Etiology
In the US, hantavirus cardiopulmonary syndrome (HCPS) has been shown to result from exposure to rodent excreta containing one of the identified pathogenic hantaviruses: Sin Nombre virus (SNV), Bayou virus (BAYV), Black Creek Canal virus (BCCV), New York virus (NYV), and Monongahela virus (MONV).
Hantaviruses have coevolved with their specific rodent hosts, are asymptomatic in the rodent host, and are transmitted intraspecies through biting and salivary exposure. Hantavirus infections are predominantly transmitted to humans through incidental contact with rodent urine or saliva.[16] Aerosol, mucous membrane, and nonintact skin exposure to rodent excreta, rodent bite, and laboratory accidents are all possible routes of exposure. Viability of the hantaviruses is 2 to 3 days at normal room temperature. Exposure to sunlight will decrease the time of viability.
No person-to-person transmission of hantaviruses has been demonstrated in North America. The outcome of 5 cases of SNV infection in pregnancy included 1 maternal death and 2 fetal losses. Exam of 2 fetal autopsies, 3 placentas, and serologic follow-up of the 3 surviving children did not show evidence of maternal-fetal transmission of SNV.[17]
SNV infection produces the classically described HCPS with an estimated mortality of 30% to 50%.[8][18] BAYV and BCCV, as well as causing HCPS, may also have significant renal involvement, but overall lower mortalities.[3][5][6]
In Latin America, HCPS has been shown to result secondary to hantavirus infection, which is most frequently acquired by contact with or through aerosols of excreta and secretions of infected rodents. Cases of human-to-human transmission of hantavirus have been reported from territories of Argentina and Chile.[19][20] However, available evidence does not support the possibility of human-to-human transmission.[21]
In Chile, person-to-person transmission was documented to occur mainly in family clusters. In a prospective study, sexual partners of an infected person had a 10-fold increased risk of infection compared with other household contacts.[22] Close contact with a sick person during the prodromal phase of the disease (12 to 27 days from initial exposure of the source case) appeared to increase the chances of person-to-person transmission.[4]
Several studies of hantavirus-infected patients have shown the presence of Andes virus (ANDV) in different body fluids such as blood, respiratory secretions, gingivocrevicular fluid, saliva, and urine. These observations might explain in part why it is possible to contract the virus by close contact with any of these fluids from a patient in the prodromal phase of illness.[23]
Nosocomial transmission has been reported in two cases in a hospital in Chile.[20] Prior seroprevalence studies conducted in Chile with healthcare personnel working at hospitals where patients with ANDV infection were treated showed the presence of anti-ANDV immunoglobulin G antibodies in healthcare workers was similar to that of the general population.[24]
In North America, asymptomatic human hantavirus infection is rare, with a seroprevalence of less than 1% in asymptomatic high-risk populations. In contrast, in Central and South America, in regions such as Chaco in Paraguay, the serologic evidence of past infection with hantavirus reaches over 40%.[25] The number of hantavirus-seropositive individuals without HCPS is much higher than the number of HCPS cases in Brazil, leading to the conclusion that many of the hantavirus infections in the area are asymptomatic.[26] In Chile, a serologic survey done in apparently healthy people from rural and urban slum communities yielded a seroprevalence of 1.07%. A higher proportion of positive samples was found among individuals from rural villages and slums, compared with farms.[27][Figure caption and citation for the preceding image starts]: Peromyscus maniculatus: the deer mouse, vector for Sin Nombre virus (SNV), which causes most cases of hantavirus cardiopulmonary syndromeCDC Public Health Image Library (PHIL), James Gathany [Citation ends].
Pathophysiology
Following inhalation exposure to hantavirus in rodent excreta, there is an incubation period of 9 to 33 days (median 14 to 17 days, and up to 3 weeks after rodent bite), during which the virus replicates in pulmonary macrophages and dendritic cells without causing cell death and is distributed to lymphoid organs.[28][29][30] A viremia is produced that infects target endothelial cells and stimulates T cells. Host neutralizing antibody is produced that may mitigate the severity of the infection.[31] Immune-stimulated T cells are distributed to areas of hantavirus concentration, particularly the lung and heart interstitium.[32] A nonspecific viral syndrome with predominantly severe myalgias and gastrointestinal symptoms follows that is often not recognized. Rarely, the illness does not progress;[33] however, usually patients are admitted to the hospital within 5 days having progressive respiratory failure with pulmonary edema, metabolic acidosis, and cardiogenic shock.
Progressive disease results from infected endothelial cell function being disturbed and local T-cell cytokine production, which causes capillary leak in target organs.[34][35] The capillary leak may be the result of pathogenic hantaviruses using an alpha-variable, beta-3 integrin ligand on the endothelial cell and platelet surfaces, resulting in disturbed endothelial cell migration and endothelial cell barrier function.[30][36]
Studies in a Syrian hamster hantavirus pulmonary syndrome (HPS) model have suggested a direct effect of Hantavirus on resting platelets through binding to the platelet beta-3 integrin with resultant platelet cross-linking and clumping on endothelial surfaces. There is also binding to the beta-3 integrin on the resting endothelial cells with disruption of vascular endothelial growth factor receptor activity, increased phosphorylation and internalization of vascular endothelial-cadherin, and loss of cellular tight junction competence.[37]
All pathogenic hantaviruses have also been demonstrated to have an immunoreceptor tyrosine-based activation motif on their G1 envelope glycoproteins, which may modulate cellular downstream signaling and endothelial and immune cell function.[38] Sensitized mononuclear cells infiltrate the lung, myocardial interstitium, and spleen to produce cytokines, particularly tumor necrosis factor-alpha and interferon-gamma, resulting in pulmonary edema and myocarditis.[39][40] Hantaviruses may also attach to beta-2 integrin receptors on neutrophils and induce the release of neutrophil extracellular traps.[41]
Classification
Taxonomy of North American hantavirus[2][3]
Family: Bunyaviridae
Genus: Hantavirus
Clinically significant New World hantaviruses identified in the US and associated with hantavirus cardiopulmonary syndrome (HCPS) include:
Sin Nombre virus (SNV)
Bayou virus (BAYV)
Black Creek Canal virus (BCCV)
New York virus (NYV)
Monongahela virus (MONV).
Taxonomy of Central and South American hantaviruses[4]
Family: Bunyaviridae
Genus: Hantavirus
Based on phylogenetic studies, the South American hantavirus strains have been separated into three monophyletic clades: Andes, Laguna Negra, and Rio Mamore. Each of these clades has been classified as a unique species.
The Andes (ANDV) clade
Found in Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay.
Can be subdivided into three well-supported groups:
Castelo dos Sonhos (CASV)
Pergamino (PERV)/Maciel (MACV)/Araraquara (ARQV)/Paranoá (PARV)
Oran (ORNV)/Bermejo (BMJV)/Lechiguanas (LECV)/Andes Central Plata (ACPV).
Not included in any of the three subgroups are the Juquitiba (JUQV), Araucaria (ARAUV), and Itapua (ITPV) genotypes.
The Laguna Negra (LANV) clade
Found in Argentina, Bolivia, Brazil, and Paraguay.
Includes only the Laguna Negra virus.
The Rio Mamore (RIOMV) clade
Found in Brazil, Bolivia, French Guyana, Paraguay, and Peru.
Includes, among others, RIOMV, Anajatuba virus (ANJV), and Maripa virus (MARV), all associated with HCPS.
Other hantavirus subtypes that are not included in any of the three clades are:
Choclo virus (CHOV), found in Panama
Jabora virus (JABV), found in Brazil
Cano-del-gadito virus (CADV), found in Venezuela.
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