Hantavirus Pulmonary Syndrome

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Chapter 265 Hantavirus Pulmonary Syndrome

Scott B. Halstead

The Hantavirus pulmonary syndrome (HPS) is caused by multiple closely related hantaviruses that have been identified from the western USA, with sporadic cases reported from the eastern USA (see Fig. 265-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com) and Canada and important foci of disease in several countries in South America. HPS is characterized by a febrile prodrome followed by the rapid onset of noncardiogenic pulmonary edema and hypotension or shock. Sporadic cases in the USA caused by related viruses may manifest with renal involvement. Cases in Argentina and Chile sometimes include severe gastrointestinal hemorrhaging; nosocomial transmission has been documented in this geographic region only.

Figure 265-1 Total number of confirmed cases of Hantavirus pulmonary syndrome, by state of exposure—USA, 1993-2006. n = 438 as of May 10, 2006. Numbers in parentheses indicate cases confirmed during January-March 2006 (n = 9).

(From the Centers for Disease Control and Prevention: Hantavirus pulmonary syndrome: five states, 2006, MMWR Morbid Mortal Wkly Rep 55:627–628, 2006.)

Etiology

Hantaviruses are a genus in the family Bunyaviridae, which are lipid-enveloped viruses with a negative-sense RNA genome composed of 3 unique segments. Several pathogenic viruses that have been recognized within the genus include Hantaan virus, which causes the most severe form of hemorrhagic fever with renal syndrome (HFRS) seen primarily in mainland Asia; Dobrava virus, which causes the most severe form of HFRS seen primarily in the Balkans; Puumala virus, which causes a milder form of HFRS with a high proportion of subclinical infections and is prevalent in northern Europe; and Seoul virus, which results in moderate HFRS and is transmitted predominantly in Asia by urban rats or worldwide by laboratory rats. Prospect Hill virus, a Hantavirus that is widely disseminated in meadow voles in the USA, is not known to cause human disease.

HPS is associated with Sin Nombre virus, isolated from deer mice, Peromyscus maniculatus, in New Mexico. Multiple HPS-like agents isolated to date belong to a single genetic group of hantaviruses and are associated with rodents of the family Muridae, subfamily Sigmodontinae. These rodent species are restricted to the Americas, suggesting that HPS may be a Western hemisphere disease.

Epidemiology

Persons acquiring HPS generally have a history of recent outdoor exposure or live in an area with large populations of deer mice. Clusters of cases have occurred among individuals who have cleaned houses that were rodent infested. P. maniculatus is one of the most common North American mammals and, where found, is frequently the dominant member of the rodent community. About half of cases occur between the months of May and July. Patients are almost exclusively 12-70 yr of age; 60% of patients are 20-39 yr of age. Rare cases are reported in children <12 yr of age. Two thirds of patients are male, probably reflecting their greater outdoor activities. It is not known whether almost complete absence of disease in young children is a reflection of innate resistance or simply lack of exposure. Evidence of human transmission has been obtained in Argentine outbreaks.

Hantaviruses do not cause apparent illness in their reservoir hosts, which remain asymptomatically infected for life. Infected rodents shed virus in saliva, urine, and feces for many weeks, but the duration of shedding and the period of maximum infectivity are unknown. The presence of infectious virus in saliva, the sensitivity of these animals to parenteral inoculation with hantaviruses, and field observations of infected rodents indicate that biting is important for rodent-to-rodent transmission. Aerosols from infective saliva or excreta of rodents are implicated in the transmission of hantaviruses to humans. Persons visiting animal care areas housing infected rodents have been infected after exposure for as little as 5 min. It is possible that hantaviruses are spread through contaminated food and breaks in skin or mucous membranes; transmission to humans has occurred by rodent bites. Person-to-person transmission is distinctly uncommon but has been documented in Argentina.

Pathogenesis

HPS is characterized by sudden and catastrophic pulmonary edema, resulting in anoxia and acute heart failure. The virus is detected in pulmonary capillaries, suggesting that pulmonary edema is the consequence of T-cell attack on virus-infected capillaries. Disease severity is predicted by the level of acute-phase viremia titer.

Clinical Manifestations

HPS is characterized by a prodrome and a cardiopulmonary phase. The mean duration after the onset of prodromal symptoms to hospitalization is 5.4 days. The mean duration of symptoms to death is 8 days (median 7 days; range 2-16 days). The most common prodromal symptoms are fever and myalgia (100%); cough or dyspnea (76%); gastrointestinal symptoms, including vomiting, diarrhea, and mid-abdominal pain (76%); and headache (71%). The cardiopulmonary phase is heralded by progressive cough and shortness of breath. The most common initial physical findings are tachypnea (100%), tachycardia (94%), and hypotension (50%). Rapidly progressive acute pulmonary edema, hypoxia, and shock develop in most severely ill patients. Pulmonary vascular permeability is complicated by cardiogenic shock associated with increased vascular resistance. The clinical course of the illness in patients who die is characterized by pulmonary edema accompanied by severe hypotension, frequently terminating in sinus bradycardia, electromechanical dissociation, ventricular tachycardia, or fibrillation. Hypotension may be progressive even with adequate oxygenation. HPS virus is excreted in the urine during the acute illness phase, and survivors may demonstrate evidence of chronic renal damage.

Diagnosis

The diagnosis of HPS should be considered in a previously healthy patient presenting with a febrile prodrome and acute respiratory distress. Occurrence of thrombocytopenia with the febrile prodrome and outdoor exposure in the spring and summer months are strongly suggestive of HPS. Specific diagnosis of HPS is made by serologic tests that detect Hantavirus immunoglobulin M antibodies. Hantavirus antigen can be detected in tissue by immunohistochemistry and amplification of Hantavirus nucleotide sequences detected by reverse transcriptase polymerase chain reaction. The state health department or the Centers for Disease Control and Prevention should be consulted to assist in diagnosis, epidemiologic investigations, and outbreak control.

Laboratory Findings

Laboratory findings include leukocytosis (median 26,000 cells/µL), elevated hematocrit resulting from hemoconcentration, thrombocytopenia (median 64,000 cells/µL), prolonged prothrombin and partial thromboplastin times, elevated serum lactate dehydrogenase concentration, decreased serum protein concentrations, proteinuria, and microscopic hematuria. Patients who die often experience disseminated intravascular coagulopathy including frank hemorrhage and exceptionally high leukocyte counts.

Differential Diagnosis

The differential diagnosis includes adult respiratory distress syndrome, pneumonic plague, psittacosis, severe mycoplasmal pneumonia, influenza, leptospirosis, inhalation anthrax, rickettsial infections, pulmonary tularemia, atypical bacterial and viral pneumoniae, legionellosis, meningococcemia, and other sepsis syndromes. The key determinant in the diagnosis of HPS is thrombocytopenia.

Treatment

Management of patients with Hantavirus infection requires maintenance of adequate oxygenation and careful monitoring and support of cardiovascular function. The pathophysiology of HPS resembles that of dengue shock syndrome (Chapter 261). Pressor or inotropic agents, such as dobutamine, should be administered in combination with judicious volume replacement to treat symptomatic hypotension or shock while avoiding exacerbation of the pulmonary edema. Intravenous ribavirin, which is lifesaving if given early in the course of HFRS, has been shown to be of no value in HPS.

Further information and advice about management, control measures, diagnosis, and collection of biohazardous specimens can be obtained from the Centers for Disease Control and Prevention, National Center for Infectious Diseases, Special Pathogens Branch, Atlanta, Georgia 30333 (404-639-1115).

Prognosis

In some geographic areas fatality rates for HPS have been 50%. Severe abnormalities in hematocrit, white blood cell count, lactate dehydrogenase value, and partial thromboplastin time, and high viral load predict death with high specificity and sensitivity.

Prevention

Avoiding contact with rodents is the only preventive strategy against HPS. Rodent control in and around the home is important. Barrier nursing is advised, and biosafety level 3 facilities and practices are recommended for laboratory handling of blood, body fluids, and tissues from suspect patients or rodents, because the virus may be aerosolized.

Armstrong LR, Bryan RT, Sarisky J, et al. Mild hantaviral disease caused by Sin Nombre virus in a four-year-old-child. Pediatr Infect Dis J. 1995;12:1108-1110.

Bryan RT, Doyle TJ, Moolenaar RL, et al. Hantavirus pulmonary syndrome in children. Semin Pediatr Infect Dis. 1997;8:44-49.

Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome: five states, 2006. MMWR Morb Mortal Wkly Rep. 2006;55:627-628.

Childs JE, Ksiazek TG, Spiropoulou CF, et al. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new Hantavirus in the southwestern United States. J Infect Dis. 1994;169:1271-1280.

Figueiredo LT, Moreli ML, de-Sousa RL, et al. Hantavirus pulmonary syndrome, central plateau, southeastern and southern Brazil. Emerg Infect Dis. 2009;15:561-567.

Godoy P, Marsac D, Stefas E, et al. Andes virus antigens are shed in urine of patients with acute Hantavirus cardiopulmonary syndrome. J Virol. 2009;83:5046-5055.

Khan AS, Khabbaz RF, Armstrong LR, et al. Hantavirus pulmonary syndrome: the first 100 U.S. cases. J Infect Dis. 1996;173:1297-1303.

Pergam SA, Schmidt DW, Nofchissey RA, et al. Potential renal sequelae in survivors of Hantavirus cardiopulmonary syndrome. Am J Trop Med Hyg. 2009;80:279-285.

Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis. 2002;34:1224-1231.

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