Patients with SAHF should be monitored during the convalescent period to ensure symptoms fully resolve and do not develop late neurological syndrome (LNS). Monitoring is based on regular clinical assessment in an outpatient setting. No specific tests are indicated unless there is the development of unusual symptoms/signs, where further investigation may be indicated, or in the relatively rare situation that the patient had organ impairment during their acute disease. In this context, monitoring of renal or liver function may be indicated depending on the system involved. Patients who survive Argentine haemorrhagic fever often have a prolonged convalescent period of up to 3 months. During this time patients may experience weakness, hair loss, irritability, and memory impairment.[4]Enria DA, Briggiler AM, Sánchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78:132-9.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10245337
http://www.ncbi.nlm.nih.gov/pubmed/18054395?tool=bestpractice.com
[34]Enria D, Mills JN, Bausch D, et al. Arenavirus infections. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. 3rd ed. Amsterdam: Elsevier; 2011:449-461. These symptoms settle gradually over a period of 1-3 months.[34]Enria D, Mills JN, Bausch D, et al. Arenavirus infections. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. 3rd ed. Amsterdam: Elsevier; 2011:449-461. The convalescent phase of Bolivian haemorrhagic fever may last up to 2 months, during which time patients may complain of fatigue, dizziness, and hair loss.[2]Patterson M, Grant A, Paessler S. Epidemiology and pathogenesis of Bolivian hemorrhagic fever. Curr Opin Virol. 2014;5:82-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028408
http://www.ncbi.nlm.nih.gov/pubmed/24636947?tool=bestpractice.com
There is little information regarding the convalescent period for the other SAHFs.
Approximately 10% of patients with Argentine haemorrhagic fever virus who receive convalescent immune plasma develop LNS. Those who suffer LNS will require monitoring until symptoms resolve, which normally begins within a few days but may last several months.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620.[54]Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2:1216-1217.
http://www.ncbi.nlm.nih.gov/pubmed/92624?tool=bestpractice.com
They may also warrant further investigation, such as cerebrospinal fluid (CSF) analysis and neuroimaging, to determine underlying pathology. In Argentine haemorrhagic fever, LNS develops after a symptom-free period following recovery and is characterised by febrile episodes, cerebellar signs, and cranial nerve palsies. The most common initial complaints are of moderate headache, nausea and/or vomiting, and dizziness. Over the course of a few days, 70% of patients' symptoms progress to include tinnitus, blurred vision, and difficulty walking.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. Approximately 40% of patients develop diplopia and a similar percentage may also present with anxiety or altered behaviour. Examination of patients reveals a fever of 38°C to 38.5°C, a cranial nerve VI palsy or paresis in 60% of patients (although light reflexes and accommodation are normal), and nystagmus and cerebellar ataxia in approximately 50% of patients.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. Reflexes are often normal or may be diminished, but a small proportion may have hyper-reflexia. Some patients may also have dysarthria and approximately 10% may have extrapyramidal signs, with a small number of patients presenting with a paresis or paralysis.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. CSF analysis, which is generally normal during the acute disease period even in the context of neurological signs, demonstrates an elevated WBC (10s-100s of cells), which is predominantly lymphocytes with a normal glucose, normal to moderately elevated protein level, and high antibody titres to Junin virus that are markedly higher than serum levels.[4]Enria DA, Briggiler AM, Sánchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78:132-9.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10245337
http://www.ncbi.nlm.nih.gov/pubmed/18054395?tool=bestpractice.com
[5]Enria DA, Briggiler AM, Feuillade MR. An overview of the epidemiological, ecological and preventive hallmarks of Argentine haemorrhagic fever (Junin virus). Bulletin Institut Pasteur. 1998;96:103-114.[34]Enria D, Mills JN, Bausch D, et al. Arenavirus infections. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, and practice. 3rd ed. Amsterdam: Elsevier; 2011:449-461. Blood tests are usually unremarkable and Junin virus has not been isolated from the blood or CSF of these patients following survival from their acute disease.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. It is unclear whether, with the advent of reverse transcription-polymerase chain reaction (RT-PCR) and its higher sensitivity, virus might be identified in the CSF of these patients either during acute disease or LNS. Management is supportive with optimum symptom control.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620.
LNS has not been witnessed in patients surviving Argentine haemorrhagic fever who did not receive any specific therapy, although a case has been described in a patient receiving ribavirin.[4]Enria DA, Briggiler AM, Sánchez Z. Treatment of Argentine hemorrhagic fever. Antiviral Res. 2008;78:132-9.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10245337
http://www.ncbi.nlm.nih.gov/pubmed/18054395?tool=bestpractice.com
There do not seem to be any predisposing factors (i.e., sex, age, geographical area, blood group, or the day of symptoms on which immune plasma was administered).[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. LNS has not been described for Bolivian haemorrhagic fever, except in early studies evaluating the efficacy of immune plasma in non-human primates where LNS developed following a symptom-free period after the acute disease, which was fatal in 6 cases.[2]Patterson M, Grant A, Paessler S. Epidemiology and pathogenesis of Bolivian hemorrhagic fever. Curr Opin Virol. 2014;5:82-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028408
http://www.ncbi.nlm.nih.gov/pubmed/24636947?tool=bestpractice.com
The pathogenesis of LNS is not well understood, although it is thought to be immune mediated or possibly related to persistence of virus in the central nervous system.[49]Kolokoltsova OA, Yun NE, Paessler S. Reactive astrogliosis in response to hemorrhagic fever virus: microarray profile of Junin virus-infected human astrocytes. Virol J. 2014;11:126.
http://virologyj.biomedcentral.com/articles/10.1186/1743-422X-11-126
http://www.ncbi.nlm.nih.gov/pubmed/25015256?tool=bestpractice.com
[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620. In humans it typically resolves over a period of time; usually symptoms begin to settle within a matter of days, although some patients may continue to have neurological signs (particularly nystagmus) for up to 4 months.[50]McLay L, Liang Y, Ly H. Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections. J Gen Virol. 2014;95:1-15.
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.057000-0
http://www.ncbi.nlm.nih.gov/pubmed/24068704?tool=bestpractice.com
[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620.[54]Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2:1216-1217.
http://www.ncbi.nlm.nih.gov/pubmed/92624?tool=bestpractice.com
A few patients with severe presentations have been described to have persistent neurological sequelae.[52]Melcon MO, Herskovits E. Complicaciones neurologicas tardias de la fiebre hemorragica argentina. Medicina (Buenos Aires). 1981;41:137-145. Rarely fatalities have been reported. In one described case, this was secondary to development of an ascending paralysis and respiratory failure.[51]Enría DA, Damilano AJ, Briggiler AM, et al. Sindrome neurologico tardio en enfermos de fiebre hemorrágica Argentina tratados con plasma immune. Medicina (Buenos Aires). 1985;45:615-620.[54]Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979;2:1216-1217.
http://www.ncbi.nlm.nih.gov/pubmed/92624?tool=bestpractice.com