Hantavirus Pulmonary Syndrome (HPS) Presentation

Brandon Thomas Suit

Hantavirus Pulmonary Syndrome

• Hantavirus was originally given attention during the Korean War when thousands of soldiers suffered from an acute renal syndrome, Hemorrhagic Fever with Renal Syndrome/HFRS)
  • This occured near the Hantaan River, for which the virus was named.
• New World Hantaviruses have been implicated as the cause of Hantavirus Pulmonary Syndrome (HPS)
  • These hantaviruses were first identified as the agent involved in a deadly outbreak in 1993 in the Southwest United States

Hantavirus Virion

Hantavirus Classification

• Family: Bunyaviridae
• Genus: Hantavirus (type species: Hantaan virus)
• Species: Sin Nombre Virus (Spanish: “No name virus”)
  • This is one of several “New World Hantaviruses” that cause Hantavirus Pulmonary Syndrome
  • Unlike HFRS, which has a mortality rate of 1-15%, SNV has a death rate of over 50%.

Species of Hantavirus

• At present there are 22 species of hantavirus, eg.
  • Hantaan, the type species, cause of HFRS
  • Sin Nombre, a cause of HPS
• It's unknown whether these constitute species due to lack of evidence:
  • Up to 7% sequence difference
  • However, reassortment viruses have been produced in a lab environment.

1993 Outbreak

• In 1993, an unidentified pulmonary disease took place in the “Four Corners” region of the Southwest United States (Arizona, New Mexico, Colorado, Utah)
• An adult male of good health came down with acute respiratory problems and died shortly after being transported to the hospital.
• Just days before, it was found that the man's fiancee died of similar causes.

1993 Outbreak (2)

• Lab tests could not identify what the virus was
• Many new cases were being reported at the same time.
• Serologic tests eventually identified the disease as a new type of Hantavirus
• Since existing Hantaviruses could be spread by rodent populations, rodents were trapped near the locations cases were reported.
• Out of a total of 53 cases, the virus caused 32 deaths.

1993 Outbreak (3)

2007 Cases

Sin Nombre Virus

• Sin Nombre was the first of the “New World” hantaviruses to be discovered during the 1993 outbreak.
• Today, there are 9 known strains:
  • Blue River (Indiana and Oklahoma)
  • Monongahela
  • Convict Creek (three strains)
  • NMH10 (three strains)

New World Hantaviruses

Molecular mechanisms

• Hantaviruses gain entry via RME:
  • β3 integrins on endothelial cells
  • Mostly in the lung where they cause pulmonary edema
  • Also in macrophages
• Specifics such as viral protein residues involved have not yet been elucidated
  • β3 integrins are being considered as a possible drug target

Sin Nombre TEM

Genome

• Hantaviruses specifically have a negative-sense ssRNA delivered in three segments:
  • small (S)
  • middle (M)
  • large (L)
• These segments circularize due to complimentary 5' and 3' base pairing.

Proteins

• Hantaviruses are simple: They only encode four genes!
• Nucleocapsid protein (N) is encoded in the S segment and forms the helical nucleocapsid
• Transmembrane glycoproteins G1 and G2 (or Gn and Gc) are cleaved from a polycistron product encoded by M
  • These dimerize
• RNA-dependent RNA Polymerase (L) is encoded in the L segment.

Proteins: Coiled-coil Domain of SNV

Proteins: G1 Tail — Dual zinc fingers

Capsid and Envelope

• All bunyaviridae have a helical nucleocapsid
• Some evidence suggests viral envelope derives from the PM.
• Most members of the family gain envelope from the Golgi.
• Conflicting evidence for both.
• Forms spherical pleomorphic particles once bud
  • These range in size from 70 to 210 nm
  • Evidence suggests range in size and shape may be due to excess genome copy number

Bunyaviridae Virion Overview

Vectors

• Most bunyaviridae spread through arthropods, eg. mosquitos.
• Hantaviruses utilize rodents as their reservoir
• Sin Nombre in particular spreads via:
  • deer mice (predominantly)
  • cotton rats
  • rice rats
  • white-footed mice

Deer Mouse

Deer Mouse

Human Infection

• Human infection is predominantly caused by inhalation of aerosolized urine, feces, or saliva.
• Bites or scratches are rare
• This is a zoonotic disease: only one case of human-to-human spread has been documented for HPS.
• Virus is subject to damage from UV light
  • Indoor spaces with poor ventilation that allow rodent access can be dangerous.
  • Many cases involve cleaning garages or attics.

Transmission

Incubation

• Incubation time not known at present
• Estimated to be between one and five weeks

Prodromal Symptoms

• Initial symptoms include
  • High fever
  • Chills
  • Muscle ache
• Half of HPS cases also report:
  • Headache
  • Abdominal pain
  • Nausea
  • Vomiting
  • Malaise
  • Diarrhea

Acute Symptoms

• Within four to ten days after the onset of initial symptoms:
  • Coughing, shortness of breath.
  • Lungs become flooded with fluids
  • Machine ventilation usually becomes necessary
• Half of the cases result in death resulting from drowning in one's own body fluids

Viral Progression

Statistics

• Most cases involve white males in rural areas
  • This may be due to occupational reasons rather than immunological ones.
• Children under 15 seem to contract a milder form of HPS
• HLA (MHC) typing suggests that those with the B35 allele are at particularly high risk of the severe form of the disease.

Detection

• Serologic tests:
  • ELISA against IgM
  • qRT-PCR
• A neutralizing plaque assay and hemagglutination inhibition assay have been described in the literature, but are not available commercially.

Study

• All research on hantaviruses are carried out under extreme care:
  • BSL-3 facilities for cell cultures
  • BSL-4 facilities for rodent work
• Isolation from human hosts has not yet been possible
• Microscopy of rodents reveals presence of inclusion bodies

Study II

• Without access to serum, retroactive analysis (perhaps of cadavers) can be done with immunohistochemistry
  • These studies reveal cases of Sin Nombre virus infections occurring as early as the 1950's.
  • (No histology course = sad)

Be careful when cleaning the basement!