INTRODUCTION

Among the Arenaviruses of the new world, the Tacaribe serocomplex shows the following: Junín (Argentina), Guanarito (Venezuela), Machupo (Bolivia) and Sabiá (Brazil), characterized by causing hemorrhagic fever (1,2,3,4). In Colombia the Pichindé Arenavirus (5) was isolated in 1965, from the liver, spleen, and kindneys of Oryzomys albigularis rodents, in a forest located in the Pichindé valley, of the department of Valle del Cauca. This arenavirus produces a persistent infection in its natural host, and it is not pathogenic for humans. Knowledge of the clinical manifestations of arenavirus infections in South America is based on the data collected from patients infected with Junín, Manchupo, and Guanarito viruses (6,7,8). Only human infections secondary to this virus have epidemiological value in a region (9). In our country, there is certainty that the Guanarito virus circulates in rodents in the department of Córdoba, but so far there have been no cases of diagnosed human infection (10). A 3.1% seroprevalence of IgC arenavirus antibodies was reported in the Emberá-Katio community in the alto Sinú region (Colombia) (11). Another study conducted in Sincelejo (Colombia) found a 10% seroprevalence, and the lymphocytic choriomeningitis genome was detected in 16 brain samples of Mus musculus rodents (12).

Etiological agent. The Arenaviridae family is comprised by a single genus, arenavirus, which includes twenty-two members formally acknowledged by the International Commitee for Taxonomy of Viruses (ICTV). It includes the Lassa serocomplex, an old-world group that includes autochthonous viruses from Africa, the worldwide distributed lymphocytic choriomeningitis virus (LCM), and the new-world Tacaribe serocomplex, which includes the native American viruses (Figure 1), subdivided in lineages A, B, and C. All of the arenaviruses causing hemorrhagic fever in humans belong to lineage B. In addition to the above-mentioned viruses, there are other B-lineage viruses that do not infect humans, including Amapari, Cupuxi, and Tacaribe (Table 1). Members of the Arenaviridae family are negative chain single-stranded RNA viruses, viral particles are spherical with diameters ranging from 50 to 300 nm. The have a helicoidally symmetrical capsid and include a variable number of ribosomes appearing grainy or sandy in electronic microphotography images (9,13,14,15).

Pathogenesis. The virus-cell interaction begins when the G1 protein of the viral spikes and the cell receptor make contact. In the case of the old-world arenavirus and the C-lineage of the new world, Alpha-dystroglican is the receptor with which the G1 protein interacts. For new-world lineages A and B, transferrin is the receptor (1,14,16,17). The virus-receptor interaction causes the cell membrane to curve, to enable endocytosis, followed by the fusion of the virus membrane and the endocytic vesicle mediated by the G2 conformation change. Later, the RNA nucleic capsid proteins that act as molds for viral transcription and replication in the cytosol (16,17).

Clinical signs. There are four infectious syndromes associated to arenaviruses in South America, to wit: viral febrile syndrome; hemorrhagic fever with or without neurologic compromise; aseptic meningitis, meningoencephalitis. For infections spread in transplanted patients (6,18) such as hantavirus, there are some symptoms and clinical signs that characterize an infection with this virus family, but their presence or lack thereof is neither sensible or specific enough to differentiate clinical picture caused by other infectious agents. Thus, diagnosis largely depends on local epidemiology and clinician’s suspicions when facing a compatible picture and lab tests have resulted negative for the most common infectious agents (6,19,20,21).

Viral febrile syndrome. The initial clinical picture of an arenavirus infection differs from the one caused by other viruses such as dengue. In studies carried out in Venezuela, most patients infected with Guanarito virus and admitted into a hospital located in endemic areas were diagnosed with dengue when admitted (15). The clinical picture shows an insidious onset with fever, shivers, headache, photophobia and generalized muscle pain. Other symptoms include nausea, vomiting, moderate diarrhea, orthostatic hypotension, and relative bradycardia. Occasionally, neurologic symptoms such as irritability, lethargy or mild ataxia may appear (15, 16). By the end of the first week, the first hemorrhagic manifestations occur, including petechiae on the trunk, as well as metrorrhagia. Bloodshot eyes, congestion in mucosae, lymphadenopathy and exanthema may also appear. Although severe in some occasions the condition is severe, hospitalization is required even without the presence of hemorrhage. In most patients the disease fails to progress and condition improves spontaneously. Clinical manifestations vary according to the virus infecting the patient. Patients infected with Guanarito virus show symptoms such as pharyngitis, diarrhea and vomiting, whereas patients infected with Machupo and Junín viruses show erythema and facial edema as well as skin hyperesthesia. Leukopenia and thrombocytopenia are lab alterations accompanying this syndrome. Other alterations such as changes in the levels of transaminases, lactate dehydrogenase (LDH), and kinase creatinine (CK) have also been described (15,14,22).

Hemorrhagic fever with or without encephalopathy neurologic manifestations. After 8 to 12 days of the onset of the early clinical manifestations, 30% of the cases show deterioration of the medical condition with shock, severe hemorrhage or serious neurological symptoms (23). Hemorrhagic manifestations are diffuse, bleeding from different puncture sites, hematemesis, hemoptysis, hematuria, and metrorraghia. The Junin virus is associated with a compromise of the central nervous system, mainly shown by a deterioration in the conscience, strong ataxia, convulsions, and coma. These complications may appear in absence of capillary infiltration or hemorrhagic signs. Convulsions are also seen in patients infected with the Guanarito virus in Venezuela(5,9,15). They also show moderate leukopenia and thrombocytopenia, and sedimentation is normal or low. Alterations in the prothrombin and plasma fibrinogen times, even though the deceased is not associated with intravascular disseminated coagulation (16,18,24,25). In the Junin virus infection, there is kidney compromise with alterations in urinary sediment, and urine protein about 1 g, not accompanied by oliguria nor any increase in creatinine, which becomes evident only in the most severe cases. Despite the presence of central nervous system alterations, spinal fluid test is normal. The Junin virus infection is more severe, with a high mortality rate (close to 30%). The deceased especially severe in women in their third trimester of pregnancy (21). Unlike other viral infections such as yellow fever or hantavirus infections, arenavirus infections produce no specific liver or lung damage. Whenever these organs are compromised, it is secondary to the shock state, to the bacterial superinfection, or hemorrhagic diathesis. Convalescence after a hemorrhagic condition is long, and may last several months, during which the patient suffers marked asthenia and loss of hair. Most of the patients recover with unimportant neurological damage (5,24,26).

Aseptic meningitis and encephalitis by arenavirus of lymphocytic choriomeningitis.

It produces a 5 to 10 day fever prodrome (5,24,26), similar to other arenaviruses. The only characteristic finding that differentiates this condition from other viral syndromes is the development of orchitis in a small group of patients, parotitis or arthritis in the metacarpophalangeal joints, of late onset during convalescence. Lymphocytic choriomeningitis can also appear as a two-stage disease, during which, after the febrile syndrome, neurological manifestations appear ranging from aseptic meningitis to severe encephalitis (5,24,27). Aseptic meningitis is similar to other viral infections, with presence of declared meningeal signs and headache. Spinal fluid analysis shows an increase in pressure and proteins. One characteristic is marked cell presence, with white cell counts above 1000/uL. 20 to 30% of patients show a mild hipoleucorraquia (5,24,27). Prognosis for the lymphocytic choriomeningitis virus infection is good, and neurological sequelae are scarce. The reservoir for this virus is the cosmopolitan domestic mouse Mus musculus. The lymphocytic choriomeningitis virus being associated in the last years with cases of disseminated infection in patients who have had liver and lung transplants, starting with fever, diarrhea, pain and everything around the incision site and is usually fatal (23,26).

Diagnosis. Diagnosis of fevers caused by arenavirus must be considered in patients with the febrile condition in endemic areas, on which more common infections such as malaria, dengue, and leptospirosis have been ruled out. In Argentina, a suspicious clinical case for endemic regions shows fever, leukopenia under 2.5/mm3, and thrombocytopenia under 10000/mm3 (28). This definition cannot be applied in our environment, since a large part of Columbia is endemic for dengue, and there are many coincidences in the hematologic alterations in both diseases. The differential diagnosis of hemorrhagic fever by arenavirus must be made first with a severe dengue infection that carries hemorrhagic and neurologic manifestations (6). Cases of encephalopathy that have been described secondary to dengue are indistinguishable from the neurologic manifestations caused by arenavirus (5, 27). Other diseases such as malaria, leptospirosis, bacterial sepsis, and rickettsiosis show similar presentations. Therefore, a hemorrhagic fever secondary to arenavirus must be suspected in regions endemic to this disease, in order to rule out the above-mentioned diseases in the lab. It is important to consider diagnosis of lymphocytic choriomeningitis in cases of liver and lung transplants (27,29,30,31).

Lab diagnosis. The rule of thumb is viral isolation during the febrile period, which may be done through a throat swab, urine, spinal fluid, or tissue samples. This technique implies direct contact with the virus, which is highly infecting, and therefore it must be carried out only in labs with category 4 biosecurity. During some years, specific RNA-PCR for arenavirus have been created which may be used in category three labs (6,32,33).

In practice, serology is the most common used method to diagnose the disease. In a patient with a compatible clinical condition, the presence of a positive ELISA titer or positive IFA IgM, allows for a presumptive diagnosis, which must be confirmed with a seroconversion three weeks later, and an increase in IgG titers after 4 weeks. There are no commercial test for arenavirus, and only specialized research groups and public health laboratories have ELISA or IFI tests. There is an important cross-reactivity between different types of viruses, and therefore the specific diagnosis can only be made with neutralizing antibodies, which appear between 12 and 30 days of symptom onset and during convalescence (6,32,33,34).

Arenavirus in South America

The Argentinian hemorrhagic fever (FHA) was first described a similar pathology in the early 1950s; in 1958 its a etiologic agent was reported as Junín virus (JUNV), a member of the Arenaviridae family. The Calomys musculinus is identified as the main reservoir (22). Currently, the FHA endemic area encompasses 150,000 km² in the provinces of Buenos Aires, Santa Fe, and Córdoba, the population of over 5 million people at risk. Over 70% of the cases notified our men between ages 10 and 39. In 1959 the Bolivian hemorrhagic fever was clinically recognized in the provinces of Mamoré, Itenez, and Yacuma, department of Beni. Between 1963 and 1964 and epidemic struck San Joaquín, capital of Mamoré, with 650 cases and 122 deaths within a population of 2500 people. All of these cases were caused by the Machupo arenavirus hosted by the Callomys callosus rodent. Sporadic cases of this zoonosis continue to appear. In 2008, a new arenavirus named Chapare was isolated in a fatal case of Bolivian hemorrhagic fever (3,21). The rodent that serves as a reservoir for this virus has not been identified.

In 1989, for the first time in the Venezuelan state of Portuguesa, a new disease appeared mainly affecting workers in sugarcane and cotton plantations, in the municipality of Guanarito and its neighboring areas. The 1990 that agent was identified, a new arenavirus that was named Guanarito, etiologic agent of the new disease known as Venezuelan hemorrhagic fever (FHV) (6,25,28).

So far, rodents Zygodontomys brevicauda and Sigmodon alstoni have been established as the natural reservoirs of the Guanarito arenavirus. In 1990, in Brazil, the Sabiá virus (4) was isolated from a fatal case of hemorrhagic fever in São Paulo, and host of the arenavirus is unknown. In 2011, in the Colombian department of Córdoba in the Caribbean coast, the presence of antibodies in rodents of the Zygodontomys brevicauda species was determined, yielding a seroprevalence of 1.1% of the Guanarito arenavirus (10). (Figure 1).

Treatment. Even though the arenavirus infection is a potentially deadly disease, most of the patient present a moderate severity condition, that only needs proper hydration antipyretics and anti-inflammatories (17,35,36). The care of patients with severe signs must include some aggressive management. There are four crucial points in this treatment: a) early recognition of severe cases; b) isolation; c) admission to intensive care units; d) antiviral drug supply.

Early recognition of severe cases. Patients with comorbidities such as kidney failure, diabetes or heart failure, and pregnant women especially, have a higher mortality rate and therefore must be hospitalized (27). Proper assessment of shock signs and hemorrhagic manifestations must be ensured for all patients.

Patient isolation. All arenavirus is our infectious when airborne. Intra-hospital transmission of other arenaviruses such as Lassa virus is a public health problem in Africa (27). Some observations indicate that patients infected by Junín, Manchupo, and Sabiá viruses who are severely sick and with an elevated viremia may transmit the virus from one person to another by air. Therefore, isolation to prevent contact with blood, but in the fluids, and respiratory secretions is recommended for this type of patients (5,38,39).

Admission to intensive care. Most of the texts that deal with tropical diseases that lack of specific therapy vaguely mention support measures. However, due to the global dengue epidemic, several researchers have demonstrated that aggressive management of tropical viral diseases through clinical protocols is associated with a reduction of mortality rates even in the absence of specific antiviral drugs.

Just as in the Dengue case, arenavirus infections may produce a shock even without hemorrhages (37-39). Early management of this condition with corticoids can help reduce mortality. Since this is a senior condition with a bad prognosis, the patient must be transferred to an intensive care unit, where they can receive continuous monitoring, respiratory support, red blood cell or platelet transfusions, and correction of metabolic and electrolytic imbalances (5). Junín virus infections, which frequently become complicated with alterations of consciousness, agitation and convulsions, provision of benzodiazepines and other anticonvulsant drugs as well as respiratory support in case of comma, play a role in managing these patients (5).

Provision of antiviral drugs and immune plasma. Since the 50s, plasma extracted from people who have been previously infected with the Junín virus has been used in treating severe cases of Argentinian hemorrhagic fever. Control essays have demonstrated the effectiveness of this treatment in reducing mortality rates up to 30%. However, 10% of the patients treated in this way show a neurologic deterioration characterized by fever, cerebellar signs and palaces of the cranial nerves (6). Onset of this syndrome, and the difficulty to keep a deposit of human immune plasma have become constraints for the use of this treatment in endemic areas (6, 27). Another alternative lies in the use of Ribavirin, which was introduced in the mid-80s. In cultural clinical studies, the use of this medication has not produced a mortality reduction, although it has been associated with a significant reduction of viremia (6, 27). As for specific treatments for other virus other than Junín, there is not enough data to recommend other measures different event support therapy in an intensive care unit.

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Author notes

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