I.

INTRODUCTION

2.1 Background
Hantaviruses are classified in the Hantavirus genus of the Bunyaviridae
family. The viruses are found worldwide and cause two serious and often fatal
human disease. There are Hemorrhagic fever with renal failure (HFRS) and
Hantavirus pulmonary syndrome (HPS). Estimated there are 100.000-200.000
cases of hanta virus infection annually worldwide. There are several distinct
hantaviruses, each associated with a specific rodent host. Hantavirus pulmonary
syndrome (HPS) will specifically discuss in this paper1.
In the 1993 an outbreak of severe respiratory illness occurred in United
States, now designated the Hantavirus pulmonary syndrome (HPS). It was found to
be caused by novel hantavirus (Sin Nombre Virus). This agent was the first
hantavirus recognized to cause disease in North America and the first to cause
primarily an adult respiratory distress syndrome. Since that time, numerous
hantaviruses have been detected in rodents in north, central, and South America.
The primary rodent reservoir for Sin Nombre Virus is The deer mouse
(Peromyscus maniculatus). Deer mice are widespread and about 10% of those
tested show evidence of infection with Sin Nombre Virus. The virus infection in
rodents are lifelong and without deleterious effects. Transmission among rodents
seem to occur horizontally, and transmission to humans occurs by inhaling aerosols
of rodents excreta (urine, feces, saliva). There are also other hantaviruses known to
cause HPS in the United State. The presence of hantavirus-associated disease is
determined by geographic distribution of the rodent reservoirs. Thereafter, several
other hantaviruses with the ability to cause severe human disease were discovered
in rodents in the Americas, with SNV and Andes virus (ANDV) predominating in
North and South America respectively2.
HPS is generally severe, with reported mortality rates of 30% or greater3.
Infection with hantaviruses are not common, and subclinical infections appear to be
unusual, particularly with Sin Nombre virus. The fatality rate is substantially higher
than that of other hantavirus infection. The disease begins with fever, headache, and

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myalgia, followed by rapidly progressive pulmonary edema, often leading to severe
respiratory compromise. Pathogenesis of HPS involves the functional impairment
of vascular endothelium. Person to person transmission of hantaviruses seldom
occurs, though it has been observed during outbreaks of HPS caused by Andes
virus.

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 II CONTENT

2.1 Clinical Manifestation

Hantavirus pulmonary syndrome (HPS) has long incubation period and
followed by rapid onset of severe pulmonary disease4. This syndrome is
characterized by four phases of disease:
1. Prodrome Phase
This Phase is characterized by febrile prodrome with the body temperature is
greater than 38,30 C lasting 3-7 days. Other non-specific complaints that may
occur are chills, infrequent headache, dizziness, non-productive cough,
myalgia, nausea, vomiting, abdominal pain, and other gastrointestinal
symptoms5,6.
2. Cardiopulmonary
Three to six days after the onset of initial symptoms the patient will enter the
cardiopulmonary phase. This phase involves symptoms which are cough and
shortness of breath, hypoxemia, cough, pleural effusion, gastrointestinal
symptoms, tachypnea (generally 26 to 30 breaths per minute), tachycardia,
myocardial depression, and cardiogenic shock. Oliguria may occur due to acute
tubular necrosis (ATN) but it is uncommon. Pulmonary edema and weakening
of cardiopulmonary function may then rapidly occur during the next 24 hours.
These changes indicate the development of worsening cardiopulmonary
disease and require hospitalization and mechanical ventilation in as little as 24
hours. Death can occur within 48 hours due to respiratory failure, myocardial
dysfunction and shock. Approximately 30-40% of HPS cases result in death,
usually within a few days of the initial symptoms4,5,6,7.
3. Diuretic
Patients who can survive the cardiopulmonary phase, they undergo to the third
(diuretic) phase and followed by rapid improvement, so their prognosis is
much better. Over two to four days, occur rapid clearance of pulmonary edema.
Other symptoms such as fever and shock also resolve6.

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 4. Convalescent
Patients who have entered the convalescent phase will have persistent
weakness, fatigue and abnormal pulmonary function (abnormal diffusion
capacity of the lungs) can last for months or years to fully normalize4.
The clinical presentation of HPS disease and the case fatality rate vary with
the strain of infecting hantavirus5.

2.2 Diagnosis Microbiology

According to the Centers for Disease Control and Prevention, a laboratory
diagnosis of HPS is based on a positive serological test result, evidence of viral
antigen in tissue by immunohistochemistry, or the presence of amplifiable viral
RNA sequences in blood or tissue, with a compatible history of HPS8.
1. Radiological findings
Characteristic radiologic findings begin with minimal changes of interstitial
pulmonary edema and progress into alveolar edema with severe bilateral
involvement. Pleural effusions are often large enough to be seen
radiographically. The common findings are Kerley B fines (short linear
opacities which are perpendicular to the pleural surfaces), peribronchial cuff,
and alveolar interstitial fluid in the basal segments. About one-third of the
patients show evidence of pulmonary edema in the initial radiograph, and
nearly all patients demonstrate interstitial edema 48 hours after the initial
radiograph and two-thirds have developed extensive bibasilar or peripheral
airspace disease.
2. Laboratory findings
The CDC recommends drawing a complete blood count and serum chemistry
panels every 8 to 12 hours in patients with suspected HCPS.
Thrombocytopenia is one of the earliest and most sensitive laboratory findings,
occurring as early as the prodromal phase and seen in more than 80% of
patients. Thrombocytopenia with platelet counts less than 15x109/L is
observed. Initially, the white blood count may be normal or elevated with
progression to very high levels. Leukocytosis with neutrophilia, a left shift

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 (possibly as high as 50%), and atypical lymphocytes. Immature granulocytes,
up to 50%, immunoblasts, and hemoconcentration are commonly seen at the
onset of pulmonary edema. Other laboratory findings include elevated
creatinine, elevated blood urea nitrogen (BUN), proteinuria, abnormal urinary
sediment, elevated hepatic enzymes with normal bilirubin levels,
hypoalbuminemia, metabolic acidosis, slightly elevated aspartate
aminotransferase, elevated lactate dehydrogenase, and in severe cases, lactic
acidosis.12-15 In most severe cases of HPS, disseminated intravascular
coagulation (DIC) develops. Therefore, abnormal partial thromboplastin time,
prolonged thrombin time, decreased fibrinogen, elevated fibrin split products,
and elevated prothrombin time (PT) may be observed. The prognosis is poor
when metabolic acidosis, prolonged PT, partial thromboplastin time (PTT), and
rising serum lactate levels develop.
3. Enzyme-Linked Immunosorbent Assay
Nucleoprotein (N protein), the most antigenic hantavirus protein, is detectable
early in the infection course and participates in the viral replication. Current
diagnostic methods for HPS include molecular and serological assays using
mainly monoclonal antibodies or hantavirus nucleoprotein (N) to detect IgM
and IgG in patient serum. IgM capture enzyme-linked immunosorbent assay
(ELISA), a widely used serological test, detects antibodies in acute infection.
The ELISA methodology also detects IgG antibody detection; therefore, acute
and convalescent phase infections can be identified by a four-fold rise in IgG
titer. The ELISA IgG has been found to be the most appropriate serological test
in epidemiological investigations of the disease, because patients who have
recovered from HPS retain the antibody for many years.
4. Immunohistochemistry
Immunohistochemistry (IHC) has been proven to be very valuable and plays an
important role in diagnosis when serum samples and frozen tissues are
unavailable. IHC tests formalin-fixed tissues with specific monoclonal and
polyclonal antibodies to detects antigens. This method has been proven to be a
sensitive method for laboratory confirmation, and is also useful in the

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 retrospective assessment of disease prevalence in a specified geographic
location.
5. Reverse Transcriptase-Polymerase Chain Reaction
Reverse transcriptase-polymerase chain reaction (RT-PCR) can detect
Hantavirus RNA in fresh-frozen lung tissues, blood clots, nucleated blood
cells, or buffy coats. It has been proven as a reliable diagnostic test at early
stages and could be used to direct the decision-making process more
efficiently. Also, an accurate and faster diagnosis is important in the
reinforcement and adherence to isolation precautions in the health personnel to
avoid nosocomial transmission4,8,9.

2.3 Management
There are no proven antiviral therapies therapies for hantavirus pulmonary
syndrome and vaccines are currently not available10. Currently the management is
primarily supportive in nature, also the physician must pay careful attention to acid-
base disturbances and fluid balance11. Some clinical management for patients with
hantavirus Pulmonary Syndrome are :
1. Intubation
The insertion of a tube into patient’s airway to protect the airway from
collapsing12. Basically intubation is a procedure where a tube is inserted
through the mouth down into the trachea to help the patient breath.
2. Mechanical Ventilation
Mechanical ventilation can be defined as the technique through which gas is
moved toward and from the lungs through an external device connected
directly to the patient. The clinical objectives of mechanical ventilation can be
highly diverse: To maintain gas exchange, to reduce or substitute respiratory
effort, to diminish the consumption of systemic and/or myocardiac O2, to
obtain lung expansion, to allow sedation, anesthesia and muscle relaxation, and
to stabilize the thoracic wall, etc13.
3. Extracorporeal Membrane Oxygenation (ECMO)

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 Extracorporeal membrane oxygenation (ECMO) is a procedure that uses an
artificial heart-lung machine to take over the work of the lung, in which a
cannula is the jugular vein is connected to a small reservoir, into which the
blood drains by gravity: the blood then pumped from the reservoir through a
membrane oxygenator and heat exchanger, and return to the Pt via the right
carotid artery cannula14. ECMO is used most often in newborns and young
children, but it also can be use as last resort for adults whose heart or lungs are
failing15.
4. Ribavirin
Ribavirin is an antiviral agent that acts against many RNA and DNA virus by
inhibiting protein synthesis and replication16. Its usually used only for aerosol
therapy to treat acute lower respiratory infections resulting from respiratory
syncytial virus. Ribavirin has been used to treat patients with Hanta Pulmonary
Syndrome, but its efficacy remains unproven11.