ failure: hypoperfusion as evidenced by lactic acidosis and renal insufficiency are common (19, 20).

Prolongation of both the INR and PTT is well described in previous reports of Ebola infection, although these derangements have not been reported as a major feature in the 2014 West African outbreak. Hypo-albuminemia occurs and exacerbates vascular leak (7, 24). Several patients treated during the current outbreak have had profound lipemia in blood samples, which has resulted in laboratory test errors (S. Jacob, personal communication). There may be less impairment of pulmonary gas exchange parameters in Ebola virus infection compared to bacterial sepsis (20). Inadequate fluid resuscitation in under-resourced settings may also contribute to the impression of relatively preserved oxygenation in Ebola virus disease.

Case Fatality Rates and Predictors of Outcome

Case fatality rates in previous African outbreaks have ranged from 45 to 90% (29). In 2014, among 87 patients treated in a government hospital in Sierra Leone with a known outcome of laboratory-confirmed Ebola virus disease, the case fatality rate was 74% (19). The case fatality rate in the present epidemic was estimated in a larger West African cohort at 71% (5). Limited


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experience to date with the current outbreak suggests that the fatality rate for travelers and health care workers with Ebola treated outside of West Africa may be considerably lower (30).

In the current outbreak, predictors of death include age over 45 years, and respiratory, neurological, or hemorrhagic symptoms (5). Presenting complaints of weakness, dizziness, and diarrhea are also associated with mortality (19). Prior and recent reports suggest that the viral load and high levels of AST, amylase, BUN, creatinine, and D-dimer are associated with fatal outcome (15, 19, 31, 32). Other studies associate impaired Ebola-specific IgG and IgM levels, reduced number of T cells, and higher concentrations of cytokines and levels of nitric oxide with death (11, 32, 33). Previous reports also suggest that patients who survive two full weeks of illness are more likely to overcome the infection (18). Pediatric Ebola case numbers historically have been lower than in adults, presumably due to outbreak dynamics and societal structure (5, 23, 34). However, recent evidence suggests increased case fatality rates in infants and children up to five years old which correlated with elevated biomarkers of inflammation (IL-10 and IP10), endothelial cell function (sICAM, sVCAM), and coagulation (PAI-1) (35).

Diagnosis It is important to make the diagnosis as early as possible in order to initiate therapy before the development of shock and multi-organ failure, to alert public health authorities, and institute infection control procedures. The CDC case definition for possible Ebola virus disease is: 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 epidemiologic risk factor such as contact with a symptomatic Ebola-infected patient within the 21 days before the onset of symptoms (36).



For individuals from West Africa, the differential diagnosis may include malaria, typhoid fever, leptospirosis, rickettsiosis, African trypanosomiasis, Lassa fever, and cholera (16, 37). Marburg virus, another highly lethal filovirus, and Crimean-Congo hemorrhagic fever virus may cause clinically indistinguishable disease (18, 38). Dengue and Chikungunya infections may present with overlapping symptoms. In all patients, other viral, bacterial, and parasitic causes of gastroenteritis should be considered, as should hepatitis, systemic bacterial infection, and influenza. Given the non-specific nature of early Ebola infection in infants and children and the frequency of febrile illnesses in this age-group, pediatric health care providers must be particularly vigilant in considering Ebola.

Confirmation of the diagnosis of Ebola is made by detection of RNA or viral antigens in blood or other body fluids. This is generally done only in specialized laboratories. Rapid blood tests are available to detect specific RNA sequences by reverse-transcription polymerase chain reaction (RT-PCR) or viral antigens by enzyme-linked immunosorbent assay (ELISA) (2, 15, 39-41). Virus can usually be detected by RT-PCR in blood by three days after the onset of symptoms (42). Negative tests in symptomatic individuals with suspected infection within this time frame should be repeated. Antigen detection can be used as a confirmatory test for immediate diagnosis but may be less sensitive early in the disease course (10, 15). Testing for Ebola IgM or IgG antibodies may be useful to monitor the immune response over time or evaluate for past infection (16).

Supportive Management


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As the vast majority of cases of Ebola infection have occurred in low resource settings, institutions such as the World Health Organization and Médecins Sans Frontières have established protocols to guide therapy in these environments (38, 43). There are few data other than case reports to guide intensive therapy in highly resourced critical care units. However, the basic principles of caring for the severely ill are universal; implementation can be titrated across a range of settings based on available resources and expertise (44-46). Management of severe Ebola virus disease is summarized in Table 2.

Infection Control and Healthcare Worker Safety Considerations Regardless of location, clinical management of Ebola infection must be performed with strict attention to infection control and healthcare worker safety considerations. Ebola virus disease is not generally considered an airborne infection but rather is primarily transmitted among humans by contact with infected bodily fluids or contaminated objects (47, 48). Ebola virus is detected in blood, urine, feces, vomit, sweat, tears, saliva, mucous, breast milk, and semen (49, 50). The viral load in blood increases exponentially as symptoms progress (15). As the infectious dose is thought to be low (50) it is essential to consider the safety of healthcare workers and prevention of nosocomial spread of infection when developing treatment plans.

Organizations with extensive experience managing viral hemorrhagic fever patients such as Médecins Sans Frontières have developed robust protocols for ensuring provider safety and limiting spread of infection that should be considered models for other institutions (8). CDC and WHO have issued detailed recommendations for patient isolation, personal protective equipment (PPE), sample handling, disposal of waste, and environmental decontamination (51, 52).



CDC advises standard, contact, and droplet precautions for management of hospitalized patients with known or suspected Ebola virus infection (53). The mainstay of personal protection for healthcare workers is isolation of patients and meticulous adherence to infection control protocols. Current CDC recommendations for PPE are listed in Table 3 (48) and shown in Figure 1. No healthcare worker skin should be exposed or touched when working with patients infected with Ebola. PPE must be put on and removed in a methodical fashion, and removal of PPE should include multiple disinfection steps to limit contamination (48). This process is complex and to minimize risk to healthcare workers should be practiced repeatedly in advance. During clinical care, donning and doffing of PPE should be supervised by a trained observer. Additionally, doffing may require the assistance of a fully protected partner.

There is debate about airborne transmission of Ebola virus. The WHO position is that no studies have documented this mode of transmission (47). However, this is disputed by some experts who point to corroborating evidence of Ebola transmission by the aerosol route that necessitates airborne precautions (54-58). Aerosols can be generated by vomiting, flushing diarrhea down the toilet, or coughing, as well as by intubation, sputum production or bronchoscopy (54). Therefore, routine use of N95 respirators or PAPRs by healthcare workers as presently recommended by CDC and WHO is the most conservative approach (48, 59). PAPRs, while more expensive than N95 respirators, do not require fit testing, may be more comfortable, and provide better protection against splashes (54). Similarly, placement of patients in negative pressure isolation rooms offers the theoretical benefit of limiting airborne transmission of Ebola when aerosols are generated (53).


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Creation of a specialized and fully trained Ebola clinical care team, including physicians, nurses, respiratory therapists, and others, is an important strategy to reduce risk to healthcare workers. Wearing full PPE renders caring for patients more difficult due to altered sensory input, decreased dexterity, and increased fatigue (60). Moreover, the margin of error working in an Ebola-contaminated environment is low (60). Therefore, staffing requirements for care of patients infected with Ebola are significant. A National Institutes of Health multi-disciplinary team concluded that the minimum personnel require to care for one severely ill patient infected with Ebola for one week were two nurses per eight hour shift (six per day, or 12 full time employees), one to two physicians per shift (three to four per day, or six full-time employees) and one PPE adherence monitor per shift (three per day, or six full time employees) (60).

It is prudent to minimize unnecessary sampling from patients as all clinical specimens are considered infectious, but this should not impede testing where indicated and appropriate provision of medical care. In light of the risks associated with obtaining and transporting each sample and the lengthy decontamination process required for each diagnostic analyzer after assaying an Ebola-infected sample, it is wise to anticipate performing as many clinical tests on each sample as feasible. Point of care laboratory testing within the patient containment zone is one approach to limit sample transport and handling. There are significant and often prohibitive infection control ramifications of transporting patients beyond the isolation area. Thus, use of portable equipment for diagnostic testing is preferable, and all equipment must be thoroughly decontaminated after entering the patient’s room. Judicious implementation of infection control and healthcare worker safety measures requires timely planning and coordination at multiple



levels within the healthcare facility, preferably well in advance of caring for patients infected with Ebola.

Co-infection and Superinfection Although there are few data to inform the topic, co-infection with malaria, bacteria, or other viruses may occur in patients with confirmed Ebola infection. In immunocompromised patients, opportunistic pathogens should also be considered. If co-infection cannot be adequately evaluated, presumptive treatment with anti-bacterial and (in at-risk patients) anti-malarial agents is appropriate (43, 61). Incident bacterial superinfections should also be considered throughout the illness. Critically ill patients with Ebola are at risk for catheter associated infection, ventilator associated pneumonia, Clostridium difficile colitis, and infection from translocation of bacteria from the inflamed gut (7).

Volume Depletion and Electrolyte Abnormalities In light of massive loss of fluids via the gastrointestinal tract (and concomitant vascular leak) reported in the present outbreak, it is critical to monitor and correct volume status and electrolyte abnormalities (e.g. hyponatremia, hypokalemia, and hypocalcemia) particularly assiduously (20, 62). Infants and young children are at risk for hypoglycemia which should be ruled out and treated appropriately. Daily weights and meticulous balancing of fluid input and output is necessary in adults but especially important in infants and children. While oral rehydration solutions should be used if intravenous fluids are not available, in most severe cases the large volumes of fluids required are more readily administered parenterally. Isotonic fluids such as lactated Ringer’s solution or normal saline should be chosen for intravenous infusion. In cholera,


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another infection characterized by large volume secretory diarrhea, lactated Ringer’s solution is preferred due to the presence of bicarbonate and potassium in the fluid (63). Moreover, large volume infusion of normal saline may precipitate the development of a hyperchloremic acidosis. These factors favor use of lactated Ringer’s solution in severe Ebola infection. Albumin infusions may also be considered for volume expansion especially if there is accompanying hypoalbuminemia or significant third spacing of fluids. Analysis of pulse pressure variation, response to passive leg raise, and use of bedside ultrasound to assess cardiac function and inferior vena cava collapsibility may facilitate determination of volume status and fluid responsiveness in the setting of marked fluid shifts. Ongoing electrolyte losses require intravenous repletion. Parenteral anti-emetics to reduce vomiting should be administered. Antidiarrheal agents have been previously used to treat Ebola virus disease and may be considered but their safety is uncertain (64). Furthermore, in cholera, no benefit to anti-motility therapy has been established (65).

Shock Shock may be a result of profound volume depletion from gastrointestinal fluid loss, sepsis physiology, or bleeding. Aggressive volume repletion with isotonic fluids is the central element of treatment for gastrointestinal fluid loss and/or sepsis. After intravascular volume repletion, vasopressors such as norepinephrine or dopamine may be added for persistent hypotension. Dobutamine may be administered for inotropic support if there is evidence of cardiac dysfunction.



Although rare, hemorrhagic shock should be managed with transfusion of red cells, plasma, and platelets, with ongoing monitoring of blood counts, coagulation parameters, and acidosis. Adrenal insufficiency should be considered in refractory shock given reports of adrenal necrosis, although the clinical impact of corticosteroid therapy during Ebola infection is unknown. Hypotension is a late sign of shock in infants and children. Adequate treatment should be initiated before development of shock in this age group.

Acute kidney injury Acute kidney injury is a common complication of severe Ebola infection (19) and should be managed by optimizing intravascular volume status and hemodynamics, and avoiding nephrotoxic agents. Standard indications for renal replacement therapy (RRT) apply for patients with Ebola infection – including intractable acidosis, profound electrolyte derangements, volume overload, and uremia. Continuous RRT may provide better control of volume status and electrolytes in unstable patients (66). Systemic anticoagulation should be avoided in patients with active bleeding; regional citrate anticoagulation may be an alternative (66). RRT carries increased risk for health care workers due to the greater potential for blood exposure. In addition, contaminated continuous RRT effluent and filter cartridges require appropriate disinfection before disposal.

Respiratory failure Respiratory failure is more likely to occur secondary to acidosis and acute kidney injury, altered mental status with failure to protect the airway, or hemodynamic instability than due to primary pulmonary insufficiency. Excessive fluid resuscitation may increase the risk for respiratory


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failure. Although it has been used successfully to manage Ebola infection (7), non-invasive ventilation has a limited role for these etiologies of respiratory failure and carries greater potential to aerosolize secretions into the environment. Therefore invasive ventilation is preferred.

Where possible, respiratory failure should be anticipated to limit “crash” intubations and associated increased safety hazards to patients and providers. Placement of an endotracheal tube using video laryngoscopy overcomes the challenge of visualizing the larynx during direct laryngoscopy while wearing hood or helmet style PPE. Mechanical ventilation airflow exhaust should pass through a HEPA or equivalent filter (67). Mechanical ventilation settings should be selected based on the patient’s acid-base and oxygenation status; lung protective ventilation should be used for acute respiratory distress syndrome.

Altered Mental Status Metabolic abnormalities that may be contributing to encephalopathy should be corrected and anti-seizure therapy such as phenytoin provided if there is evidence of seizure or concern for subclinical status epilepticus. Intraparenchymal hemorrhage should be considered in obtunded patients with coagulopathies.

Coagulation Abnormalities Thrombocytopenia should be anticipated, and in severe cases, a syndrome consistent with disseminated intravascular coagulation should be sought. As for other causes of disseminated intravascular coagulation, in the setting of active bleeding correction of thrombocytopenia and



coagulation factor deficiencies, and anemia should be undertaken by transfusing platelets, plasma, cryoprecipitate, and red cells.

Analgesia and Psychosocial Support Patients with severe Ebola infection are likely to feel physically uncomfortable, suffer a sense of profound isolation, and be terrified of their prognosis. The ability to communicate, demonstrate empathy, or provide comfort is restricted when caregivers are clad in high containment PPE, yet providers should make every effort to acknowledge and address patient psychosocial concerns. Anti-pyretics, analgesics, and anxiolytics should be administered, and spiritual care providers engaged as appropriate. Use of video conferencing can permit interactions between care providers, patients and family or friends while reducing infection control concerns. Infants and children who require isolation and who may be separated from their family pose a specific problem. Whether available parents or caregivers should be placed with their children in isolation will depend on what opportunities for transmission may have occurred before seeking medical care for the child, and on the health of the parent or caregiver. This decision should be made on an individual basis and may be institution- and staff-dependent.

Nutrition Patients infected with Ebola should be evaluated for malnutrition and – once appropriately resuscitated – given enteral nutrition if possible. However, this may be limited by copious vomiting and diarrhea, ileus, or hiccups (7). Placement of a feeding tube should be performed cautiously in the event of thrombocytopenia or gastrointestinal hemorrhage. In patients with


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prolonged inability to take enteral feeding, administration of parenteral nutrition may be necessary (7) but this should be discontinued once enteral feeds can be initiated.

Extracorporeal Life Support Use of extracorporeal life support measures in severe Ebola infection has not been reported. Due to concerns that cardiorespiratory failure in Ebola infection may be related to multiple organ failure and uncontrolled hemorrhage – possible contraindications for the modality – and because of potential risks to healthcare workers and logistical challenges, the use of extracorporeal life support is not advised (68).

Experimental Therapies No anti-viral therapy is currently fully tested and approved for treatment of Ebola infection by the US Food and Drug Administration (FDA) (69, 70). Several experimental modalities are summarized in Table 4. Brincidofovir, an oral nucleotide analog, was authorized by the FDA for emergency use in patients with Ebola infection on October 6, 2014, after activity against Ebola virus in vitro was demonstrated (71). Brincidofovir is in Phase 3 trials for CMV and adenovirus infections.

Other experimental treatments include convalescent whole blood or plasma infusion, monoclonal antibodies, RNA-based drugs, and small antiviral molecules. A World Health Organization meeting on September 4-5, 2014 to identify novel therapies prioritized convalescent whole blood or plasma infusion, ZMapp (a cocktail of three monoclonal antibodies), and TKM-Ebola (an interfering RNA molecule used to block expression of two viral replication genes) (72, 73). The



supply of ZMapp is currently exhausted (74). TKM-Ebola had been undergoing testing in a phase 1 trial but was placed in a hold status by the FDA; however, its emergency use has since been authorized for Ebola infection (75). In September 2014, the Wellcome Trust funded clinical trials of various treatments in West Africa by a consortium of partners, which are to start soon (76). There are currently no approved forms of post-exposure prophylaxis for Ebola. No trials of experimental medications have been performed in children. To request experimental medications in the USA, an Emergency Investigational New Drug (EIND) application must be filed with the FDA. A supply of convalescent whole blood or plasma is not widely available at present, but the WHO has developed a protocol for establishing this (77).

Other Management Considerations Intravascular Access Concern about needle-stick injuries to care-givers has historically resulted in limited intravenous catheter placement in Ebola outbreak situations (62). Notably, performing invasive interventions in full personal protective equipment can be difficult due to diminished dexterity, and may escalate agitation and risk for needle-stick injuries in delirious or panicked patients or small children. However, if it can be performed safely, intravenous access greatly enhances the management of severely ill patients for whom enteral therapies are untenable, and should be initiated as soon as it is apparent that frequent blood testing and intravenous medication administration will be necessary.

Placement of a central venous catheter offers the benefit of needle-less blood draws, ability to provide large volumes of intravenous fluids, intravascular monitoring, and safer administration


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of vasoactive agents. Patients undergoing acute dialysis also require placement of a central venous dialysis catheter. Using ultrasound and selecting the compressible internal jugular or femoral veins for catheter placement may minimize complications in unstable and thrombocytopenic patients (78). However, the femoral site may be more likely to be soiled in patients with large volume diarrhea. Avoidance of the femoral vein as catheter placement site is preferred in adults with large volume diarrhea but given limited options for safe central venous access in infants and children, the femoral vein should still be considered for access in this age group. An alternative to insertion of a central venous catheter is to place a peripherally inserted central catheter (PICC). In general, the choice of catheter and site should depend on the particular clinical circumstances and local expertise.

Non-Invasive and Invasive Monitoring Severely ill patients with Ebola should undergo continuous electrocardiographic and pulse oximetry monitoring. Surveillance for cardiac arrhythmias is especially important in the setting of profound electrolyte imbalances (24). Fluid balance should be carefully recorded. However, quantifying diarrheal output may be difficult and the large volumes produced may exceed the capacity of fecal management systems. Accurate daily weights are therefore essential. Noninvasive blood pressure monitoring should be performed at least hourly. In patients with shock or requiring vasoactive agents, or those with anasarca or bruising limiting the use of non-invasive cuffs, invasive blood pressure monitoring should be undertaken by placing an arterial catheter. For patients undergoing mechanical ventilation, use of end-tidal carbon dioxide monitoring and pulse oximetry to monitor gas exchange may be a safer alternative to the use of arterial blood gas testing (79).



Prevention of Complications Severely ill patients with Ebola are at risk of developing complications during their hospitalization, including nosocomial infection, stress ulceration of the gastrointestinal tract, and venous thromboembolism. Standard prophylactic measures used for all critically ill patients should be implemented in Ebola-infected patients in the absence of contraindications.

Ethical Considerations, Resuscitation, and End of Life Care Providing intensive care for a severely ill patient with Ebola infection raises a number of ethical concerns (80). For example, what are providers’ obligations to provide care to patients with Ebola virus disease? What is the right balance between providing invasive but potentially lifesaving therapies and minimizing risk to providers? Caring for even one patient with Ebola consumes a tremendous amount of material, personnel, and logistical resources, potentially impacting care of other hospitalized patients. What is the most appropriate allocation of resources within an institution? In light of limited data informing intensive care of severely ill patients with Ebola, should experimental treatments be offered? How should participation in research be considered if clinical trials become available? A recent American College of Chest Physicians consensus statement provides guidance in addressing these issues (81), which become even more pressing as the number of infected patients increases. Convening key stakeholders and ethics panels at each institution is advisable to establish a practical, transparent, and uniformly applied ethical framework to guide provision of intensive care.


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The decision to perform cardiopulmonary resuscitation (CPR) on patients with Ebola virus disease exemplifies some of these ethical challenges. Management of an acute decompensation such as cardiac arrest in a high containment environment is physically and logistically difficult, and a crisis scenario poses additional risk to health care workers. Important factors to consider are the medical indication and utility of CPR, ability to provide effective CPR, safety to healthcare workers, and patient preferences (79). To the degree possible, this decision-making process should undertaken prospectively for each critically ill patient. For severely ill patients with intractable multisystem organ failure, redirecting the goals of care from attempts to cure to a focus entirely on comfort should be considered (82, 83).

Hospital Discharge Considerations RT-PCR testing can be used to determine when a patient can be discharged from a hospital setting after recovery from Ebola infection. According to WHO recommendations, individuals who no longer have signs and symptoms of Ebola virus disease can be discharged if they have two negative PCR tests on whole blood, separated by at least 48 hours (84), although it is known that recovering individuals can shed virus in semen for several months (85). Decisions when to release recovered patients should be made in conjunction with public health authorities, accompanied by appropriate post-discharge precautions such as avoiding unprotected sexual intercourse.

Concluding Comments In the absence of proven anti-viral therapies for Ebola infection, the widely used term “supportive care” may be construed as implying that there is little else that can be done to



improve clinical outcome. In contrast, several interventions for the severely ill Ebola-infected patient are likely to reduce the high mortality rate reported to date from West Africa. The proposed recommendations for clinical management integrate proven best practices in critical care with relatively limited available data about treatment of severely ill pediatric and adult Ebola-infected patients. Fluid resuscitation and electrolyte repletion are the most important elements of care but these therapies are only part of a package of interventions that intensive supportive care offers these patients. New clinical observations and research data will further inform and refine this care. With careful planning, these treatments can be integrated into systems ensuring care provider safety and appropriate infection control in order to optimize outcomes from this severe disease.


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Acknowledgments We thank Shevin Jacob MD for providing information about clinical presentation and management, and Shawn Skerrett MD for review of the manuscript. Figure 1 photograph provided by John Hansen-Flaschen MD.



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Table 1. Common Symptoms, Signs, and Laboratory Test Abnormalities in Ebola Virus Disease

Symptoms

Signs

Laboratory Test Abnormalities

Fever (87%)

Elevated temperature

Leukopenia -> Leukocytosis, atypical lymphocytosis

Fatigue (76%)

Pulse temperature dissociation

Thrombocytopenia

Vomiting (68%)

Transaminitis (AST>ALT)

Diarrhea (66%)

Hyponatremia

Loss of appetite (65%)

Hypokalemia

Headache (53%)

Hypocalcemia

Abdominal pain (44%)

Elevated BUN and creatinine

Arthralgias (39%)

Lactic acidosis

Mylagias (39%)

Prolonged INR and PTT Hypoalbuminemia

Data from refs 5, 7, 17, 18, 19, 20, 21, 22, 24



Table 2. Summary of Management of Patients with Severe Ebola Virus Disease

Ensure personal safety (see Table 3) and observe infection control protocols at all times; establish a specialized and suitably staffed care team Assess for co-infection and superinfection Monitor and correct massive volume losses and severe electrolyte abnormalities; administer lactated Ringer’s solution, electrolytes, and anti-emetics intravenously Use non-invasive measures of volume status and fluid responsiveness to guide therapy where possible After volume repletion, use vasoactive agents for non-hemorrhagic shock; consider adrenal failure in refractory shock Resuscitate with blood products correcting anemia, thrombocytopenia, and coagulopathy in major hemorrhage Manage acute kidney injury by optimizing volume status and hemodynamics, and by avoiding nephrotoxins; use renal replacement therapy as necessary Manage respiratory failure preferentially with invasive mechanical ventilation; intubate using video laryngoscopy if available Consider subclinical status epilepticus and intracranial hemorrhage in obtunded patients unresponsive to therapy Treat fever, pain, anxiety, and offer maximum psychosocial support


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Provide nutrition by the enteral route if possible; otherwise consider parenteral nutrition support Do not initiate extracorporeal life support measures Consider experimental therapies listed in Table 4 Place a central venous catheter or peripherally inserted central catheter when frequent blood testing and intravenous therapies are required; perform needle-less blood draws Perform continuous electrocardiographic and pulse oximetry monitoring and frequent non-invasive blood pressure assessments; use invasive continuous blood pressure monitoring if necessary Employ standard prophylactic measures to minimize hospital acquired complications such as infection, stress ulceration, and venous thrombo-embolic disease Anticipate and prospectively address ethical issues around treatment Actively weigh the risks and benefits of cardiopulmonary resuscitation in each circumstance Focus on comfort rather than life-sustaining measures in intractable disease



Table 3. CDC Recommended Personal Protective Equipment for Providers Treating Patients with Ebola Virus Disease

Equipment

Notes

Powered Air Purifying Respirator (PAPR) with Any reusable helmet or headpiece must be covered with a disposable hood full face shield, helmet, or headpiece OR

that extends to the shoulders and fully covers the neck and is compatible with

N95 Respirator (disposable) with disposable

the selected PAPR. If using N95 respirator, provider must not touch face

surgical hood and disposable face shield

under the face shield during patient care

Gown or Coverall

Disposable, fluid-resistant or impermeable gown that extends to at least midcalf or coverall without integrated hood. Thumb hooks desired

Gloves, 2 pairs

Disposable nitrile exam gloves with extended cuffs

Boot covers

Disposable, fluid-resistant or impermeable boot covers that extend to at least mid-calf or – only if wearing coveralls with integrated socks – disposable shoe covers


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Apron

Disposable, fluid-resistant or impermeable apron that covers the torso to the level of the mid-calf when exposure to vomiting or diarrhea

Data from ref 48



Table 4. Selected Experimental Therapies for Ebola Virus Disease

Agent

Mechanism

Status

Brincidofivir

Oral nucleotide analog

In Phase 3 trials for CMV and adenovirus infections. Authorized by the FDA for emergency use in patients with Ebola infection

ZMapp

Monoclonal antibody cocktail

Supply exhausted

TKM-Ebola

Interfering RNA molecule

Authorized by the FDA for

blocking expression of viral

emergency use in patients with

replication genes

Ebola infection

Convalescent

Unknown. Antibodies may

No widely available supply at

whole blood or

confer protection

present

plasma infusion

Data from refs 69, 70, 71, 72, 73, 74, 75


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Figure Legends Figure 1: Enhanced personal protective equipment (PPE) with a Powered Air Purifying Respirator (PAPR).



Figure 1 65x101mm (300 x 300 DPI)


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Ebola virus disease: clinical management and guidance.

Ebola virus disease in West Africa--clinical manifestations and management.

Clinical Management of Ebola Virus Disease in the United States and Europe.

Ebola virus disease: clinical care and patient-centred research.

Clinical predictors of mortality in patients with Ebola virus disease.

Ebola virus disease.

[Ebola virus disease].

Ebola virus disease.

Ebola virus disease.

Ebola virus disease epidemic.

Ebola virus disease.

The clinical presentation and management of carcinoid heart disease.

Ebola virus disease candidate vaccines under evaluation in clinical trials.

Treatment of Ebola virus disease.

Diarrhea Can Be an Important Clinical Presentation of 2014 Western Africa Ebola Virus Infection.

Ebola virus disease and Marburg disease in pregnancy: a review and management considerations for filovirus infection.

Predicting Ebola Severity: A Clinical Prioritization Score for Ebola Virus Disease.

Eyes on Ebola Virus Disease.

Ebola virus disease--current knowledge.

Preparedness for Ebola Virus Disease.

Ebola virus disease: history, epidemiology and outbreaks.

Ebola virus disease and critical illness.

Ebola virus disease and the veterinary perspective.

Ebola virus disease and blood purification techniques.