Approach
Correct triage of Marburg virus disease is a critical first step in both outbreak and isolated case settings. Once the diagnosis is suspected, patient isolation is a critical first step to prevent nosocomial transmission.[21] There are currently no Marburg-virus-specific treatments.
Early and aggressive supportive care is the mainstay of management.[4][21] In general, despite clear differences in disease pathogenesis and clinical course between patients with filovirus infection and other forms of sepsis, patients can be treated according to guidelines for severe sepsis or dengue management.[39][40] Initial vital signs should guide initial treatment. Fluid resuscitation is the main supportive treatment, and in patients who have significant gastrointestinal volume loss, massive fluid repletion with strict attention to repleting ongoing losses may be required.[4][30][40]
Since Marburg virus infection presents with similar features to Ebola virus infection, and because there is more information published on Ebola virus infection, some general statements and conclusions on the best type of care for Marburg virus infection are based on current knowledge of Ebola.
Urgent considerations
Infection control and isolation are extremely urgent when considering a diagnosis of Marburg virus disease or another viral haemorrhagic fever. Rapid fluid resuscitation (whether using oral rehydration solution or intravenous crystalloid) is also urgent.
Isolation and infection control
Infection control is of immediate concern. As soon as a clinician decides Marburg virus disease is a possible diagnosis for their patient’s illness, high-level precautionary isolation procedures and personal protective equipment (PPE) should be used until the infection is either confirmed or excluded. It is extremely important to minimise the risk of transmission while working up the patient.[18][20] Although 'wet symptoms' such as vomiting/diarrhoea may increase transmission risk, Marburg virus should be considered highly infectious and high-level precautions should be used regardless of symptoms at presentation.
The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) produce detailed guidance on PPE when filovirus disease is suspected:
The WHO also produces detailed infection-control guidance for healthcare workers in viral haemorrhagic fever outbreak settings:
Supportive care
Correct triage of people with suspected Marburg virus disease versus other infectious, haemorrhagic diseases, or other disorders, is a challenging but critical first step in both outbreak and isolated case settings. Once a diagnosis of Marburg virus disease or other viral haemorrhagic fever is suspected, patient isolation is a critical first step to prevent nosocomial transmission.[21] There are currently no Marburg-virus-specific treatments. Early and aggressive supportive care is the mainstay of management.[4][21] Patients suspected of Marburg virus disease should be admitted to an intensive care unit or other highly monitored isolation bed, when resources allow.[30] In general, despite clear differences in disease pathogenesis and clinical course between patients with filovirus infection and other forms of sepsis, patients can be treated according to guidelines for severe sepsis or dengue management.[39][40]
Once a diagnosis of Marburg virus disease is suspected and isolation is initiated, a provider should wear full PPE and collect 4mL whole blood in a non-heparinised, preservative-coated tube, and refrigerate or freeze immediately for shipment to a reference lab. Outside of North America and Europe, either reverse transcriptase polymerase chain reaction (RT-PCR) blood tests or oral swabs are used to detect Marburg virus RNA.[41] These tests may return within a few hours or days depending on whether a local or reference lab is used. At this time, providers should consider obtaining good intravenous access with careful central catheter placement (where possible) or multiple peripheral intravenous catheters.[31] Laboratory testing for possible differential diagnoses, malaria testing, FBC, renal function and electrolytes, and blood lactate level should be sent as soon as intravenous access is obtained, where possible.[31][42]
Initial vital signs should guide initial treatment. Fluid resuscitation is the main supportive treatment, and in patients who have significant gastrointestinal volume loss, massive fluid repletion with strict attention to repleting ongoing losses may be required.[4][30][40] Adult patients usually require ≥ 5-10L/day of intravenous or oral fluids to maintain circulating blood volume in the setting of ongoing gastrointestinal loss.[31] Monitoring and aggressive correction of potassium levels, acid-base disturbances, and other electrolyte abnormalities can help prevent life-threatening arrhythmias and metabolic complications.[31] Empiric broad-spectrum antibiotics (e.g., ceftriaxone, ciprofloxacin, or ampicillin/sulbactam) should be started to treat possible bacterial translocation from the gut.[31][42]
Empiric artesunate-based antimalarial treatment is recommended for all patients with suspected filovirus disease due to 31% lower risk of death in Ebola virus disease patients receiving these medications compared with other antimalarials. Increased survival may be due to treatment of malaria co-infection, prophylaxis preventing co-infection (especially in areas of high malaria-burden), or possibly even some of these drugs having a direct effect on filiovirus activity.[23]
Fever and pain should be treated with paracetamol first line. Opioid analgesics (e.g., morphine) are preferable for more severe pain. Non-steroidal anti-inflammatory drugs (including aspirin) should be avoided due to their associated increased risk of bleeding and potential for nephrotoxicity.[43]
Early administration of anti-emetics and anti-diarrhoeal therapy is recommended as long as diarrhoea is not bloody and other enteric pathogens are not suspected.[26][31][42] Transfusion of blood products including transfusion of platelets, packed red blood cells, and even plasma from convalescent donors may also be beneficial.[42]
Multi-organ dysfunction is a common feature of advanced infection and may include acute kidney injury, pancreatitis, adrenal failure, and liver damage. Liver damage (e.g., transaminitis) is common; however, jaundice is not a common feature.[12][25][44] Renal dysfunction is common in the advanced stages, but may be reversible in early stages with aggressive fluid resuscitation.[12][44] One Marburg virus disease patient with anuria not responsive to fluid resuscitation was treated with renal replacement therapy, an intervention which has also been used in patients with severe Ebola virus disease. However, there are no trial data to support the efficacy of this intervention. Of the five critically ill Ebola virus disease patients with multi-organ failure managed with both invasive mechanical ventilation and renal replacement therapy in Europe and North America, three died.[42][45][46][47][48]
Where resources allow, respiratory supportive care may be helpful, including supplemental oxygen, non-invasive ventilation, or invasive mechanical ventilation if non-invasive ventilation fails.[42] Full supportive care should be provided when possible, and can reduce filovirus disease mortality, with a reported survival rate of 82% in Ebola virus disease patients managed outside the West African setting.[42] Historically, Marburg virus disease is often fatal, with death occurring in approximately 70% (range 23% to 100%) of historical cases.[5] High case fatality rates in Marburg and Ebola virus disease patients in sub-Saharan Africa may be related to the lack of full supportive care available in resource-poor, rural settings where outbreaks have occurred.[49]
Vital signs and clinical monitoring should guide the aggressiveness of supportive care and other treatments.[26][31][42] Patients developing hypotension should receive vasopressor support therapy as needed.[26][31][42] Vitamin K should be considered to improve coagulopathy, and can be given to patients developing haemorrhage.[26][31][42] Platelet transfusion and cryoprecipitate may also be helpful when platelet or fibrinogen levels are low.[26][31][42] It should be noted that treatment recommendations for filovirus disease are based on clinical experience treating patients during outbreak settings, and evidence-based guidelines are limited.
Children
Children should be managed by teams of healthcare workers with paediatric expertise, and early involvement of intensivists has been advocated whenever feasible.[50] General principles of management for children with Marburg or Ebola virus disease are the same as for adults, with a focus on supportive care and volume resuscitation.[50] Care providers in the 2014 to 2016 West Africa Ebola virus outbreak advocate liberal use of oral rehydration solution (ideally flavoured to improve intake) and early, aggressive parenteral fluid resuscitation, even among apparently well-hydrated children.[51] Obtaining intravenous access may be easiest at time of admission, before further fluid losses make vascular access difficult, and a second intravenous line should be considered in 'wet' patients with active vomiting or diarrhoea.[51] Intra-osseous and subcutaneous routes of fluid resuscitation may be necessary in children unable to tolerate oral or intravenous rehydration.[51] Nutrition should also be a high priority in children with filovirus disease, using prepared or ready-to-use therapeutic food, and treating malnourished children according to therapeutic feeding protocols for acute malnutrition.[51] It should be noted that treatment recommendations for filovirus disease are based on clinical experience treating patients during outbreak settings, and evidence-based guidelines are limited.
Pregnant women
For filovirus-infected pregnant women, the value of usual obstetric interventions such as fetal monitoring, caesarean delivery, induction of labour, or pregnancy interruption must be considered on a case-by-case basis.[4] In addition to careful deliberation about obstetric intervention, appropriate anticipatory guidance should be provided to all pregnant women. Towards this end, urine pregnancy testing should be considered as part of routine triage testing to appropriately counsel pregnant women on pregnancy complications and management options. Pregnant filovirus patients are at high risk of spontaneous, pre-term labour and healthcare providers should be prepared for delivery at any time. Pregnancy outcomes can include spontaneous abortion, stillbirth, or delivery of a live fetus, and appropriate precautions should be taken. Regardless of the pregnancy outcome, all products of delivery should be considered potentially infectious and handled accordingly. Neonatal survival from Ebola virus-infected mothers is almost universally poor, and high fetal loss rates underscore the need to focus efforts on treatment of the pregnant mother, caveats which likely also apply to Marburg virus disease.[52]
Ebola virus has been cultured from breast milk 15 days after symptom onset and Ebola virus RNA has been detected in breast milk by RT-PCR 26 days after disease onset.[53][54] This evidence suggests that theoretically Ebola virus might be transmitted through breast milk, though frequent intimate contact between mothers and their children leaves open other possible modes of transmission. One study of Ebola survivors in Sierra Leone demonstrated no excess risk of Ebola virus transmission to infants during breast feeding.[55] Despite this, it is recommended that mothers with suspected or confirmed Ebola virus infection avoid close contact with their infants if safe alternatives to breastfeeding exist.[56] This includes cessation of breastfeeding. The US Centers for Disease Control and Prevention has determined there is insufficient evidence on when it is safe to resume breastfeeding.[56] The same caveats likely apply to Marburg virus infection, though there are no studies of breast milk or breastfeeding in Marburg virus disease to provide evidence-based guidelines.
Haemorrhage or disseminated intravascular coagulation
Haemorrhage and disseminated intravascular coagulation (DIC) are uncommon and are usually manifestations of late or severe disease. Vitamin K should be considered to improve coagulopathy, and can be given to patients developing haemorrhage.[26][31][42] Platelet transfusion and cryoprecipitate may also be helpful when platelet or fibrinogen levels are low.[26][31][42]
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