Approach

All SAHFs are notifiable diseases, and cases should be reported to the relevant public health authority.

The SAHFs are comprised of 5 different diseases caused by 5 different clade B New World arenaviruses. The different viruses are specific to different locations in South America (i.e., Junin virus in Argentina; Machupo and Chapare viruses in Bolivia; Guanarito virus in Venezuela; and Sabia virus in Brazil), and infections are generally confined to these endemic regions. The virus is transmitted to humans from rodents, which are its natural reservoir and natural vector.[2][3][5][6][8][9]

All SAHFs generally present in a similar manner, although there are limited clinical data for two of the diseases (Chapare virus infection and Brazilian haemorrhagic fever). The disease for which the most clinical information is available is Argentine haemorrhagic fever due to annual, sizeable outbreaks from 1958 until the development of the Candid#1 vaccine.[3][4][5] Diagnosis is based on clinical suspicion, history, and physical examination, with laboratory testing to confirm diagnosis. The presence of clinical features, such as fever, headache, malaise, arthralgia, and myalgia, in conjunction with a recent history of travelling, working, or residing in endemic regions, should raise suspicion.

Isolation and personal protective equipment (PPE)

Patients with suspected SAHF should be isolated in a room with private bathroom facilities. All healthcare workers attending the patient should have full PPE available to them and be trained in using it.[30]​​ PPE should be used in any contact with the patient or items belonging to them.​ All items (e.g., clothes, bed linen) and waste should be considered contaminated and disposed of accordingly. The World Health Organization (WHO), United Nations International Children's Emergency Fund (UNICEF), US Centers for Disease Control and Prevention (CDC), and NHS England have published guidance on PPE:

History

A detailed history including occupation and recent travel is essential to the identification of the SAHFs. The rodent hosts are located in very specific regions within Argentina, Bolivia, Venezuela, and Brazil, and only in certain parts of these regions are the rodents known to carry the relevant virus. Identifying where the patient has been living or travelled to, will help to highlight whether they are at risk of SAHF and, if so, which one may be more likely.

Exposure risk

The rodent vectors are rarely found in or around human dwellings as their usual habitat is long grass areas on the peripheries of fields.[5][6] For this reason agricultural workers in rural areas are particularly at risk.[2][5][6][8]

Exposure in a hospital setting should be considered for healthcare workers and patients if there are cases of SAHF infection in the hospital that are not appropriately isolated.[2] This particularly applies to Bolivian haemorrhagic fever, which appears to have a higher risk of nosocomial and person-to-person transmission compared with the other SAHFs.[2] Laboratory workers should also be considered at risk, particularly in the context of Argentine, Bolivian, and Brazilian haemorrhagic fever.[9][10]​​ Although experience is somewhat limited, laboratory exposure has been reported in Brazilian haemorrhagic fever both in Brazil and in the US.[9]

For the 3 diseases where large numbers of cases have been described (i.e., Argentine, Bolivian, and Venezuelan haemorrhagic fevers), there is an adult male preponderance.[2][5][6][11]​ This is probably because more men work as agricultural labourers in these countries compared with women. Children are not commonly affected, with all diseases being either very rare or not documented in children <5 years of age.[2][5][6]

Symptoms

The incubation period of the SAHF viruses is approximately 3-16 days, but varies between diseases. Argentine haemorrhagic fever has an incubation period of 6-14 days,​​ whereas Bolivian haemorrhagic fever has an incubation period of 3-16 days.[2][3][4]​​​ Incubation periods have not formally been described for the other 3 haemorrhagic fevers, although case descriptions suggest a similar incubation period, with a case of Venezuelan haemorrhagic fever presenting 19 days after likely exposure.[2][5][6][8][9]

As in other viral haemorrhagic fevers, early symptoms are often non-specific with fever (often >38°C), malaise, myalgia, arthralgia, and headache; therefore, they may resemble flu or dengue fever.[2][5][6] Approximately 5-7 days following onset of early symptoms (i.e., during the second week of illness), some patients develop gastrointestinal symptoms (e.g., abdominal pain and nausea/vomiting, with or without diarrhoea), which may be followed by haemorrhagic symptoms (e.g., petechiae, bleeding gums, and gastrointestinal bleeding), and in severe cases neurological symptoms (e.g., confusion, ataxia, prostration, and seizures).[2][5][6] Those who progress to severe haemorrhagic symptoms or who develop neurological symptoms have a poor prognosis and the majority do not survive.[4][5] There are insufficient data for Brazilian haemorrhagic fever and Chapare virus infection to comment, but cases described appear similar, with signs and symptoms similar to the other SAHFs.[8][9]

The most common signs and symptoms reported for Argentine haemorrhagic fever and Venezuelan haemorrhagic fever (percentages related to Venezuelan haemorrhagic fever) are:[5][6][7]

  • Fever (approximately 90%)

  • Malaise (74%)

  • Headache (58%)

  • Bleeding gums (52%)

  • Arthralgia (52%)

  • Vomiting (34%)

  • Abdominal pain (30%)

  • Myalgia (30%)

  • Diarrhoea (27%)

  • Seizures (18%)

  • Petechiae (16%).

Cough and sore throat have been reported in Venezuelan haemorrhagic fever, but are rarely seen in the other haemorrhagic fevers.[2][4][5][6]​​ Approximately 20% to 30% of patients with any of the SAHFs appear to develop haemorrhagic symptoms, although data are limited for Brazilian haemorrhagic fever and Chapare virus infection.[2][5][6]

Physical examination

Where possible a full physical examination should be undertaken while ensuring prevention of exposure to healthcare workers. This may help to exclude other potential causes of the symptoms and should involve assessing the patient for sepsis and other conditions amenable to prompt intervention.

Physical findings may include:

  • Fever (>37.5°C but often >38°C) present in approximately 90% of patients. Other observations may indicate a relative bradycardia in the initial stages of the disease, which may develop into a tachycardia as the disease progresses. Features of shock may be present in the later stages of the diseases with profound hypotension[2][5][6]

  • Features of dehydration in those with vomiting and diarrhoea[5][6]

  • Lymphadenopathy is present in nearly 25% of patients[6]

  • Petechiae are common, particularly in Argentine haemorrhagic fever, and tend to develop during the first week of symptoms when they are commonly found over the soft palate, in the axillae, and across the upper chest and arms[2][5][6]

  • The gums may be congested and may bleed spontaneously or when gentle pressure is applied. Bleeding from the gastrointestinal tract, such as melaena, rectal bleeding, or haematemesis, may develop later in the disease, usually in the second week of illness.[5][6] Metrorrhagia is also common in women[5]

  • Conjunctival congestion/injection and peri-orbital oedema occur in approximately 15% of patients with Venezuelan haemorrhagic fever, and have also been reported in Argentine and Brazilian haemorrhagic fevers[4][5][6][9]

  • Neurological signs including seizures may develop during the second week of disease, and carry a poor prognosis. Some patients may develop prostration and a reduced conscious level[2][4][5][6]

  • Hepatomegaly and splenomegaly are infrequent and unlikely to be present, with hepatomegaly featuring in only 5% of patients with Venezuelan haemorrhagic fever and splenomegaly occurring in less than 2%.[5][6]

Initial investigations

All specimens should be collected in accordance with WHO guidance for the collection of specimens potentially containing blood-borne pathogens. WHO: how to safely collect blood samples from persons suspected to be infected with highly infectious blood-borne pathogens (e.g., Ebola) Opens in new window Specimens should be labelled appropriately to ensure laboratory workers are aware of the content and potential risk associated with the specimen. Samples should be handled and processed appropriately to ensure safety of the operators, and to prevent any environmental contamination by the virus, in a laboratory experienced in handling dangerous organisms.[30]​ All samples should be handled initially in a biosafety cabinet and, wherever possible, inactivated before extraction for molecular testing. Following extraction, samples for molecular testing can be handled at biosafety level (BSL) 2. Any other work involving live viruses should be undertaken in a BSL-4 facility.

The main confirmatory test for all SAHFs is a reverse transcription-polymerase chain reaction (RT-PCR) test.[2][3][8][9] While potentially available in the relevant affected countries, it may be hard to obtain appropriate primers in a local setting and, therefore, often only reference laboratories have the facilities to run RT-PCR.[2]

Enzyme-linked immunosorbent assay (ELISA) can be ordered if RT-PCR is unavailable.[7]​ ELISA may identify IgM and IgG antibodies against the viruses, although these are often not present until approximately 12 days into the disease process and so may delay the diagnosis.[2][3][5][6][9] Fatal cases that present with a rapid disease process may not mount a humoral immune response and so may result in a false-negative ELISA result.[5] Some laboratories may opt to do ELISA in parallel with RT-PCR; however, it may need to be repeated at a later stage if done initially during the early symptomatic stage and results are negative.

In the absence of RT-PCR and ELISA, a full blood count can aid in diagnosis and may help as a screening tool, as patients with SAHFs often have a notable leukopenia and thrombocytopenia.[3][5][6][9]​ It is also useful for monitoring patient progress. Standard screening tests for urea (or BUN) and electrolytes, liver, and renal function are essential.

Other investigations

All investigations should be performed in a laboratory that is able to manage BSL-4 pathogens safely, and has appropriate safety measures and training are in place to protect laboratory workers. Most tests needed for supportive management of the patient and correction of electrolyte and acid-base abnormalities, haemoglobin, and platelet levels can be performed safely using closed path automated machinery. If this is unavailable, analysers should be used in a class 3 microbiological safety cabinet or isolator, and any material taken outside the cabinet inactivated before further use.

Further investigations should include those that rule out other differential diagnoses or detect concomitant disease, such as a malaria screen; RT-PCR for dengue fever, chikungunya, Zika, yellow fever, Oropouche, hantavirus, measles, and influenza viruses; PCR for leptospirosis and rickettsia infection; stool culture for Salmonella enterica (in typhoid fever); and a sepsis screen. It should be borne in mind that a positive malaria screen or blood culture does not necessarily exclude the diagnosis of SAHF as malaria may co-infect the patient, and in the later stages of haemorrhagic fever bacterial sepsis may develop.[3][5]

Other investigations include:

  • Renal panel and electrolytes

    • In the context of dehydration and diarrhoea, monitoring of electrolytes is important. Renal impairment is rare unless in the terminal stages of the disease or as a result of profound shock[5]

  • Liver function

    • Mildly raised hepatic enzymes have been reported, but a marked transaminitis is rare[5][9]

  • Coagulation screen

    • A coagulation screen is important in patients with haemorrhagic disease or to monitor those at risk of developing haemorrhagic disease. The activated partial thromboplastin time is often prolonged with a raised fibrinogen in severe cases. There are no fibrin deposits in the microcirculation though and the alteration in levels of prothrombin and clotting factors rule out disseminated intravascular coagulation as contributing to the pathogenesis[3]

  • Lactate dehydrogenase

    • The blood lactate is often mildly to moderately raised in patients with SAHF[4]

  • Creatine phosphokinase

    • The creatine phosphokinase may be mildly elevated in patients with SAHF[4]

  • Arterial blood gas

    • In patients with severe disease these parameters may be useful in determining need for escalation of care (e.g., intensive care with organ support). Although intensive care has not been described in patients with SAHF, it is not contraindicated as long as it can be done safely and with optimal protection for healthcare staff. Caution should be applied in obtaining an arterial blood gas in those with haemorrhagic symptoms

  • CXR

    • Respiratory symptoms are uncommon in SAHFs but where respiratory symptoms are present a CXR may be useful in identifying other pathologies.

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