Clinlab Navigator

H1N1 Influenza A Virus

A swine-origin influenza A virus has been identified as the cause of outbreaks of the febrile respiratory infection that has spread throughout the world since April 2009. As of October 3, 2009, 99% of circulating influenza viruses in the United States were 2009 H1N1 influenza. This virus has genes from human, swine and avian influenza A viruses and has been called novel influenza A (H1N1).

Age-specific attack rates for 2009 novel influenza A (H1N1) virus infection cases are higher in younger persons and lower in older persons, compared with seasonal influenza infections. Older persons, as a group, might have preexisting immunity to the 2009 H1N1 virus. One small study indicated that approximately one third of adults aged >60 years had cross-reactive antibody to 2009 influenza A (H1N1) virus detected, compared with none detected among children. Another factor might be higher contact rates among teenagers.

Clinical Course

The most common symptoms are fever and cough, followed by sore throat and shortness of breath. Other symptoms include headache, rhinorrhea, myalgias, arthralgias, fatigue, vomiting, and diarrhea.

Worldwide, the majority of patients infected with the pandemic virus continue to experience mild symptoms and recover fully within a week, even in the absence of any medical treatment. A small subsets of patients have rapidly developed very severe progressive pneumonia. The risk of severe or fatal illness appears to be highest in three groups: pregnant women, especially during the third trimester of pregnancy, children younger than 2 years of age, and people with chronic lung disease, including asthma. Neurological disorders can increase the risk of severe disease in children. However, many severe cases have occurred in previously healthy young people. Predisposing factors that increase the risk of severe illness in this population have not been identified.

Disadvantaged populations, such as minority groups and indigenous populations, have been disproportionately affected by severe disease. Obesity and especially morbid obesity have been present in a large portion of severe and fatal cases. Obesity has not been recognized as a risk factor in either past pandemics or seasonal influenza.

Primary viral pneumonia is the most common finding and is often associated with organ failure or marked worsening of underlying asthma or chronic obstructive airway disease. Secondary bacterial infections have been found in approximately 30% of fatal cases. Bacteria frequently reported include Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant strains in some cases. Respiratory failure and refractory shock have been the most common causes of death.

In severe cases, patients generally begin to deteriorate around 3 to 5 days after symptom onset. Deterioration is rapid, with many patients progressing to respiratory failure within 24 hours, requiring immediate admission to an intensive care unit. Upon admission, most patients need immediate respiratory support with mechanical ventilation. However, some patients do not respond well to conventional ventilatory support, further complicating the treatment. Prompt treatment with the antiviral drugs, oseltamivir or zanamivir, reduces the severity of illness and improves the chances of survival

Contagiousness

Seasonal human influenza viruses are thought to spread from person to person primarily through large-particle respiratory droplet transmission (e.g., coughing or sneezing near a susceptible person). Transmission via large particle droplets requires close contact between source and recipient persons because droplets do not remain suspended in the air and generally travel less than 6 feet. Contact with respiratory-droplet contaminated surfaces is another possible source of transmission. All respiratory secretions and bodily fluids should be considered potentially infectious. Incubation period is 1 to 7 days.

The duration of shedding with novel influenza A (H1N1) virus is unknown, but is probably similar to seasonal influenza virus infection. Persons with novel influenza A (H1N1) virus infection should be considered potentially contagious from 1 day before to 7 days following illness onset. Persons who remain ill longer than 7 days should be considered potentially contagious until symptoms have resolved. Children might be contagious for longer periods, up to 10 days.

CDC recommends that people with influenza-like illness remain at home (except when necessary to seek required medical care) until at least 24 hours after they are free of fever (100° F [37.8°C]), or signs of a fever without the use of fever-reducing medications. This recommendation applies to camps, schools, businesses, mass gatherings, and other community settings where the majority of people are not at increased risk for influenza complications. Keeping people with a fever at home may reduce the number of other individuals who get infected, since elevated temperature is associated with increased shedding of influenza virus. CDC recommends this exclusion period regardless of whether or not antiviral medications are used.

Infection Control

Patients with influenza like illness should be separated from patients without influenza.Hospitalized patients should be placed in a single-patient room with the door kept closed. If available, an airborne infection isolation room with negative pressure air handling can be used.Doors to patient rooms with influenza like illness should remain closed as much as possible. Surfaces should be disinfected frequently. The ill person should wear a surgical mask when outside of the patient room, and should be encouraged to wash hands frequently and follow respiratory hygiene practices. Staff should stay home if they are ill.

All waiting areas should be segregated to the extent possible. All visitors who exhibit signs and symptoms of influenza like illness should be asked to put on a surgical mask, instructed in respiratory etiquette and instructed not to visit patient care areas if their presence is not critical to a patient's emotional well being.

Standard, Droplet and Contact precautions should be used for all patient care activities and maintained for 7 days after illness onset or resolution of symptoms, whichever is longer. Personnel providing care to or collecting clinical specimens from suspected or confirmed cases should wear disposable non-sterile gloves, gowns, surgical mask, and eye protection to prevent conjunctival exposure.Healthcare workers should wash their hands with soap and water or use hand sanitizer immediately after removing gloves and other equipment and after any contact with respiratory secretions.

Personnel engaged in aerosol generating activities (e.g. collection of clinical specimens, endotracheal intubation and extubation, nebulizer treatment, bronchoscopy, open suctioning of airways, resuscitation involving emergency intubation or cardiac pulmonary resuscitation and autopsies) should wear a fit-tested disposable N95 respirator or Powered Air Purifying Respirator (PAPR) in addition to standard precautions. Only personnel who are essential to patient care should be present during these procedures.These procedures should be conducted in a negative pressure room if possible. There is currently no recommendation for reuse of surgical or N95 masks due to the risk of inoculating the virus into the eyes.

Treatment

Influenza antiviral medications can reduce the severity and duration of influenza illness and can reduce the risk of influenza-related complications, including severe illness and death. For antiviral treatment of 2009 H1N1 virus infection, either oseltamivir or zanamivir is recommended. CDC guidance states that most healthy persons who develop an illness consistent with uncomplicated influenza, or persons who appear to be recovering from influenza, do not need antiviral medications for treatment. However, persons presenting with suspected influenza and more severe symptoms such as evidence of lower respiratory tract infection or clinical deterioration should receive prompt empiric antiviral therapy, regardless of previous health or age. Antiviral treatment is also recommended for all persons with suspected or confirmed influenza requiring hospitalization. In addition, early empiric antiviral treatment should be considered for persons with suspected or confirmed influenza who are at higher risk for complications including:

• Children younger than 2 years old;
• Persons aged 65 years or older;
• Pregnant women and women up to 2 weeks postpartum (including following pregnancy loss);
• Persons of any age with certain chronic medical or immunosuppressive conditions and,
• Persons younger than 19 years of age who are receiving long-term aspirin therapy.

Chronic medical conditions include pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurologic, neuromuscular or metabolic disorders (including diabetes mellitus)

Children 2 year to 4 years old are more likely to require hospitalization or urgent medical evaluation for influenza compared with older children and adults, although the risk is much lower than for children younger than 2 years old. Children aged 2 years to 4 years without high risk conditions and with mild illness do not necessarily require antiviral treatment.

The Centers for Disease Control (CDC) recommends treatment with oseltamivir as soon as possible after the onset of influenza symptoms. Treatment is most beneficial if it is started within 48 hours of onset. Data from studies on seasonal influenza indicate benefit for hospitalized patients even if treatment is started more than 48 hours after onset. Treatment should not be delayed while waiting for the results of viral testing. The recommended duration of treatment is five days.

Some cases of oseltamivir resistant H1N1influenza have been reported worldwide. All of them have the same genetic mutation in the neuraminidase gene, known to be associated with resistance to oseltamivir. So far, all of these cases have been susceptible to zanamivir.

Chemoprophylaxis

The widespread use of antiviral medications for chemoprophylaxis is not encouraged due to the concern of developing resistance. Antiviral chemoprophylaxis should generally be reserved for persons at higher risk for influenza-related complications who have had close contact with someone likely to have been infected with influenza. Early treatment is an alternative to chemoprophylaxis after a suspected exposure. Household or close contacts (with risk factors for influenza complications) of confirmed or suspected cases can be counseled about the early signs and symptoms of influenza, and advised to immediately contact their healthcare provider for evaluation and possible early treatment if clinical signs or symptoms develop. Early recognition of illness and treatment when indicated is preferred to chemoprophylaxis for vaccinated persons after a suspected exposure.

Vaccination

Four influenza vaccine manufacturers have received approval from the Food and Drug Administration (FDA) for their 2009 H1N1 monovalent influenza vaccines. Both live, attenuated and inactivated influenza vaccine formulations have been approved. Because the initially available quantities of these vaccines are limited, they are being given to persons in the following priority groups:

• Pregnant women,
• Persons who live with or provide care for infants aged <6 months (e.g., parents, siblings, and daycare providers),

• Health-care and emergency medical services personnel who have direct contact with patients or infectious material,
• Children aged 6 months - 4 years, and

• Children and adolescents aged 5 - 18 years who have medical conditions that put them at higher risk for influenza-related complications. These conditions include chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematologic, or metabolic disorders (including diabetes mellitus); or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus).

Once vaccine availability increases, the following five groups will then be prioritized to receive the vaccine:

• Pregnant women,
• People who live with or provide care for infants younger than 6 months of age (e.g., parents, siblings, and day care providers),

• Health care and emergency medical services personnel,
• People 6 months through 24 years of age, and,

• People 25 years through 64 years of age who have certain medical conditions that put them at higher risk for influenza-related complications.

Then, when vaccination programs and providers are meeting the demand for vaccine among persons in these target groups, vaccination should be expanded to all persons aged 25-64 years.

Finally, once demand for vaccine among younger age groups is being met, vaccination should be expanded to all persons aged ≥65 years.

Testing

The CDC recently updated testing recommendations for novel H1N1 influenza A (MMWR 58(30);826-829, 8/7/09 and www.cdc.gov/h1n1flu/guidance/rapid_testing.htm).A number of different laboratory diagnostic tests can be used for detecting the presence of influenza viruses in respiratory specimens, including direct antigen detection tests, virus isolation in cell culture, or detection of influenza-specific RNA by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR).These tests differ in their sensitivity and specificity in detecting influenza viruses as well as their ability to distinguish between different influenza virus types (A versus B) and influenza A subtypes (e.g. novel H1N1 versus seasonal H1N1 versus seasonal H3N2 viruses).

Rapid influenza diagnostic tests are antigen detection tests that detect influenza viral nucleoprotein antigen. The major advantage of rapid tests is that they can provide results within 30 minutes or less. Rapid tests can either:i) detect and distinguish between influenza A and B viruses; ii) detect both influenza A and B viruses but not distinguish between them; or, iii) detect only influenza A viruses. None of them can distinguish between influenza A virus subtype.

For detection of seasonal influenza A virus infection in respiratory specimens, rapid tests have low to moderate sensitivity compared to viral culture or rRT-PCR. The sensitivity for influenza B is lower than influenza A viruses.Higher sensitivity is obtained with specimens collected from children than from adults.

Three recent analytical studies indicate that commercially available RIDTs are reactive with the nucleoprotein of novel influenza A (H1N1) virus. Rapid tests have variable sensitivity (40-70%) for novel H1N1 flu, with optimal performance when testing occurred in the first 3 days of illness. The CDC has concluded that a positive rapid influenza result can be useful in making treatment decisions, however, a negative result does not rule out infection. Rapid influenza testing can be performed on nasopharyngeal swabs or aspirates.

The CDC recommends that when definitive determination of influenza infection is necessary, rRT-PCR testing should be performed. Two PCR testing options for novel influenza A H1N1 are available. One option includes a screening PCR test for influenza A and B, followed by reflex testing for H1N1 when the screening PCR is positive for influenza A. There is an additional charge when the reflex testing is performed. The second option is PCR testing for influenza A only with H1N1 reported specifically when present. Acceptable specimens for PCR testing are nasopharyngeal swabs or aspirates. Turnaround time for influenza PCR testing is 48-72 hours.

It is not necessary to collect two specimens for influenza testing, unless both rapid testing and PCR testing are needed. Acceptable swabs for influenza testing include sterile Dacron, rayon, or nylon swabs with plastic shafts. All specimens should be placed in viral transport media and refrigerated or transported to the laboratory immediately. A summary of currently available influenza testing is as follows:

Test	Physician should order	Comments
Rapid Influenza A & B	Rapid flu A & B	A negative result does not exclude influenza infection of any type.
PCR for Influenza A & B with reflex testing for novel H1N1 influenza A	Influenza A, B & H1N1 PCR	Detects seasonal influenza A & B and the novel H1N1 strain
PCR for novel H1N1 Influenza A	Influenza A H1N1 PCR	Detects all influenza A strains with novel H1N1 reported when present