Interim Information for Clinicians about Human Infections with H3N2v Virus

Background

Influenza A viruses circulating in pigs that have infected humans are referred to as “variant” viruses. Human infections with an influenza A (H3N2) variant (H3N2v) virus that contains the M gene from the influenza A(H1N1)pdm09 virus (2009 H1N1 pandemic virus) were first detected in 2011. Notably, a large increase in cases of H3N2v virus infection has been identified since July 2012. (This virus has been circulating among pigs in the U.S. since 2010, has been detected in pigs in many states, and appears to be circulating widely in swine in the U.S.) The majority of H3N2v cases have been in children, although some adults have been infected, and linked to recent direct or indirect exposure to pigs. Almost all of the H3N2v cases in 2012 were epidemiologically linked to agricultural fairs, either through exhibiting pigs or walking through a swine barn. Occupational exposure to pigs was reported in one H3N2v case. Limited, non-sustained human-to-human transmission of H3N2v virus was first reported in 2011, including in households and a child care setting. Some H3N2v case-patients have been hospitalized, including previously healthy people and persons with chronic underlying conditions, and one death has been reported. (MMWR, September 27, 2012: Influenza A (H3N2) Variant Virus-Related Hospitalizations – Ohio, 2012. MMWR 2012; 61(38);764-767.)

For updated information on confirmed H3N2v cases, hospitalizations and deaths, see Case Count: Detected U.S. Human Infections with H3N2v by State since August 2011.

CDC is monitoring the situation closely with state health departments and will issue updates accordingly as additional information is available.

Clinical Presentation and Risk Groups

Clinical characteristics of human cases of influenza A (H3N2) variant virus infection generally have been similar to signs and symptoms of uncomplicated seasonal influenza, including fever, cough, pharyngitis, rhinorrhea, myalgia, and headache. Vomiting and diarrhea have also been reported in some pediatric cases. Milder clinical illness is possible, including lack of fever. The duration of illness in most cases appears to be similar to uncomplicated seasonal influenza, approximately 3-5 days. While assumed to be similar to seasonal influenza virus infection, the duration of viral replication and possible infectiousness in H3N2v cases has not been studied.

Exacerbation of underlying conditions (e.g. asthma) has occurred. The same people at increased risk for complications of seasonal influenza are likely at high risk for serious complications from H3N2v virus infection, including children aged <5 years, pregnant women, people 65 years and older, those who are immunosuppressed, and persons with chronic pulmonary, cardiac, metabolic, hematologic, renal, hepatic, neurological or neurodevelopmental conditions, as well as those with other co-morbidities, including morbid obesity.

Limited serologic data suggest that children born after 2001 (age ≤9 years at 2010) lack immunity to H3N2v virus and therefore are likely to be most susceptible to H3N2v virus infection. Adolescents and younger adults may have cross-protective antibodies, but some would be expected to be susceptible. Middle-aged adults and elderly may have lower levels of cross-protective antibodies and may also be susceptible to H3N2v virus infection. Seasonal influenza vaccination does not provide protection against H3N2v virus infection.

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Clinical Diagnosis

H3N2v virus infection cannot be distinguished by clinical features from seasonal influenza A or B virus infection, or from infection with other respiratory viruses that can cause influenza-like illness (fever and either cough or sore throat). Therefore, the key to suspecting H3N2v virus infection in an ill patient at this time is to elicit an epidemiological link to recent swine exposure in the week prior to illness onset:

• Direct contact (raising pigs, feeding pigs, cleaning pig waste) or indirect exposure to pigs – visiting a pig farm, walking through a swine barn at a county fair, etc.), especially if pigs were known to be ill; or
• Close contact (within 2 meters or approximately 6 feet) to an ill person who had recent swine exposure.

A patient with influenza-like illness and an epidemiological link to recent swine exposure should be considered a probable H3N2v case.

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Clinician Reporting

Clinicians should notify the local public health department regarding any probable H3N2v virus cases as soon as possible.

• Clinicians evaluating ill patients suspected to be cases of probable H3N2v virus infection in persons with recent exposure to swine or to an ill person who had swine exposure should obtain a nasopharyngeal swab or aspirate (or a combined nasal swab and throat swab) from the patient, place the swab or aspirate in viral transport medium, and contact their local or state public health department to arrange transport and testing for H3N2v virus at a state public health laboratory.

Laboratory Diagnosis and Test Interpretation – Hospital and Clinical Laboratories

Antigen detection tests, such as commercially available rapid influenza diagnostic tests (RIDTs) and immunofluorescence assays [e.g. direct fluorescent antibody staining (DFA)] are likely to detect H3N2v virus in respiratory specimens, although some RIDTs may NOT detect this virus (e.g. false negative results). False negative result can also occur with other influenza viruses. While some H3N2v cases have tested positive by RIDTs, other confirmed H3N2v cases have tested negative by RIDTs. In addition, DFA and RIDTs CANNOT specifically identify H3N2v virus infection, and a positive test result does not differentiate between seasonal influenza A virus infection or H3N2v virus infection. In summary:

• A negative RIDT result does not exclude infection with H3N2v or any influenza virus.
• A positive RIDT result for influenza A cannot specifically identify H3N2v virus infection because these tests cannot distinguish between influenza A virus subtypes (they do not differentiate between human influenza A (H3N2) virus and H3N2v virus). Therefore, if H3N2v virus infection is suspected, respiratory specimens should be collected and sent to a state public health laboratory for rRT-PCR testing using the CDC FLU rRT-PCR Dx Panel assay.

A variety of commercially available molecular assays, including RT-PCR assays, that can detect influenza viruses are available. All of the available assays are likely to detect influenza A virus infection. However, commercially available molecular assays CANNOT differentiate H3N2v virus from seasonal influenza A (H3N2) virus, and the sensitivity and specificity of molecular assays to detect H3N2v virus are unknown. Some medical center laboratories may utilize non-commercially available molecular assays for influenza (“home brews”); the sensitivity and specificity of home brew molecular assays to detect H3N2v virus is unknown. Therefore:

• A person with a positive result of a molecular assay on respiratory specimens for influenza A, or positive results for influenza A and for H3 (A+, H3+) or influenza A nonsubtypeable (A+, H1-, H3-) in a patient with an epidemiological link to swine exposure should be considered a probable H3N2v case. Specimens from probable H3N2v cases should be forwarded to the state health department laboratory for additional testing. Clinicians who suspect influenza in persons with recent exposure to swine should obtain a nasopharyngeal swab or aspirate (or a combined nasal swab and throat swab), place the swab or aspirate (or combined specimen) into viral transport medium, and contact their state or local health department to arrange transport and request a timely diagnosis at a state public health laboratory
• A negative RT-PCR result for influenza does not rule out H3N2v virus infection because the sensitivity and specificity of the commercially available and “home brew” assays are not known at this time.
• Reverse-transcription polymerase chain reaction (RT-PCR) testing for influenza should be considered for patients with influenza-like illness prior to the start of the traditional influenza season in October.
• RT-PCR testing for influenza at state public health laboratories should be considered throughout the year for patients with influenza-like illness reporting recent swine exposure and for those who can be epidemiologically linked to confirmed cases of variant influenza.

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Laboratory Diagnosis and Test Interpretation – State Public Health Laboratories

All state health department laboratories and some other public health laboratories can perform the CDC FLU real-time reverse transcription polymerase chain reaction (rRT-PCR) Dx Panel influenza assay [CDC FLU rRT-PCR Dx Panel assay] on respiratory specimens. Positive results for influenza A, pandemic A, and H3 (Influenza A+, H1-, H3+, pandemic A+, pandemic H1-) by testing respiratory specimens with the CDC FLU rRT-PCR Dx Panel on respiratory specimens are considered presumptive positive for H3N2v virus.

• Persons with presumptive positive H3N2v virus results of laboratory testing using the CDC FLU rRT-PCR Dx Panel assay are considered confirmed H3N2v cases. Specimens from confirmed H3N2v cases should be forwarded by state health departments to the Influenza Division, CDC for additional testing and virus sequencing.
• State health departments are required to report cases of novel influenza A virus infection, including confirmed cases of H3N2v virus infection, to CDC.

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Clinical Management

Clinical management of H3N2v virus infection is similar to management of seasonal influenza A or B virus infections. Patients with uncomplicated H3N2v virus infection can be managed on an outpatient basis, with close monitoring for clinical progression and development of complications. Early neuraminidase inhibitor antiviral treatment is indicated for all hospitalized patients, severe and progressive illness, and for any high-risk patients with suspected or confirmed H3N2v. Management of mild to moderate complications such as non-severe exacerbation of underlying co-morbidities may be managed on an outpatient basis. However, hospitalization may be required for severe complications or clinical progression to severe illness. At hospital admission, antiviral treatment should be started as soon as possible for previously untreated patients. If secondary invasive bacterial infection is suspected, appropriate empiric antibiotic therapy should be started promptly. Additional care includes supportive care of potential complications (supplemental oxygen for hypoxia; mechanical ventilation for respiratory failure; vasopressors for shock; renal replacement therapy for acute kidney injury, etc.).

Antiviral Treatment

H3N2v viruses tested to date are susceptible to the neuraminidase inhibitor drugs oseltamivir, peramivir, and zanamivir. These drugs can be prescribed to treat H3N2v infections. However, H3N2v viruses are resistant to the antiviral drugs amantadine and rimantadine; therefore, amandtadine and rimantadine should not be prescribed.

• Oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir are recommended for treatment of H3N2v viruses.
• For probable H3N2v cases (persons with influenza-like illness and an epidemiological link to swine exposure) who are hospitalized, have severe or progressive illness, or are in a high-risk group, empiric antiviral treatment should be started as soon as possible, without waiting for the results of influenza testing.
• For hospitalized patients and patients with severe or complicated illness, treatment with oral or enterically administered oseltamivir is recommended. While early antiviral treatment (within 48 hours of illness onset) is generally most effective, antiviral treatment may still be effective when administered later in patients with moderate and severe illness.
• Antiviral treatment with oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir is recommended for outpatients with suspected influenza, including H3N2v virus infection, if they are in a group considered to be at high risk for complications from influenza.
• Antiviral treatment with oral oseltamivir,inhaled zanamivir, intravenous peramivir, or oral baloxavir can also be considered for any previously healthy, symptomatic outpatient not at high risk with confirmed or suspected H3N2v on the basis of clinical judgment, if treatment can be initiated within 48 hours of illness onset.

Antiviral treatment recommendations for H3N2v virus infection are based upon those for seasonal influenza (note age approved indications and dosing, and contraindications Cdc-pd [433 KB, 22 pages]); see also Antiviral Drugs.

Antiviral Chemoprophylaxis

Antiviral chemoprophylaxis (before or after swine exposure) is not routinely recommended, but can be considered for persons who are at higher risk for influenza complications in certain circumstances (See IDSA Influenza Clinical Practice Guidelines). If such high-risk persons become ill, they should seek medical care as soon as possible and early antiviral treatment should be started if influenza, including H3N2v, is suspected.

In most cases, variant flu viruses have not shown the ability to spread easily and sustainably from person to person. In general, even for influenza viruses that are transmitted easily from person to person, CDC does not recommend widespread or routine use of antiviral medications for chemoprophylaxis, so as to limit the possibilities that antiviral resistant viruses could emerge. Please see chemoprophylaxis recommendations for seasonal influenza at Influenza Antiviral Medications: Summary for Clinicians.

Corticosteroids

Systemic corticosteroids should not be routinely administered to patients with suspected or confirmed influenza, including H3N2v virus infection, except for patients on chronic corticosteroid therapy for other co-morbidities (COPD, asthma).

Over-the-Counter Medications

Clinicians should remind parents that aspirin or aspirin-containing products should not be given to children with influenza-like illness, including suspect or confirmed cases of H3N2v virus infection, because of the risk of Reye’s syndrome.

Infection Control – Patient Care

Limited, non-sustained human-to-human transmission of H3N2v viruses has been reported. While very limited data are available, it is assumed that H3N2v viruses may be transmitted from person-to-person similarly to seasonal influenza viruses. Therefore, in health care settings, infection control recommendations are the same as for seasonal influenza, including standard, droplet (surgical mask), and contact precautions. For aerosol-generating procedures, a fit-tested N95 respirator or equivalent should be used. See Prevention Strategies for Seasonal Influenza in Healthcare Settings and also Infection Control in Health Care Facilities.

Infection Control – Specimen Collection

Health care personnel who collect respiratory specimens from ill persons for influenza testing should follow standard, contact, and droplet precautions, as recommended for patient care.

Caring for a Sick Family Member at Home

Ill persons who are suspect or confirmed H3N2v cases and who do not require hospitalization should be isolated at home away from other family members as much as possible. Household members who are at increased risk for influenza complications should avoid coming within 2 meters (or approximately 6 feet) of ill persons. For seasonal influenza guidance, see The Flu: Caring for Someone Sick at Home.

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Vaccination

No specific H3N2v vaccine is available at this time. Immunization with seasonal influenza vaccine does not provide protection against infection with H3N2v virus.

Seasonal influenza viruses are expected to circulate during this fall and winter. Therefore, seasonal influenza vaccination is recommended for all persons aged 6 months and older to prevent seasonal influenza. For more information, see Recommendations of the Advisory Committee on Immunization Practices (ACIP).

Prevention

Persons who are at higher risk for influenza complications, including young children, are not routinely recommended for antiviral chemoprophylaxis – they should avoid exposure to pigs and to ill persons with swine exposure. If exposure to pigs cannot be avoided, persons at higher risk for influenza complications should consider wearing appropriate personal protective equipment. Guidance for people who work with or raise pigs is available at Guidance Documents Related to Preventing the Spread of Influenza A Viruses. Other information related to H3N2v is available at Fact Sheet: Protect Yourself Against H3N2v.