Hantavirus Pulmonary Syndrome

Etiology

Hantaviruses were first discovered in the early 1950s by soldiers involved in the Korean War. They named the condition "Hantaan" because of the nearby Hantaan River, where most cases reportedly occurred. The most common virus strain in North America is the Sin Nombre virus, predominantly transmitted by the deer mouse (Peromyscus maniculatus) in the southwestern United States. This virus was found after a cluster of hantavirus cases occurred in 1993. In South America, the predominant strain is the Andes virus, which is especially virulent and the only strain known to cause human-to-human infection.[5]

Hantaviruses (genus Orthohantavirus) are enveloped, negative-sense, single-stranded ribonucleic acid (RNA) viruses. Components include a large viral segment encoding an RNA-dependent RNA polymerase, a glycoprotein precursor, and a nucleoprotein. The virion size ranges from 70 to 160 nm.[2] Hantaviruses infect endothelial, epithelial, dendritic, and lymphocyte cells by attaching the viral glycoprotein to the cell surface receptors.[7]

Immature dendritic cells likely serve as carriers for the virus through lymphatic tissue and allow further viral replication once at the regional lymph nodes. In addition, once exposed to the endothelial cells, immune activation is induced, especially by CD8+ T cells and macrophages.

Hantaviruses induce the maturation of infected dendritic cells and elicit a profound T-cell response in the acute infection phase, unlike other hemorrhagic fever viruses that inhibit dendritic cell maturation.[3]

Critical adhesive receptors, beta-3 integrins, regulate platelet activation and vascular permeability and mediate hantaviruses' cellular entry. Invasion of the endothelium is believed to induce interferon-alpha (IFN-α), which is possibly the cause of the prodromal manifestations. Once the infection has progressed, immunoblasts may be seen in the peripheral blood smear. T cell clones will be hantavirus-specific. Activated macrophages, in conjunction with these immunoblasts, will migrate to the interstitium of the lung. Capillary endothelial permeability greatly increases after the secretion of tumor necrosis factor-alpha (TNF-α), IFN-γ, and nitric oxide, which results in pulmonary edema. Soluble mediators such as TNF-α, IFN-γ, and nitric oxide are suggested as etiologies of myocardial depression in this infection, resulting in cardiogenic shock.

Epidemiology

HPS is the primary form of Hantavirus syndrome in North and South America. In the United States, sporadic cases of Hantavirus have been seen as far east as Maine, but most of the 697 cases (as of January 2017) were west of the Mississippi River. Seven states account for approximately 70% of all cases reported in the United States, with the most cases in New Mexico (109 cases), Colorado (104 cases), Arizona (77 cases), California (63 cases), Washington (47 cases), Texas (42 cases), and Montana (41 cases).

The following list of Hantavirus presentations contains the virus serotype, specific rodent vector, and geographic distribution:

• Sin Nombre Virus: Peromyscus maniculatus, Canada, United States—the major cause of Hantavirus in Canada and the United States
• New York Virus; Peromyscus leucopus, eastern United States
• Monongahela Virus: Peromyscus maniculatus nubiterrae, eastern United States
• Bayou Virus: Oryzomys palustris, southeastern United States
• Black Creek Canal Virus: Sigmodon hispidus, Florida, United States
• Laguna Negra: Calomys laucha, Paraguay, Bolivia—first South American Hantavirus isolated
• Andes: Oligoryzomys longicaudatus, Argentina, Chile, Uruguay—only Hantavirus with a person-to-person transmission reported
• Oran: Oran longicaudatus; northern Argentina—regularly causes disease in cane-growing areas
• Choclo: Oligoryzomys fulvescens, Panama
• Rio Mamore: Neacomys spinosus, Peru
• Lechiguanas: Oligoryzomys flavescens, Argentina

The literature suggests that around 50% of infections are due to exposure in or around the home, 10% from the workplace, and 5% during recreation. The rest of the exposures are from mixed or unknown causes.[3]

Pathophysiology

Pathophysiology of HPS includes:

• Inhalation of the infectious virus can result in viral deposition in the alveoli or terminal bronchioles. Viremia is likely generated after infection of alveolar macrophages or other primary targets, resulting in widespread infection of the pulmonary capillary endothelium. 
• Replication within the vascular endothelium does not have direct cytopathic effects. Instead, tissue injury appears due to the immune response and viral replication.
• Increased viral RNA causes a cytokine storm, ultimately leading to vascular permeability and pulmonary edema.
• Upon the development of pulmonary edema, multiorgan failure may ensue.

History and Physical

Patients usually present after contact with rodents, feces, or a rodent bite. Farmers, those in forestry occupations, or people with a history of cleaning rodent-infested areas are especially vulnerable. Those who have close contacts of such persons are also at risk. Initial complaints are often flu-like and nonspecific.[8] 

Normal presentation is around 7 to 39 days after viral exposure, and initial symptoms include a prodrome of headache, myalgia, vomiting, and abdominal pain. About 3 to 6 days after the initial prodromal phase, respiratory compromise can quickly develop, involving dyspnea, pulmonary edema, hypotension, and shock.[2] Respiratory compromise often occurs within 48 hours and rapidly turns into respiratory failure. Bilateral, diffuse interstitial pulmonary edema is characteristically seen radiographically. Cardiovascular collapse is possible during this stage.[4] Patients often develop metabolic acidosis due to severe infection. Descent into the pulmonary syndrome carries a mortality rate of around 50% to 70%.[9] Other possible signs are decreased urine output, petechiae, and hemorrhage.

Evaluation

A chest x-ray may demonstrate bilateral pulmonary edema on the initial radiograph in about one-third of patients; however, nearly all patients will have findings of interstitial edema at 48 hours after admission. Almost two-thirds of patients will develop bibasilar opacities or perihilar opacities with some degree of pleural effusions.

Thrombocytopenia may be present on blood count once admission is necessary for staging the disease and helps predict disease progression.[8] Other critical laboratory findings include circulating immunoblasts, atypical lymphocytes, and elevated hematocrit. Once the patient needs hospitalization, a peripheral blood smear may demonstrate myelocytes, metamyelocytes, and promyelocytes with severe thrombocytopenia and hypocapnia. Hyponatremia may also be present along with slightly prolonged activated partial thromboplastin time, a decreased protein level, mildly elevated low-density lipoprotein level, and microscopic hematuria. Diagnosis can be made by immunofluorescent or immunoblot assay. An enzyme-linked immunosorbent assay utilizing immunoglobulin M is preferred. Quantitative polymerase chain reaction is also an option.[3]

Treatment / Management

Treatment is supportive (namely, with aggressive cardiopulmonary support). Key treatment features are as follows:

• Symptom intensity often drives patients to seek medical attention, but lack of significant findings necessitating admission often results in supportive care for discharge. 
• Respiratory failure can be severe, with around 40% of cases requiring mechanical ventilation.
• Extracorporeal membrane oxygenation for advanced HPS has been used at the University of New Mexico with a 70% success rate if intervention was early. However, given the condition's rarity, clinical trials cannot establish efficacy.[9]
• Despite appropriate treatment in intensive care units, around one-third of patients will die in the first 48 hours after admission. 
• Almost half of the patients admitted with Hantavirus will not require mechanical ventilation via intubation if appropriately managed with judicious fluids and close monitoring. 
• Ribavirin has been proposed as a treatment option with some benefit to inhaled ribavirin; overall effectiveness has yet to be proven. 
• Fluid balance should be attempted to maintain normal-high filling pressures for cardiac output and minimize pulmonary edema.
• Inotropic agents such as dobutamine are encouraged early. 
• Death is often associated with disseminated intravascular coagulation, which includes frank hemorrhage and drastic leukocytosis. 
• Should patients improve in the first few days, there is a good probability of extubation within the first week.
• Vaccines have been used in China and Korea, but long-term results are unavailable.[9][10][11][12]
(B2)

Differential Diagnosis

Acute Respiratory Distress Syndrome 

• Acute onset of dyspnea with bilateral chest x-ray non-cardiogenic infiltrates and partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen concentration (PaO₂/FiO₂) less than 300.
• There is difficulty delineating acute respiratory distress syndrome from Hantavirus. 
• The inciting factors must be evaluated.
• Management is similar in terms of respiratory support.

Mycobacterial Pneumonia

• If the patient requires mechanical ventilation and bronchoalveolar lavage is obtained, other presenting pathogens may guide antibiotic therapy.
• Broad-spectrum antibiotic treatment has not been shown to change the outcomes of Hantavirus for better or worse.

Influenza Pneumonia

• Influenza polymerase chain reaction (PCR) helps rule in influenza pneumonia instead of Hantavirus.

Viral Hemorrhagic Fevers

• Specific PCRs are necessary to diagnose a single etiology.
• Treatment is supportive care in the intensive care unit.

Pertinent Studies and Ongoing Trials

Pertinent studies include the following:

• Fresh frozen plasma from patients who have recovered from HPS has been used with good effect (eg, results from a study showed a decrease in mortality from 32% to 14%).[2] 
• Animal studies are being conducted that use recombinant antibodies to the Hantavirus.[2]
• Hantavax has been used in Asia since the 1990s; this is believed to effectively decrease the incidence of new cases.[13]

Staging

By the time a patient requires hospitalization, transformation into the second stage of the disease has most likely already developed, with cough and vomiting dominating the clinical presentation. Orthostatic hypotension, tachycardia, and tachypnea will likely all be present. Platelet count is the first significant abnormal laboratory test, which is also the most useful. Thrombocytopenia or decreasing platelet count warrants admission to the hospital for further evaluation. Hematuria has been noted as a marker of kidney injury but has not been correlated with thrombocytopenia.[14][15][16]

Prognosis

Despite appropriate treatment in the intensive care unit, around one-third of patients will die in the first 48 hours after admission. However, almost half of the patients admitted with Hantavirus will not require mechanical ventilation via intubation if appropriately managed with judicious fluids and close monitoring.Should patients improve within the first few days, there is a good probability of extubation within the first week, and there are often no major long-term complications. However, subjective complaints of dyspnea, fatigue, and myalgias may occur. Higher titers of antibodies neutralizing the viral nucleocapsid immune complexes correlate with a higher likelihood of survival.