Hantaviruses are a genus of single-stranded, negative sense RNA viruses in the family Bunyaviridae. It normally infects rodents. Hantavirus causes pulmonary syndrome (HVPS) in the Americas and causes hemorrhagic fever with renal syndrome (HFRS) in other parts of the world, notably Europe and East Asia (China, Russia, and Korea). 

Hantaan is a river in Korea where the first virus in this genus was identified in 1976. This virus caused Korean hemorrhagic fever in the American troops who fought the Korean war in the 1950s. The first outbreak on US soil was reported from the four-corner region amongst the native Indian tribes in 1993. In this four-corner southwest region of the United States, Arizona, New Mexico, Colorado, and Utah come together. The first patient was a woman, who presented with acute onset of dyspnea and was found to have bilateral diffuse infiltrates. Her autopsy showed that the lungs were twice the weight of normal lungs for her age. During the evaluation of the outbreak, all victims were found to have exposure to deer mice. There was no person-to-person transmission during this outbreak. The health care workers who resuscitated these patients did not get infected. The American species of hantavirus, which caused the outbreak at four-corner regions was eventually named Sin Nombre hantavirus.[1][2][3]

Hantaviruses are enveloped RNA viruses measuring 80 nm to 120 nm. The genome is divided into three segments. The large (L) segment coding for viral transcriptase, the medium (M) segment coding for glycoproteins of the capsule and the small (S) segment coding for the protein of the viral nucleocapsid.

There are several species of hantavirus causing hantavirus pulmonary syndrome (HPS) also known as hantavirus cardiopulmonary syndrome (HCPS). The host for Sin Nombre hantavirus is the deer rat (Peromyscus maniculatus) found in rural regions along the Mississippi river. The New York virus is associated with the white footed mouse (Peromyscus leucopus). The other hantaviruses are the Black Creek Canal virus, the Bayou virus with the main host being wild rats from the Muridae family.[4][5][6]

Since 1995, hantavirus pulmonary syndrome is a reportable disease, and in 2015 the hantavirus non-pulmonary disease was made reportable as well. In the United States, most cases have occurred west of the Mississippi River, but overall 36 states have reported hantavirus pulmonary syndrome cases. In 2001, there were 255 cases reported by the United States. Brazil has the highest number of cases. The cases from South America outnumber the North American cases. The countries with most cases are Brazil, Argentina, and Chile.[7]

In the United States, most cases of hantavirus infection have occurred as outbreaks, the most recent being at the Yosemite National Park amongst the park visitors during July to August of 2012.

Transmission occurs by exposure to aerosolized dried feces and urine from rodents of Muridae family, which are the main reservoir in nature.

Person-to-person transmission has been recorded in the outbreak in Argentina due to Andes virus in 1996. The health care workers including five physicians got infected during the Andes virus outbreak. A review of cases with well-defined exposures from the registry suggests that the incubation period of hantavirus pulmonary syndrome is 9 to 33 days (median 14 to 17 days). Such person-to-person transmission has not been reported with Sin Nombre or other species of Hanta viruses.

Worldwide, hantaviruses infect about 30,000 humans per year and cause hemorrhagic fever with renal syndrome (HFRS).[8]

There is no ideal model to study hantavirus infection leading to hantavirus pulmonary syndrome. In a recently described rhesus macaque model, the Sin Nombre virus causes a hantavirus pulmonary syndrome-like illness characterized by low platelets, leukocytosis, and rapid onset of respiratory distress due to interstitial pneumonia. The first clinical features of infection in this model were a cough, tachypnea, and respiratory crackles. The earliest onset of symptoms occurred at day six, but the overall range was 14 to 16 days. Within 72 hours of the onset of respiratory symptoms, there was an acute respiratory failure with severe multilobar pulmonary infiltrates right ventricular enlargement, and pleural effusion due to heart failure. Nasal, oral, and rectal swabs were consistently negative for the viral RNA even at the peak infection. This suggests that unlike the Andes species, the Sin Nombre virus is not transmissible from person-to-person. While the swabs for negative, viremia was demonstrated in the infected models prior to the onset of the respiratory symptoms by an average of two days.

The virus caused a predominantly pro-inflammatory cytokine (Th1/Th2 cytokines, IFN-g, IL-1beta, IL-6, IL-18, and IL-13) release in the macaque models and noted at about 12 days post infection. The anti-inflammatory cytokine release (IL-1 receptor antagonist, IL-15, and GM-CSF) occurred only when the respiratory symptoms were present. Neutrophilia with left shift was present in the infected model, which is like hantavirus pulmonary syndrome infection in humans. In humans, neutrophilia with left shift supports the diagnosis of hantavirus pulmonary syndrome. Interestingly one may see a mixed pattern (viral and bacterial) on complete blood count (CBC) with increased atypical lymphocytes and increased bands, and overall normal white blood cells (WBC). Polymorphonuclear cells may or may not be elevated.

There was no elevated D-dimers in the macaque models. In human infection, however, prothrombin time is usually normal; studies in human infections have shown that the tissue plasminogen activator (tPA) is elevated.

Host response: Immunoglobulin M (IgM) is produced by the host at first followed by immunoglobulin G (IgG) antibodies. Immunoglobulins E (IgE) antibodies are also found and notably, contribute to the host defense against the Hanta virus infection.

The immune complexes coat the red blood cells and the platelets.  Thrombocytopenia is frequently noted on CBC in human hantavirus pulmonary syndrome infections.

Tests for liver injury become abnormal late in the disease and reflect end stage in the natural history of the disease.

While there was a diffuse endothelial infection of a variety of tested in this model organs (heart, kidney, spleen, and liver), the cytokine responses were predominantly in the lungs which is suggestive of compartmentalization of the immune response noted in human hantavirus pulmonary syndrome. The hantaviruses are capable of preferentially entering the endothelial cells, and immunohistochemistry studies demonstrate hanta virus nucleic acids in the pulmonary endothelial cells and the macrophages. Recently decay accelerating factor, and CD55 receptors on the endothelial cells have been identified as co-factors required for attachment and entry of the hanta viruses into the human endothelial cells. Differences in co-factors may explain the different clinical manifestations (hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome of the hantaviruses). Hanta viruses are capable of multiplying in the endothelial cells without causing visible cytopathic effect and injury in in-vitro models.

There is a functional impairment of the vascular endothelium with capillary dilation. The direct mechanism for vascular endothelial injury needs further elucidation. 

In early stages, lung histology shows multifocal thickened alveolar septae with edema, macrophages, fibrin, and few neutrophils. There is very little cellular debris, thick membranes, and few type II reparative pneumocytes. The type I pneumocyte processes are intact in the early phase, and there is a minimal external injury to the endothelium. This is different from the histological findings of diffuse alveolar damage, where there is extensive cellular debris, destruction of type 1 pneumocytes, prominent neutrophilic infiltrate with fibrosing alveolitis.

In late stages, or in survivors, the histology is like that of exudative and proliferative phases of diffuse alveolar damage. There is a distortion of the lung architecture and proliferation of reparative type 2 pneumocytes.

Vascular changes are also seen in other organs notably spleen. In liver, there is scattered coagulative necrosis. There is no single pathognomonic feature on histology. Early histological features of lung tissue obtained by biopsy may give a clue but are seldom obtained in clinical practice.