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Hantavirus Cardiopulmonary Syndrome
Synopsis
Urgent Action
- Anticipate rapid deterioration and prepare preemptively for invasive monitoring, mechanical ventilation, extracorporeal membrane oxygenation, and administration of inotropic agents
- Early transfer to a tertiary care center (preferably with the ability to institute extracorporeal membrane oxygenation) is recommended and appropriate even without viral confirmation if CBC and blood smear findings are strongly suggestive 1
- Early placement of arterial line and pulmonary artery catheter is recommended; in settings where extracorporeal membrane oxygenation is available, consider anticipatory placement of appropriate vascular access 2
8 Interesting Facts of Hantavirus Cardiopulmonary Syndrome
- Hantavirus cardiopulmonary syndrome is a severe, potentially fatal, febrile illness characterized by noncardiogenic pulmonary edema and cardiogenic shock. It is carried by rodents; humans are infected by inhaling aerosolized rodent excreta
- Occurs in areas of North, Central, and South America; in the United States and Canada, most cases occur in western regions
- Begins with nonspecific prodrome of fever, headache, myalgias, gastrointestinal symptoms, and abdominal pain, followed by sudden onset of pulmonary capillary leak syndrome and myocardial depression that can escalate rapidly, culminating in respiratory failure and cardiovascular collapse
- Diagnosis is suggested by compatible history and clinical illness coupled with characteristic changes on CBC (elevated hematocrit, thrombocytopenia) and peripheral blood smear (immunoblastosis, granulocytic left shift, absence of toxic neutrophil changes)
- Diagnosis is confirmed by presence of virus-specific IgM and/or 4-fold rise in titer of virus-specific IgG between acute and convalescent specimens
- There is no specific antiviral agent. Treatment is supportive, with supplemental oxygen (including mechanical ventilation if necessary) and judicious fluid replacement. Extracorporeal membrane oxygenation appears to offer the best outcome in severely ill patients
- Survivors of the 24- to 72-hour 1 cardiopulmonary phase diurese spontaneously and recover completely, in most cases
- Mortality rates are about 35% to 40% 1
Pitfalls
- Fluid challenge has little effect in raising blood pressure, hastens cardiopulmonary deterioration, and should be avoided. Target pulmonary capillary wedge pressure should be no higher than 8 to 12 mm Hg. Use of an inotropic agent (eg, dobutamine) is recommended as the primary means of hemodynamic support
Terminology
Clinical Clarification
- Hantavirus cardiopulmonary syndrome is a severe febrile illness characterized by noncardiogenic pulmonary edema, cardiogenic shock, and high mortality rate
- Occurs in 4 clinically distinct phases: 1
- Nonspecific prodrome of 3 to 6 days
- Cardiopulmonary phase associated with high mortality, usually in first 24 hours; lasts 3 to 6 days in survivors
- Diuresis with very high urine output (300-500 mL/hour) for 24 to 48 hours
- Convalescence may require months to years for full recovery
- Caused primarily by New World species of hantavirus associated with certain rodents, which shed virus in saliva, urine, and feces; humans are infected through inhalation of aerosolized virus, inadvertent ingestion, or—less commonly—rodent bites 3
Clinical Presentation
History
- Prodrome is nonspecific and lasts for several days
- Characterized by fever, chills, headache, and myalgia
- Nausea, vomiting, and/or diarrhea are common; some patients have abdominal pain, which can be very severe
- Onset of cardiopulmonary phase is abrupt and rapidly progressive
- Cough, which may be productive, occurs; secretions are thin, clear, amber, or pink and may be foamy. Dyspnea occurs
- Onset of shock, in conjunction with hypoxemia, may be accompanied by confusion or delirium
- History may reveal recognized or possible exposure to rodent excreta within previous 1 to 5 weeks 4
- Working in forestry, agriculture, or construction
- Performing military exercises
- Hunting or camping
- Cleaning infested living spaces or outbuildings
- In patients who acquire disease in South America, where the implicated virus may be transmitted person-to-person, history may include close (eg, household, sexual) exposure to people with similar (possibly undiagnosed) illness 5
Physical examination
- Prodrome
- Fever is usually present
- Examination is otherwise nonspecific in many patients
- Abdominal tenderness is fairly common
- Cardiopulmonary phase
- Patients appear ill and in distress
- Tachycardia and tachypnea are common on presentation; hypotension may be present or may develop within hours
- Fine rales may be heard on auscultation
- Abdominal tenderness may be elicited on palpation and may be severe enough to suggest acute abdomen
- Disease acquired in South America may be associated with conjunctival hemorrhage, facial flushing, and peripheral edema; these findings are not characteristic of disease in North America 1
Causes and Risk Factors
What causes Hantavirus Cardiopulmonary Syndrome?
- Several species of New World (western hemisphere) hantavirus cause cardiopulmonary disease; each is associated with a specific small mammal host, and distribution of the virus follows the territory of the host
- North America 6
- Sin Nombre virus is the one most commonly implicated and is associated with the deer mouse; Sin Nombre virus occurs throughout most of the United States (most commonly western), subarctic Canada, and central Mexico
- Cotton rats, which harbor Black Creek Canal virus, live in southeastern and south central United States and Mexico
- Rice rats carry Bayou virus; these semi-aquatic animals are native to the southeastern and eastern sections of the mid-Atlantic states
- White-footed mice, which live throughout eastern and central Unites States and Mexico, carry New York virus
- Central America
- Choclo virus (carried by pygmy rice rats) has been implicated as a cause of hantavirus cardiopulmonary syndrome in Central America 7
- Cotton rats, which harbor Black Creek Canal virus, live in Central America as well 6
- South America
- Andes virus, the most important pathogenic hantavirus in South America, occurs primarily in Argentina and Peru and is transmitted by long-tailed pygmy rice rats 7
- The type of hantavirus disease caused by Araraquara virus has been reported in Brazil and is associated with particularly high mortality; it is carried by hairy-tailed bolo mice 7
- Cotton rats, which harbor Black Creek Canal virus, live in some countries in South America 6
- Sylvilagus aquaticus, a semi-aquatic rodent species, has been reported to carry a newly identified strain of hantavirus (Leyes virus) in Central Argentina 8
- Old World (eastern hemisphere) hantaviruses do not generally cause cardiopulmonary syndrome but are associated with hemorrhagic fever with renal syndrome 9
- North America 6
- Virus is excreted by the rodent host in saliva, urine, and feces; human infection occurs through inhalation of aerosolized virus, inadvertent ingestion, or rodent bite
- Human-to-human transmission has been documented only with Andes virus; the means is unclear, but sexual and close household contact, as well as nosocomial transmission, have been implicated 5
- Infection induces a pulmonary capillary leak syndrome and myocardial depression (possibly myocarditis 4 10) 2
Risk factors and/or associations
Other risk factors/associations
- Climate and environment
- In temperate areas, most cases occur in late spring and early summer 4
- In southwestern United States, increased frequency of infection has been observed in years of higher precipitation, which apparently fosters an increase in rodent populations owing to increased food supply 7
- Acquired most often in rural areas but can occur in urban and suburban settings 4
- Activity
- Sleeping or working in rodent-infested areas
- Opening and cleaning buildings that have been closed (eg, for the winter)
- Sweeping and vacuuming promote aerosolization of rat urine, feces, and saliva
- Camping, hiking, and hunting
- Occupational exposure
- Construction
- Utility work
- Pest control
- Agricultural and forestry work 11
- Military
Diagnostic Procedures
Primary diagnostic tools
- Hantavirus cardiopulmonary syndrome is a nationally notifiable disease in the United States 12
- Suspect disease in patients with febrile illness characterized by unexplained pulmonary edema and hemodynamic compromise; attempt to obtain a history of possible exposure
- Obtain a chest radiograph and CBC; characteristic findings on blood count and peripheral smear may provide early clues to the diagnosis of hantavirus infection and aid in directing early phases of management 4
- Serial CBCs and examination of blood smears are recommended when disease is suspected and initial smear does not show suggestive features 13
- Definitive diagnosis is made by one of several methods: 14
- Serology
- Serologic tests are commercially available; state health departments and CDC can facilitate testing, if needed 15
- Polymerase chain reaction testing on blood, body fluids, or tissue specimens
- CDC does not recommend routine use of polymerase chain reaction testing to diagnose hantavirus infection 14 because this test has technical and performance issues; additionally, hantavirus RNA is present in the blood for a very short time 16
- Immunohistochemical demonstration of antigen in tissue
- Serology
- Obtain other laboratory studies needed to manage critically ill patients who have respiratory and hemodynamic compromise (eg, renal and liver function, lactate, electrolyte, and coagulation studies; arterial blood gases; urinalysis) 4
- Many patients require a Swan-Ganz catheter to be placed to manage shock; hemodynamic parameters, although not specifically diagnostic of hantavirus cardiopulmonary syndrome, are distinctive and may suggest the diagnosis over sepsis from other causes 1
- Disease may occur in the context of local outbreaks that result from conditions that favor increases in the rodent population; consult local public health officials to determine whether other cases have occurred 1
Laboratory
- CBC
- Leukocytosis is common 4
- A constellation of 5 findings (5-Point screen) has been found to be highly predictive of cardiopulmonary syndrome caused by Sin Nombre virus in patients presenting with a compatible clinical illness in an endemic area (southwestern United States): 1317
- Hemoconcentration (elevated hemoglobin greater than 16 g/dL in women or 18 g/dL in men)
- Thrombocytopenia (less than 150 × 10⁹ cells/L)
- Left shift (often with circulating myelocytes)
- Lack of toxic changes (toxic granulation, Döhle bodies, vacuolization) in granulocytes
- Increased immunoblasts (more than 10% of circulating lymphocytes)
- Presence of all 5 findings in the constellation correlates with a sensitivity of 35%, specificity of 100%, and positive predictive value of 100% 13
- Presence of 4 of 5 findings in the constellation correlates with a sensitivity of 88.9%, specificity of 93%, and positive predictive value of 85.7% 13
- In patients with infection caused by Andes virus, a platelet count of less than 115 × 10⁹ cells/L at presentation was associated with progression to moderate or severe disease 18
- Serology
- IgM antibody to hantavirus is detectable very early and is positive in most patients at the time of presentation; a rapid test is available. IgG also is detectable early in the clinical course 19
- Presence of IgM or demonstration of a 4-fold rise in IgG titers between acute and convalescent specimens confirms diagnosis 14
- IgM antibody to hantavirus is detectable very early and is positive in most patients at the time of presentation; a rapid test is available. IgG also is detectable early in the clinical course 19
- Immunohistochemistry
- Requires formalin-fixed tissue (most often from lung biopsy)
- Sensitive for diagnosis, but practical applicability in acute illness is limited 7
- Chemistry
- Transaminase and amylase levels may be mildly elevated 4
- Creatinine and urine protein levels may be slightly increased, but significant renal impairment is unusual in North American disease; it is more common with South American variants 1 4
- Hypoalbuminemia is common 1
- Lactate levels may rise as a result of hypotension and poor tissue perfusion 4
- Coagulation studies
- Prolonged prothrombin time/elevated INR and prolonged partial thromboplastin time may be noted; rarely, disseminated intravascular coagulopathy may occur 4
- Arterial blood gas levels
- Progressive hypoxemia and metabolic acidosis are characteristic of severe disease 4
- Urinalysis
- Proteinuria has been shown to be a predictor of in-hospital mortality independent of age, gender, and severity 20
Imaging
- Chest radiograph 1
- Early in the cardiopulmonary phase, findings may be limited to interstitial edema with Kerley B lines, hilar fullness, and peribronchial cuffing
- May progress rapidly to florid pulmonary edema with an alveolar pattern and pleural effusion
- Lobar infiltrates are not typical and suggest an alternate diagnosis
Functional testing
- Hemodynamic parameters
- Typical pattern in hantavirus cardiopulmonary syndrome is low cardiac index and normal or high systemic vascular resistance, whereas typical pattern in sepsis is high cardiac index and low systemic vascular resistance 1
Differential Diagnosis
Most common
- Influenza
- Like the prodrome of hantavirus cardiopulmonary syndrome, influenza is characterized by myalgias (which may be severe), headache, and fever
- Unlike hantavirus cardiopulmonary syndrome, rhinorrhea and sore throat are common features of influenza and gastrointestinal and abdominal complaints are not
- Like hantavirus cardiopulmonary syndrome, cough is often prominent; patients who develop influenza pneumonia may be dyspneic and chest radiographs may show interstitial infiltrates
- Diagnosis is made by rapid antigen or polymerase chain reaction tests for influenza
- Bacterial pneumonia
- Severe pneumonia due to a variety of bacterial pathogens can, like hantavirus cardiopulmonary syndrome, manifest as overwhelming respiratory compromise with dyspnea and hypoxemia
- Although pulmonary disease may progress rapidly, prodrome of bacterial pneumonia is usually short or does not occur at all
- Although generally uncommon, pneumonic plague and tularemia may present in fulminant fashion and may result from exposure to rodents, similar to hantavirus cardiopulmonary syndrome
- Differentiated by demonstrating bacterial pathogen through culture of blood or pulmonary secretions or other methods particular to the infecting species (eg, antigen testing, serology)
- COVID-19 infection212223
- Presenting symptoms are similar to hantavirus cardiopulmonary syndrome: fever, fatigue, cough, dyspnea, myalgias; imaging also presents with similar findings of pulmonary infiltrates 22 23
- Differentiated by serology or molecular (RT-PCR) testing
- The 5-Point Screen has been shown to assist with differentiation between hantavirus cardiopulmonary syndrome and COVID-19 24
- Septic shock
- Like hantavirus cardiopulmonary syndrome, septic shock may present with fever, hypotension, tachycardia, and tachypnea; acute respiratory distress syndrome may complicate sepsis, adding to the clinical similarity
- Unlike hantavirus cardiopulmonary syndrome, the hemodynamic picture of sepsis is that of high cardiac index and low systemic vascular resistance
- Definitive distinction is made by recovery of the pathogen by culture or other laboratory methods of identification (eg, molecular diagnostics)
Treatment Goals
- Provide optimal ventilatory and hemodynamic support through the critical cardiopulmonary phase
- Anticipate rapid deterioration and prepare preemptively for invasive monitoring, mechanical ventilation, extracorporeal membrane oxygenation, and administration of inotropic agents
Disposition
Admission criteria
Admit all patients with suspected hantavirus cardiopulmonary syndrome to the hospital; compatible history and presence of thrombocytopenia are sufficient criteria to admit 1
Criteria for ICU admission
- Because deterioration often occurs rapidly, manage patients with any evidence of pulmonary edema in ICU 1
- Early transfer to a tertiary care center (preferably with capacity for extracorporeal membrane oxygenation) is advisable and appropriate—even without viral confirmation—if CBC and blood smear findings are strongly suggestive 113
- Transfer patient as soon as diagnosis is suspected, preferably before onset of respiratory compromise
Recommendations for specialist referral
- For management, refer to critical care specialists who have expertise treating respiratory failure and shock and experience administering extracorporeal membrane oxygenation (if the technology is available)
- Consult infectious disease specialist for assistance with diagnostic testing and communication with public health officials
- Consult a vascular surgeon for placement of vascular access for extracorporeal membrane oxygenation, as needed
Treatment Options
It is often necessary to institute treatment before confirming diagnosis based on compatible clinical picture, including CBC and peripheral smear criteria 13
No specific antiviral or antiinflammatory agent has been shown as consistently effective and approved for use by regulatory bodies; treatment is aimed at providing adequate oxygenation and hemodynamic support 25
- Ribavirin has been in several small studies of patients with hantavirus cardiopulmonary syndrome, but results have been conflicting 25 26
- A study of patients with Andes virus–related hantavirus cardiopulmonary syndrome who were given high doses of corticosteroids found no significant adverse effects attributed to corticosteroid therapy, but survival outcomes were no different than in the comparison placebo arm 27
- A small preliminary study in Chile of immune plasma derived from survivors appeared to produce a promising reduction in case fatality rates of patients with hantavirus cardiopulmonary syndrome caused by Andes virus 28
Provide supplemental oxygen to all patients. Many patients require intubation and mechanical ventilation; noninvasive ventilation is not advised 4
Early placement of arterial line and pulmonary artery catheter is recommended; in settings in which extracorporeal membrane oxygenation is available, consider anticipatory placement of appropriate vascular access 4 2
Avoid fluid challenge, as it has little effect in raising blood pressure and hastens cardiopulmonary deterioration. Use of an inotropic agent (eg, dobutamine) is recommended as the primary means of hemodynamic support 1
Prompt initiation of extracorporeal membrane oxygenation appears to offer significant survival benefit to patients with severe disease refractory to standard recommended ventilatory and hemodynamic support
- Longitudinal study of 51 patients with severe hantavirus cardiopulmonary syndrome (predicted mortality, 100%) treated with extracorporeal membrane oxygenation reported survival of 66.6%, with complete recovery of all survivors 29
- Earlier institution of extracorporeal membrane oxygenation was associated with greater likelihood of survival 29
Laboratory confirmation may take hours or longer; most experts recommend administering empiric broad spectrum antibiotics to cover other possible sources of infection until the diagnosis is confirmed 4
Drug therapy
- Dobutamine
- Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute.
- Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
Nondrug and supportive care
Fluid management
- Fluid administration must be judicious and restrictive; target pulmonary artery wedge pressure is 8 to 12 mm Hg 1 4
Mechanical ventilation
- Indications for and timing of intubation and mechanical ventilation are somewhat controversial
- Some authorities recommend initiating early in the course of declining oxygenation to optimize oxygenation to the extent possible, avoid or mitigate metabolic effects of respiratory failure, and avert need for emergency intubation 1
- Other authorities favor delaying as long as possible to maintain natural adrenergic effects and avert hemodynamic decompensation 2
Procedures
Extracorporeal membrane oxygenation
General explanation
- Heart-lung bypass is a technique in which blood is circulated from patient through bypass machine, where transmembrane exchange of oxygen and carbon dioxide occurs before blood is returned to patient
- In patients with hantavirus cardiopulmonary syndrome, the technique used is venoarterial (ie, blood enters the loop from venous side and is returned to arterial circulation) 16
Indication
- Refractory hypoxemia and hemodynamic compromise despite standard supportive measures 2
- In published studies, criteria were cardiac index of less than 2.3 L/min/m² and arterial oxygen tension/fractional inspired oxygen (PaO₂/FiO₂) ratio of less than 50 4
Contraindications
- Neurologic impairment
- Severe preexisting disease
Complications
- Limb ischemia distal to vascular access catheters
Special populations
- Little published data exist regarding hantavirus cardiopulmonary syndrome in children, but a series of 13 patients aged 10 to 16 years reported using treatment strategies similar to those used in adults, with similar outcomes 30
- Pregnant patients and their fetuses have been shown to have more severe symptoms and worse clinical outcomes, although findings vary according to the causative virus 31
Monitoring
- Frequent reassessment of CBC and blood chemistry results (eg, every 8-12 hours) is recommended until patients stabilize (ie, through the diuresis phase) 4
Complications
- Mortality rates vary with causative virus but are about 35% to 40% for patients with Sin Nombre and Andes viruses 1
- Death results from progressive myocardial dysfunction and cardiovascular collapse 1
Prognosis
- Indicators of poor prognosis include: 4
- Falling serum albumin level
- Hemoconcentration
- Progressive thrombocytopenia
- Prolonged prothrombin time/elevated INR and prolonged partial thromboplastin time
- Disseminated intravascular coagulation
- Metabolic acidosis with elevated lactate levels
- Cardiac index less than 2.2 L/min/m² 4
- In patients who survive, the cardiopulmonary phase lasts about 3 to 6 days and is followed by spontaneous onset of diuresis, which continues for several days. Most survivors recover completely, although convalescence may extend for months or even years 1
Prevention
- At present, there are no World Health Organization or FDA-approved vaccines for the various species that cause hantavirus cardiopulmonary syndrome 9 25
- Prevention centers on controlling rodent populations around living and camping areas and avoiding mice, their nests, and their droppings; it is particularly important to avoid aerosolization of nest materials and droppings 19
- CDC provides detailed guidance about trapping and removing animals and cleaning spaces and surfaces 32
- Eliminate food sources
- Keep food in sealed storage containers or cupboards, and maintain cleanliness in kitchen and eating areas
- Seal all openings to living and storage spaces
- Trap rodents until none are trapped for a week to ensure openings are sealed in home and other spaces (eg, summer cabin, camping trailer, attic)
- Clean up after rodents
- When cleaning infested area, first open doors and windows to allow ventilation for 30 minutes
- Wear gloves and do not sweep or vacuum to avoid aerosolization of nest materials and droppings
- If it is a heavy infestation, wear additional protective gear, including coveralls, rubber boots or disposable shoe covers, goggles, and a respirator
- Saturate dead rodents, droppings, and nesting materials with disinfectant or a bleach and water solution for 5 minutes before double bagging and cleaning area with paper towels
- Disinfect items that may have been contaminated
- Steam clean or shampoo carpets and upholstery. Launder clothing and bedding in hot water and dry at high temperature setting
- Decontaminate books and papers by exposing to direct sunlight for several hours
- Eliminate food sources
References
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