Hantavirus Cardiopulmonary Syndrome

Epidemiology

History

Four Corners (Southwestern US) Outbreak in 1993
- Sin Nombre Virus (SNV) was First Identified
- Outbreak Appeared to Originate from Deermouse Population
- In Retrospect, Similar Cases were Identified as Far Back as 1959

Geography

Hantavirus Cases Have Been Reported in Every State in the US
Hantavirus (and Leptospirosis) Outbreaks May Be Associated with Flooding (J La State Med Soc, 2014) [MEDLINE]
- Due to Rainfall-Induced Wildgrass Seed Production with Expansion of Arthropod and Rodent Populations
- Flooding Forces Rodents Out of Their Burrows and into the Built Environment and Closer Contact with Humans

Reportable Disease

Hantavirus Cardiopulmonary Syndrome is a Reportable Disease in the US

Transmission/Virology

Transmission

Rodent Vector
- Inhalation of Hantavirus and Infection of Lung Parenchyma: virus is taken up by phagocytes and transported to draining lymph nodes

Virology

Hantavirus Genus

Hantavirus was Named for the Hantan River in South Korea (Where an Early Outbreak Occurred)
There are at Least 12 Hantaviruses Known to Cause Human Disease
Hantaviruses Associated with Hantavirus Cardiopulmonary Syndrome
- Andes Virus
  - Geography: Brazil, Chile, Argentina
  - Reservoir: Oligoryzomys Longicaudatus
- Bayou Virus
  - Geography: US
  - Reservoir: Oryzomys Palustris
- Black Creek Canal Virus
  - Geography: Florida
  - Reservoir: Sigmodon Hispidus
- Choclo Virus
  - Geography: Panama
  - Reservoir: Oligoryzomys Fulvescens
- Laguna Negra Virus
  - Geography: Paraguay, Bolivia
  - Reservoir: Calomys Laucha
- New York Virus
  - Geography: Long Island (New York)
  - Reservoir: Peromyscus Leucopus
- Rio Mamore Virus
  - Geography: Peru
  - Reservoir: Oligoryzomys Microtis
- Sin Nombre Virus (SNV)
  - Geography: US, Canada
  - Reservoir: Peromyscus Maniculatus (North American Deermouse)
  - Prognosis: high case-fatality rate (30-50%)
Hantaviruses Associated with Hemorrhagic Fever with Renal Syndrome (HFRS) (Hemorrhagic Fever with Renal Syndrome, [[Hemorrhagic Fever with Renal Syndrome]])
- Dobrava/Belgrade Virus
  - Geography: Central and Western Europe
  - Reservoir: Apodemus Flavicollis
- Hantaan Virus
  - Geography: China, Korea, Russia
  - Reservoir: Apodemus Agrarius
- Seoul Virus (Baltimore Rat Virus)
  - Geography: China, Korea, United Kingdom (rare cases), US (rare cases) (Nephron, 1994) [MEDLINE]
  - Reservoir: Rattus Norvegicus, Rattus Rattus
- Puumala Virus
  - Geography: Scandinavia, Western Europe, Russia
  - Reservoir: Myodes Glareolus

Diagnosis

Serology

Serology is the Main Method Diagnosis of Hantavirus Infection
- Anti-Hantavirus IgM (Usually Against the Nucleocapsid or N Antigen): always present in acute infection
- Anti-Hantavirus IgG: usually present in acute infection
- Acute Infection Can Be Distinguished by the Presence of Anti-Hantavirus IgM or a 4x-Increase in Anti-Hantavirus IgG
Techniques: none of these assays have been approved by the FDA
- Complement Fixation Assay
- Enzyme-Linked Immunosorbent Assay (ELISA)
  - CDC-Provided ELISA Assay (Against N Antigen) is Commonly Used in the US
- Focus/Plaque Reduction Neutralization Assay
- Hemagglutinin Inhibition Assay
- Indirect Immunofluorescence Assay (IFA)
- Strip Immunology Assay (SIA)
- Western Blot (Using Recombinant Antigens and Isotype-Specific Conjugates for IgM and IgG Differentiation)
  - Performs Similarly to the CDC-Provided ELISA Assay (Against N Antigen)

Nested Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) for Hantavirus

Although Diagnostic, This Technique is Usually Not Necessary Due to the Diagnostic Accuracy of the Serologic Assays Above
- This Technique May Also Be Used Post-Mortem
Specimen
- Blood Cells
- Plasma
- Tissues

Immunohistochemical Assay for N Antigen

May Be Used to Diagnose Hantavirus Infection Post-Mortem
Specimen
- Kidney
- Lung

Clinical Manifestations

General Comments

Incubation Period: usually 2-3 wks (range: 9-33 days) (Am J Trop Med Hyg, 2000) [MEDLINE]

Prodromal Phase

General Comments
- Duration: 2-8 days
- Disease Progresses at a Rapid Pace
Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])
- Clinical: may be significant in some cases
Cough (see Cough, [[Cough]])
- Epidemiology: may be present, but not a prominent symptom
Diarrhea (see Diarrhea, [[Diarrhea]])
Fever/Chills (see Fever, [[Fever]] and Chills, [[Chills]])
Headache (see Headache, [[Headache]])
- Clinical: may be prominent
Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
Myalgias (see Myalgias, [[Myalgias]])
- Clinical: may be severe
Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
- Epidemiology
  - Precipitous Thrombocytopenia May Appear During the Prodromal Phase (Am J Clin Pathol, 2001) [MEDLINE]
Absence of Pharyngitis/Coryza: although children may manifest pharyngitis
Absence of Meningismus

Cardiopulmonary Phase

General Comments

Rapid Onset of Symptoms
- Symptoms Correspond to the Development of Capillary Leak into the Lungs
Duration: 2-7 days (depending on severity of the Hantavirus infection)
Onset of Dry Cough May Herald the Abrupt Transition to the Cardiopulmonary Phase of the Infection (Chest, 2001) [MEDLINE]

Cardiovascular Manifestations

Arrhythmias
Hypotension/Shock (see Hypotension, [[Hypotension]])
- Diagnosis
  - Swan-Ganz Catheterization (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]]): demonstrates low cardiac output/high SVR state (which is unusual for sepsis)

Gastrointestinal Manifestations

Elevated Transaminases (see Elevated Liver Function Tests, [[Elevated Liver Function Tests]])
- Diagnosis
  - Transaminitis Occurs Later in the Phase
Hypoalbuminemia (see Hypoalbuminemia, [[Hypoalbuminemia]])
- Epidemiology
  - Hypoalbuminemia Occurs Concomitantly with an Increase in Hemoglobin/Hematocrit: these are markers for capillary leak

Hematologic Manifestations

General Comments
- Simultaneous appearance of thrombocytopenia, a left-shifted granulocytic series, and an immunoblast abundance that exceeds 10 percent of the total lymphoid series is referred to as the diagnostic triad. This triad is sufficiently diagnostic that it is used at centers with substantial experience with HCPS to triage patients for extracorporeal membrane oxygenation and other specialized tertiary care (Am J Clin Pathol, 2001) [MEDLINE]
Coagulopathy (see Coagulopathy, [[Coagulopathy]])
- Epidemiology
  - Abnormal Coagulation Tests are Common in Severe Hantavirus Infection, But Overt Bleeding is Uncommon
- Diagnosis
  - Elevated PT/INR
  - Elevated PTT
Elevated Serum Lactate Dehydrogenase (LDH) (see Elevated Serum Lactate Dehydrogenase, [[Elevated Serum Lactate Dehydrogenase]])
- Diagnosis
  - Elevated Serum LDH Occurs Early in the Phase
Hemoconcentration/Polycythemia (see Polycythemia, [[Polycythemia]])
- Epidemiology
  - Hypoalbuminemia Occurs Concomitantly with an Increase in Hemoglobin/Hematocrit: these are markers for capillary leak
Leukocytosis with Bandemia (see Leukocytosis, [[Leukocytosis]])
- Diagnosis
  - Peripheral Blood Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])
    - Hematologic/Peripheral Blood Smear Criteria from a University of New Mexico Retrospective Study of the Value of Peripheral Blood Smears in the Diagnosis of Hantavirus Infection (Am J Clin Pathol, 2014) [MEDLINE]
    - Absence of Toxic Changes
    - Granulocytic Left Shift
    - Hemoconcentration (see Polycythemia, [[Polycythemia]])
    - Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
    - Over 10% Immunoblasts
    - Peripheral Blood Smears Had an 89% Sensitivity/93% Specificity for the Diagnosis of Hantavirus Infection (Am J Clin Pathol, 2014) [MEDLINE]
    - Number of Immunoblasts Appears to Correlate with More Severe Disease, Suggesting a Prominent Role of Neutrophils in Disrupting the Endothelial Barrier in Hantavirus Infection (Front Microbiol, 2015) [MEDLINE]
Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
- Epidemiology
  - Precipitous Thrombocytopenia Occurs Early in the Phase (Perhaps Even Starting During the Prodromal Phase) (Am J Clin Pathol, 2001) [MEDLINE]

Pulmonary Manifestations

Acute Respiratory Distress Syndrome (ARDS) see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])
- Epidemiology: xxx
Bronchorrhea (see Bronchorrhea, [[Bronchorrhea]])
- Clinical:
Cough (see Cough, [[Cough]])
Dyspnea (see Dyspnea, [[Dyspnea]])
- Clinical
  - May Rapidly Progress to Acute Respiratory Distress Syndrome (ARDS)
Pleural Effusion (see Pleural Effusion-Transudate, [[Pleural Effusion-Transudate]] and Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
- Clinical
  - Pleural Effusion is Initially Transudative (Probably Due to Cardiac Dysfunction) and Subsequently Becomes Exudative

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
- Physiology
  - Due to Capillary Leak
Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
- Epidemiology
  - Lactic Acidosis Occurs Later in the Phase

Oliguric/Diuretic Phase

Oliguric Phase: usually 3-7 days
Diuretic Phase: variable length

Convalescent Phase

Occurs Acutely and Dramatically Over as Short as 24-48 hrs
- However, Complete Recovery is More Gradual

Prevention

xxxx

Treatment

Pharmacologic Therapy

Ribavirin (see Ribavirin, [[Ribavirin]])

Clinical Efficacy
- Ribavirin May Be Effective in the Treatment of Hemorrhagic Fever with Renal Syndrome (HFRS) Due to the Hantavirus Strain, Hantaan Virus (HTNV) (J Infect Dis, 1991) [MEDLINE] and (Antimicrob Agents Chemother, 2007) [MEDLINE]

Corticosteroids (see Corticosteroids, [[Corticosteroids]])

Clinical Efifcacy
- Methylprednisolone is Not Effective (Clin Infect Dis, 2013) [MEDLINE]

Respiratory Management

Mechanical Ventilation

xxxx

Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) (see Venovenous Extracorporeal Membrane Oxygenation, [[Venovenous Extracorporeal Membrane Oxygenation]])

VV-ECMO Has Been Used Successfully in a Number of Cases (Crit Care Med, 1998) [MEDLINE] and (J Thorac Cardiovasc Surg, 2008) [MEDLINE]

Prognosis

xxx

References

General

Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. 1994;330(14):949 [MEDLINE]
Hantaviruses: a global disease problem. Emerg Infect Dis. 1997;3(2):95 [MEDLINE]
The incubation period of hantavirus pulmonary syndrome. Am J Trop Med Hyg. 2000;62(6):714 [MEDLINE]
Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review. Am J Clin Pathol. 2001;116(5):665 [MEDLINE]
Hantavirus pulmonary syndrome due to Andes virus in Temuco, Chile: clinical experience with 16 adults. Chest. 2001;120(2):548 [MEDLINE]
Hantaviruses: molecular biology, evolution and pathogenesis. Curr Mol Med. 2005;5(8):773 [MEDLINE]
Diagnosis and treatment of new world hantavirus infections. Curr Opin Infect Dis. 2006;19(5):437 [MEDLINE]
Bench-to-bedside review: pulmonary-renal syndromes–an update for the intensivist. Crit Care. 2007;11(3):213 [MEDLINE]
Successful triage of suspected hantavirus cardiopulmonary syndrome by peripheral blood smear review: a decade of experience in an endemic region. Am J Clin Pathol. 2014 Aug;142(2):196-201. doi: 10.1309/AJCPNFVWG46NUHED [MEDLINE]
Recognition and management of rodent-borne infectious disease outbreaks after heavy rainfall and flooding. J La State Med Soc. 2014 Sep-Oct;166(5):186-92. Epub 2014 Oct 11 [MEDLINE]
Hantavirus-induced disruption of the endothelial barrier: neutrophils are on the payroll. Front Microbiol. 2015;6:222. Epub 2015 Mar 25 [MEDLINE]

Treatment

Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis. 1991;164(6):1119 [MEDLINE]
Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation. Crit Care Med. 1998;26(2):409 [MEDLINE]
Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5′-triphosphate, not with inhibition of IMP dehydrogenase. Antimicrob Agents Chemother. 2007;51(1):84. Epub 2006 Oct 23 [MEDLINE]
Extracorporeal membrane oxygenation support improves survival of patients with severe Hantavirus cardiopulmonary syndrome. J Thorac Cardiovasc Surg. 2008;135(3):579 [MEDLINE]
High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial. Clin Infect Dis. 2013;57(7):943. Epub 2013 Jun 19 [MEDLINE]