Approach
All SAHFs are notifiable diseases to the relevant public health authority.
The mainstay of treatment is prompt identification of the condition, with admission to a healthcare facility with appropriate isolation capabilities and good supportive care. There are no large clinical studies assessing best practice in supportive care. Although escalation to intensive care with organ support has not been described for SAHFs, it is not contraindicated as long as it can be done safely and with optimal protection for healthcare staff. For example, management of patients with Ebola virus disease in intensive care settings in well-resourced countries has demonstrated it is safe for healthcare workers and significantly improves survival rates.[31]
Evidence for specific therapies for the management of SAHFs is limited to convalescent (immune) plasma in Argentine haemorrhagic fever.[4][32] The antiviral drug ribavirin has also been considered in the management of Argentine, Bolivian, and Brazilian haemorrhagic fever. The use of ribavirin in SAHFs is still being evaluated, it has been used in Lassa fever but the evidence supporting this is currently under review.[33] It is, therefore, used in select patients with SAHFs despite the lack of evidence in these diseases.[2][4][9][34]
Isolation and infection control
Patients identified as being at risk of having SAHF should be admitted to a healthcare facility with appropriate isolation capabilities (including private bathroom facilities) and good supportive care, where possible. All healthcare workers attending the patient should have full personal protective equipment (PPE) available to them, and be trained in using it.[32] PPE should be used in any contact with the patient or items belonging to them. UNICEF: viral haemorrhagic fevers personal protective equipment specifications note Opens in new window All items (e.g., clothes, bed linen) and waste should be considered contaminated and disposed of accordingly. The World Health Organization, United Nations International Children's Emergency Fund (UNICEF), US Centers for Disease Control and Prevention (CDC), and NHS England have published guidance on PPE:
Specimens for laboratory investigations should be collected and sent to an approved laboratory with suitable facilities for testing samples for potential biosafety level 4 (BSL-4) pathogens, in accordance with local and national policies for high-risk samples and with clear labelling of the specimen to protect laboratory workers. Samples being sent for local testing, such as FBC and biochemistry, should also be clearly labelled. WHO has published guidance on handling blood samples containing highly infectious pathogens:
Minimising invasive investigations and repeated venepuncture may be achieved by siting a central venous line early in the course of the disease.
Nosocomial transmission of SAHFs has mainly been documented in Bolivian haemorrhagic fever and occasionally in Argentine haemorrhagic fever.[2][5] Laboratory transmission has been described for Brazilian haemorrhagic fever.[9] Although nosocomial transmission appears less common than in the filoviral haemorrhagic fevers (e.g., Ebola and Marburg), there remains a small risk of infection with a pathogen that causes severe disease and high mortality rates. For this reason full PPE is advised.[5]
Supportive care
The mainstay of care for all symptomatic patients with SAHFs is supportive, which includes fluid replacement (i.e., for dehydration or shock) and symptom management.[32]
Patients may present with dehydration or shock. Replacement of fluid and electrolytes is essential to management and should be undertaken diligently with close monitoring of input and output and electrolyte status. Oral rehydration solutions may be adequate for this purpose in patients who only have mild features of dehydration and are able to tolerate oral fluids at an adequate volume. For those who are more severely dehydrated or not tolerating oral fluids, intravenous fluids such as 0.9% saline or Hartmann’s solution/lactated Ringer’s, are recommended. Consideration should be given to electrolyte replacement in the context of severe or persistent derangement on monitoring.
There are currently no specific guidelines for the management of SAHFs; therefore, management of symptoms such as fever, pain, nausea, diarrhoea, vomiting, and seizures should be undertaken in accordance with local guidelines. For example, an analgesic/antipyretic (e.g., paracetamol) may be given for fever and pain. Antiemetics may be considered for nausea and vomiting. Anticonvulsants should be used to control seizures in accordance with local protocols and availability. Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated due to their propensity to increase bleeding and the risk of nephrotoxicity, particularly in the context of dehydration.
Convalescent plasma
Convalescent plasma (i.e., from the blood of patients immune to the disease) has been used in the treatment of Argentine haemorrhagic fever for several decades. Convalescent plasma should be administered within 8 days of the onset of symptoms in Argentine haemorrhagic fever to obtain maximum benefit.[4] A randomised, placebo-controlled trial was undertaken from 1974 to 1978 and demonstrated a reduction in mortality from 16.5% in the placebo arm (normal plasma infused) to 1.1% in the treatment arm (immune plasma infused).[4] The original dose administered was one 500 mL infusion of immune plasma given within the first 8 days since symptom onset. However, large variations were determined in the concentration of antibodies in immune plasma being collected from Argentine haemorrhagic fever survivors. For this reason attempts were made to standardise the dose of antibody received from immune plasma.[4] Studies assessing outcomes based on antibody concentration in immune plasma have concluded that a dose of 3500 ‘therapeutic units’ of neutralising antibodies per kilogram bodyweight should be administered.[4] The administration of convalescent plasma in the context of Argentine haemorrhagic fever has been associated with the development of late neurological syndrome (LNS) with features including febrile episodes, cerebellar signs, and cranial nerve palsies in approximately 10% of patients. This syndrome is more likely to develop if immune plasma is administered more than 8 days into symptoms.[4]
Convalescent plasma has not been studied in any of the other SAHFs. It has been used in clinical cases of Bolivian haemorrhagic fever, but there are no clinical data on safety or efficacy.[2] Trials in non-human primates with Bolivian haemorrhagic fever revealed that many developed LNS, similar to what has been described in some patients receiving convalescent plasma for Argentine haemorrhagic fever. In one study, 3 of 4 primates that developed LNS succumbed to death after clinical signs of Bolivian haemorrhagic fever had subsided.[35] A further study in rhesus monkeys identified a lethal chronic neurological disease, which 6 animals succumbed to following treatment with convalescent plasma.[2]
Convalescent plasma is only available in the endemic areas of Argentina and Bolivia, and may be difficult to obtain.[2][4][5] Convalescent plasma has not been described in the context of Venezuelan haemorrhagic fever and there have been insufficient cases of Chapare virus infection and Brazilian haemorrhagic fever for immune plasma to be available as a treatment option.[6][8][9]
Ribavirin
A trial of the guanosine analogue ribavirin, which is known to be effective in Lassa fever, was conducted in patients with Argentine haemorrhagic fever. As there was already a proven treatment, ribavirin was only administered to those who had symptoms for longer than 8 days prior to presentation and who were outside the therapeutic window for convalescent plasma. This study did not reveal a significant improvement in survival, with mortality rates in the treatment arm of 28.6%.[4] While survival was not improved, there was evidence for an antiviral effect, with viral titres falling to undetectable within 4 days of commencing treatment.[4] A study evaluating ribavirin for the treatment of Argentine haemorrhagic fever in a guinea pig model has shown significant reductions in mortality rate.[36] Earlier treatment (within the first 8 days of symptoms) with ribavirin may prove beneficial for SAHFs, but this has not been fully investigated in trials involving humans. Ribavirin has also been administered in Bolivian haemorrhagic fever, but only in a limited number of patients so efficacy has not been established. Early studies do, however, show promise.[2][37] A case of Brazilian haemorrhagic fever, managed in the US, was treated with ribavirin with apparent good effect; the patient became afebrile and asymptomatic 48 hours into treatment with undetectable virus on blood culture.[9]
There is no specific guidance for the management of subgroups of the population, such as children or pregnant women. The SAHFs largely occur in the adult male population; however, due consideration should be given to amending management accordingly for children and pregnant women. For example, ribavirin is teratogenic and should not be administered to pregnant women. Ribavirin should also be avoided in women who are lactating and wish to continue breastfeeding, although in this context the potential benefit to the patient must be weighed against the risks to the infant of stopping breastfeeding.
Haemorrhagic disease
Haemorrhagic disease is found in approximately 30% of patients.[2][4][5][6] Haemorrhagic features of the SAHFs are not consistent with disseminated intravascular coagulation (DIC). Haemorrhage is thought to result from thrombocytopenia, abnormal platelet function, alteration of levels of coagulation factors (depletion of factors VIII and IX, increase in factor V and von Willebrand factor), and activation of fibrinogen.[3][4] Management of haemorrhagic symptoms does not, therefore, follow standard management of DIC. Transfusion of platelets is indicated in the context of thrombocytopenia and active bleeding, in accordance with local protocols, and further management with fresh frozen plasma may also be appropriate in the context of active haemorrhage. There is no evidence for the benefit or harm of replacement of clotting factors, where these may be available.
Sepsis
Identification of sepsis should be made in a timely fashion and the patient started on broad-spectrum antibiotics promptly if sepsis is suspected as a differential diagnosis or concomitant aetiology. Management of confirmed sepsis should be in accordance with standard local guidelines with appropriate antibiotic therapy for the offending pathogen, attention to fluid resuscitation, airway management, and maintaining adequate urine output. Appropriate antibiotics will be dictated by local protocols, but should be broad spectrum and include cover for gram-negative organisms, under the assumption of possible gut translocation. Consideration should be given, where facilities are available, to intensive care support if required. See Sepsis in adults.
Malaria co-infection
Patients should be tested for malaria if presenting from a malaria-endemic area. Those with malaria co-infection should be treated with appropriate antimalarial therapy for the region which they have been resident in, taking into account local sensitivities. See Malaria.
Intensive care
While renal and hepatic impairment are less common in the SAHFs when compared with filoviral disease, approximately 20% of patients may progress to advanced disease with multi-organ failure.[2][3][4][5] Intensive care has not been described in the context of the SAHFs, and has only recently become part of the management of filoviral haemorrhagic fevers, when it is available. While there is no evidence in this specific disease context, the benefits of intensive care where organ support is required are self-explanatory and management of patients with Ebola virus disease has shown significant improvement in survival rates.[31] Where the facilities are available and it is safe for healthcare workers to do so, intensive care should be given due consideration.
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