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AUTHOR AND EDITOR INFORMATION

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Author: Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Editors: Kenneth C Earhart, MD, Deputy Head, Disease Surveillance Program, United States Naval Medical Research Unit #3; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Author and Editor Disclosure

Synonyms and related keywords: hantavirus pulmonary syndrome, hantaviruses, Bunyaviridae, bunyaviruses, Sin Nombre virus, SNV, HPS, lung infection, lung disease, rodent infestation, zoonotic, zoonoses, Bayou virus, Black Creek Canal virus, New York virus, viral infection, acute respiratory failure, circulatory collapse, Hantaan virus, Seoul Hantavirus, Dobrava/Belgrade Hantavirus, Puumala virus, hemorrhagic fever with renal syndrome, HFRS, hemorrhagic fever with renal failure syndrome, Four Corners disease


INTRODUCTION

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Background

Hantaviruses are RNA zoonotic viruses that are transmitted to humans from rodent hosts. They are members of the family Bunyaviridae that are generally spherical in shape (70-100 nm in diameter). The lipid envelope contains 2 major glycoproteins. On electron microscopy, characteristic inclusion bodies and a distinctive gridlike pattern can be seen. Examples are distributed worldwide. Hantaan virus, Seoul Hantavirus, Dobrava/Belgrade Hantavirus, and Puumala virus produce the syndrome of hemorrhagic fever with renal failure syndrome (HFRS).

In 1993, an unusual cluster of deaths occurred in the southwest United States. The outbreak was characterized by a febrile prodrome that was followed by acute respiratory failure and finally death due to circulatory collapse. This outbreak was initially named Four Corners disease because it seemed to be focused at the juncture of the borders of 4 states. Physicians from the Indian Health Service and the Centers for Disease Control and Prevention determined that a rodent vector was responsible for this infection. This disease was subsequently renamed Hantavirus pulmonary syndrome (HPS).

The Sin Nombre virus (SNV) is the Hantavirus species primarily responsible for HPS. However, closely related strains (Bayou and Black Creek Canal viruses), found in the southeastern United States, may produce a variant of the syndrome that is characterized by a greater degree of renal failure. The New York virus is the cause of cases of HPS in New York and Rhode Island. Retrospective analyses indicate that HPS has been present in North America since as early as 1959.

Hantavirus has now been reported in more than 24 states in the continental United States, Canada, and South America.

Pathophysiology

The basic pathophysiological lesion of HPS, and indeed of all Hantavirus infections, is a generalized increase in capillary permeability that results from endothelial damage. This injury appears to be a consequence of the host's immunological response to viral antigens that have penetrated the endothelium by means of the cells' own integrins. The onset of clinical symptoms is correlated with the development of specific antibodies to the virus. The increased capillary permeability gives rise to widespread protein-rich edema. The particular organs affected are related to the specific species of Hantavirus. In HFRS, a large outpouring of edema fluid flows into the retroperitoneum and is associated with hemorrhage and necrosis. Individuals with HPS have edema concentrated in the pleura and lungs.

The endothelial cells appear swollen. Lung examination findings reveal an interstitial pneumonitis made up of edema fluid, mononuclear cells, and lymphocytes with polymorphonuclear leukocytes. Hyaline membranes appear along with a proliferation of type 2 alveolar lining cells. As the disease progresses, the alveolar septa become increasingly fibrotic. The spleen in patients with HPS shows infiltration of immunocompetent cells within the red pulp and the periarteriolar sheaths.

Severe cases of HPS present clinically as noncardiogenic pulmonary edema. The pathophysiology of the pulmonary findings is that of a pulmonary capillary leak syndrome. The heart is not directly affected. The pulmonary capillary leak syndrome is the primary underlying pathophysiological defect responsible for both cardiopulmonary and renal dysfunction. Prerenal azotemia is due to the inadequate intravascular volume of the hypotensive patient and not to direct infection. Hantavirus particles are not found within the renal tubular cells of patients with HPS. Hypoxia also contributes to the state of shock.

Frequency

United States

HPS occurs primarily in the fall, when small rodents (eg, field mice) inhabit human dwellings to protect themselves from the cold weather. In the wild, many small rodents (eg, voles, white-footed deer mice) also transmit the virus. Inhalation of infected aerosolized rodent urine or dried excreta can lead to infection with HPS. Human-to-human transmission of HPS has not been reported in the United States, nor have nosocomial infections been reported. HPS is a zoonosis and parallels the distribution of the associated rodent vectors. The climactic conditions of El Niño promote the transmission of the causative virus.

International

Hantavirus infections occur in eastern Asia, Latin America, and North America, including Canada. However, HPS seems to be restricted to North and South America. While human-to-human transmission has not been reported in the United States, an outbreak of HPS reported from Argentina was possibly associated with human-to-human transmission.1, 2

Breed

The small rodent vectors of Hantavirus are thought to be lifelong carriers of the virus and are not subject to infection by the virus. The deer mouse is the reservoir for SNV in the western United States. The white-footed mouse serves that role for SNV and the New York virus in the northeastern United States.

Mortality/Morbidity

Initially, HPS was thought to be uniformly lethal. Current experience indicates that HPS represents a wide spectrum of clinical disease, from mild infection in ambulatory patients to severe infection requiring mechanical ventilation. The fatality rate is approximately 50%.

Race

HPS has no race predilection.

Sex

HPS has no sex predilection; however, because of cultural sex roles, males are more likely than females to encounter small rodents in hunting and/or field exposures.

Age

HPS is conspicuously absent among very young persons and very elderly persons. This absence may reflect their relative lack of contact with rodents in the outdoor setting.


CLINICAL

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History

  • The incubation period of Hantavirus pulmonary syndrome (HPS) ranges from 1-4 weeks. HPS has been divided into 3 clinical phases: (1) the prodromal phase, (2) the cardiopulmonary phase, and (3) the convalescent phase.
    • Prodromal symptoms resemble those of many viral illnesses, including fever, headache, and myalgias. Vomiting, diarrhea, and abdominal pain are common. Because symptoms initially referable to the respiratory tract are minimal or absent, the physician may conclude that the patient has viral gastroenteritis. Neurologic symptoms, except dizziness, are uncommon. This phase lasts 3-5 days.
    • The cardiopulmonary phase is initiated by dyspnea, nonproductive cough, and circulatory collapse. This stage lasts only 24-48 hours. Seventy-five percent of patients with pulmonary edema require mechanical ventilation. Oliguric renal failure is uncommon. When it does occur, it is due to acute tubular necrosis (ATN), as compared to the renal tubular cell damage caused by the endotheliosis observed in hemorrhagic fever with renal failure syndrome (HFRS).
    • Resolution of the cardiopulmonary stage of HPS is heralded by the onset of the significant diuresis. After this occurs, the patient improves quite rapidly (ie, convalescent phase). The chronic sequelae of HPS are minimal.

Physical

  • Physical findings, reported in 80-90% of patients, include fever, tachypnea, tachycardia, and rales.
  • Upon presentation, hypotension is found in only one third of patients.
  • Rash is quite uncommon.

Causes

  • Sin Nombre virus (SNV) is thought to cause most cases of HPS in the United States.


DIFFERENTIALS

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Other Problems to be Considered

Drug-induced noncardiac pulmonary edema

An appropriate ingestion history of medications that are associated with noncardiac pulmonary edema may differentiate drug-induced noncardiac pulmonary edema from Hantavirus pulmonary syndrome (HPS).

Patients with cardiac pulmonary edema usually have a left ventricular S3 gallop rhythm and often have cardiomegaly upon physical examination, which is not the case with HPS.

Acute respiratory distress syndrome

In contrast to HPS, the distribution of the infiltrates associated with acute respiratory distress syndrome (ARDS) observed on chest radiographs is peripheral rather than central. In addition, pleural effusions are common in HPS but are not a feature of ARDS.

HPS is accompanied by perihilar cuffing, earlier appearance of interstitial edema (Kerley B lines), and pericardiac haziness (fuzzy heart sign), which are characteristic of HPS and are not found with ARDS.

Pneumonic plague

Patients with pneumonic plague are critically ill with hemoptysis, which is not a feature of HPS. Pneumonic plague occurs in the setting of an outbreak of antecedent bubonic plague. Patients with HPS are less ill and have no adenopathy suggesting preceding or concomitant pneumonic plague.

Atypical community-acquired pneumonias

Among the nonzoonotic atypical pneumonias, Legionnaires disease may resemble HPS. Levels of serum transaminases may be mildly elevated in patients with Legionnaires disease and in those with HPS. Relative bradycardia uniformly accompanies Legionnaires disease but not HPS. Gastrointestinal symptoms, particularly diarrhea, may be observed in both. Severe renal insufficiency is uncommon in HPS and is unusual in Legionnaires disease. Cardiopulmonary collapse frequently occurs in HPS and seldom complicates Legionnaires disease, except in the terminal stages.

Tularemia and Q fever are zoonotic atypical pneumonias that are in the differential diagnoses of HPS. However, the vectors are different for these zoonotic infections. Contact with sheep or parturient cats is the usual epidemiological antecedent for Q fever pneumonia. Similarly, contact with deer, rabbits, or deer flies is the usual history suggesting tularemia. Symptoms common to Q fever, tularemia, and HPS are headache and myalgias. Q fever may feature splenomegaly and relative bradycardia, which are findings not observed in HPS. Bilateral hilar adenopathy and bloody pleural effusion characterize tularemic pneumonia and are not associated with HPS.

Viral influenza

Influenza begins abruptly, with patients often recalling the exact minute and/or hour they became acutely ill. A dry nonproductive cough and a sore throat, usually accompanied by rhinorrhea, characterize influenza. These are not features of HPS. Headache and myalgias are common in both infections.


WORKUP

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Lab Studies

  • Usually, the patient has leukocytosis with a shift to the left, thrombocytopenia, and an elevated hematocrit value due to hemoconcentration.
  • Atypical lymphocytes are commonly seen in the peripheral smear. The presence of the leukocytosis with a shift to the left combined with the atypical lymphocytosis strongly suggests the presence of a Hantavirus infection.
  • Hepatic transaminase values are only mildly elevated, but the serum lactate dehydrogenase level is markedly increased.
  • A mild elevation of the activated partial thromboplastin time occurs in most patients with a normal level of fibrinogen. A clue that disseminated intravascular coagulation has developed is when the concentration of fibrinogen begins to fall.
  • Significant elevation of creatinine and BUN levels is uncommon. Fifty percent of patients exhibit proteinuria, but not to the same degree as patients with hemorrhagic fever with renal failure syndrome (HFRS).
  • A low serum bicarbonate level reflects the degree of acidosis.
  • The serum albumin level is decreased in almost all patients with Hantavirus pulmonary syndrome (HPS). Although this depression represents an acute phase reactant that may be observed in many types of infections, the presence of severe hypoalbuminemia in a previously healthy patient with an acute onset of respiratory distress should suggest HPS.
  • The development of lactic acidoses, combined with rapid respiratory deterioration, usually indicates death within 1-2 days.
  • The serum creatine kinase level is elevated in 50% of patients.
  • Isolation of Hantavirus in tissue culture is not clinically available because of the technical difficulty of achieving this and because of issues related to biosafety.
  • Specific diagnosis may be achieved by serological techniques, polymerase chain reaction (PCR), and immunohistochemistry (IHC) studies.
    • PCR can help detect viral RNA in blood and tissues.
    • IHC can help detect viral RNA in formalin-fixed tissues with specific antibodies.
    • Most commonly, HPS is confirmed by Hantavirus immunoglobulin M (IgM)– and immunoglobulin G (IgG)–specific serology results, usually measured by performing an enzyme-linked immunoassay. Approximately one third of patients with HPS have an elevated IgM titer at the time of clinical presentation. Another one third of patients have elevated titers of IgM and IgG to Hantavirus at the time of presentation. The remaining third develop an increase in IgG titers without an increase in the IgM titer during convalescence.

Imaging Studies

  • The chest radiographic findings typically show a pattern of noncardiac pulmonary edema.
    • The cardiac silhouette is not enlarged.
    • Perihilar haziness (shaggy heart sign) is characteristic.
    • Virtually all patients have interstitial edema due to pulmonary capillary leak, which manifests radiologically as peribronchial cuffing or Kerley B lines.
    • Pleural effusions are common.

Other Tests

  • Arterial blood gas evaluation may reveal hypoxemia related to respiratory failure. The patient's concurrent hypocapnia confirms that the respiratory distress is not due to problems in ventilation but to those of gas exchange.
  • Patients with HPS have a normal pulmonary wedge pressure, decreased cardiac index, and elevated systemic vascular resistance.

Histologic Findings

Histology of lung tissue reveals capillaritis, pulmonary capillary leak syndrome, or both. Hemorrhage is not a feature of HPS in lung sections (see Pathophysiology).

In patients with severe and/or prolonged hypotension, the kidneys may develop histological findings consistent with ATN.


TREATMENT

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Medical Care

  • Approximately 25% of patients develop severe cardiopulmonary symptoms; such patients require hospitalization and often require intubation and mechanical ventilation.
  • Currently, treatment is primarily supportive in nature. The attending physician must pay careful attention to acid-base disturbances and fluid balance.
  • The nucleoside analogue ribavirin has been shown to be effective in hemorrhagic fever with renal failure syndrome (HFRS) caused by the Hantaan virus. One trial of the use of ribavirin in treating Hantavirus pulmonary syndrome (HPS) showed little effect. This may have been because of the rapidity of death in the most acutely ill patients. Further controlled trials are being conducted.
  • Extracorporeal membrane oxygenation has been employed successfully in several patients.3

Consultations

  • Obtain a consultation with an infectious diseases specialist for every patient considered to have HPS or a zoonotic infectious disease.
  • Obtain a consultation with a pulmonary and critical care specialist for severely ill patients with HPS who require intubation, mechanical ventilation, or both.

Activity

  • Recovery is promoted by the restriction of physical activity.


MEDICATION

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No therapy has proven beneficial in patients with Hantavirus pulmonary syndrome (HPS). Ribavirin has been used to treat Hantavirus infections, but its efficacy in HPS remains unproven.


FOLLOW-UP

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Further Inpatient Care

  • Admit patients with severe cardiopulmonary compromise to the intensive care unit.
  • Provide respiratory support as needed.
  • The use of vasopressors and the judicious administration of intravenous fluids constitute the mainstays of therapy.
  • Pay careful attention to systemic acidosis and electrolyte abnormalities.

Further Outpatient Care

  • Continue monitoring patients with mild Hantavirus pulmonary syndrome (HPS) in an outpatient setting until they are completely well.
  • Patients with mild HPS often complain of substernal discomfort. In patients with such symptoms, perform an ECG and/or cardiac enzyme test to help exclude myocardial infarction. Substernal discomfort that is oppressive in character is common in patients recovering from HPS. Although a cardiac explanation for the chest pain is suggested by its sternal location, myocardial infarction is not a complication of HPS.

Deterrence/Prevention

  • Caution patients against having contact with rodents or aerosolized rodent urine or excreta.
  • Dead rodents should not be handled without taking proper precautions and wearing protection.
  • Make dwellings rodent-proof; follow cleanliness and maintenance procedures such that dwellings do not attract small rodents.

Complications

  • Renal failure due to ATN may occur.
  • Severe capillary pulmonary leakage may result in intractable noncardiogenic pulmonary edema and cardiorespiratory collapse and/or shock.

Prognosis

  • The prognosis is excellent for mild cases of HPS.
  • Patients who recover from near-fatal HPS have no residual cardiopulmonary sequelae.

Patient Education

  • Caution patients to avoid contact with rodents or aerosolized rodent urine or excreta.
  • Do not handle dead rodents without taking proper precautionary and protective measures.
  • Make dwellings rodent-proof.
  • Maintain dwellings in such a manner as to avoid attracting small rodents.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Differentiate viral influenza and atypical pneumonias from Hantavirus pulmonary syndrome (HPS; see Other Problems to be Considered).
  • Be alert to a history of potential aerosol or direct contact with rodents in patients presenting with otherwise unexplained acute respiratory symptoms characterized by noncardiogenic pulmonary edema.
  • Avoid misdiagnosing influenza, ARDS, and severe typical and atypical community acquired pneumonias as HPS.
  • In summary, the diagnosis of HPS should be strongly considered in patients who present with fever and myalgias (especially of the large muscle groups) associated with gastrointestinal complaints. The absence of rash, conjunctivitis, sinusitis, pharyngitis, and arthritis distinguishes HPS from most other viral syndromes. Hypoxia, findings of pulmonary edema on chest radiographs, thrombocytopenia, elevated hematocrit values, and leukocytosis with a left shift and atypical lymphocytes should prompt serologic testing specific for the hantaviruses.


REFERENCES

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Hantavirus Pulmonary Syndrome excerpt

Article Last Updated: Jun 25, 2008