Influenza

INFLUENZA 
 
Although most persons who become infected with influenza viruses will recover without sequelae, influenza can cause serious illness and death, particularly among persons aged ≥65 years and <2 years and those with medical conditions that confer high risk for complications from influenza.  
 
Vaccination
Routine annual influenza vaccination for all persons aged ≥6 months who do not have contraindications has been recommended by the CDC and CDC's Advisory Committee on Immunization Practices (ACIP). 
 
U.S. trivalent influenza vaccines will contain an A/California/7/2009 (H1N1)–like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/ 2011, and a B/Massachusetts/2/2012–like virus. Quadrivalent vaccines will include an additional vaccine virus strain, a B/Brisbane/60/2008–like virus. 
 
At risk Population: 
Persons at high risk for influenza complications include infants and young children aged <2 years, pregnant women, elderly, persons of any age with certain chronic co-morbidities [cardiac: coronary artery disease, CHF (but not HTN alone); pulmonary; COPD, asthma; renal disease; hematologic disorders; metabolic disorders; neurologic and neuromuscular disorders; immunocompromised; morbid obesity; nursing home residents. 
 
Transmission:
When humans exhale or talk, small respiratory droplets are generated on a routine basis, but these are generally less than 1 micron. With a cough, larger droplets (> 5 microns) are generated. The size of the droplet dictates the distance that the droplet can be carried by air currents (airborne vs. droplet spread). Smaller droplets remain airborne longer, and thus spread further. Though rigorous data are lacking, influenza is thought primarily transmitted from person to person by large droplets (> 5 microns) that are generated when infected persons cough or sneeze. 
 
If patients with influenza are admitted to the hospital, especially early in the clinical course while they are actively shedding virus, they should be isolated with “droplet precautions”. CDC defines this as placing the patients in private rooms (or cohorting patients with influenza) and having personnel entering the room or within 3 feet of a person use a surgical or procedure mask and standard precautions (i.e., hand washing, gloving, and gowning when soiling with the patient’s respiratory secretions is likely). There is no demonstrated added value of placing patients with influenza in rooms for airborne infection isolation (i.e., negative-pressure rooms) or using N95 respirators. Respirators (N95 or powered air purifying respirators) are only recommended during aerosol-generating procedures such as bronchoscopy or intubation.
 
Who should be tested? 
  1. Patients with fever and the acute onset of respiratory signs and symptoms.  
  2. Persons with fever and acute exacerbation of underlying chronic lung disease  
  3. Elderly persons with new or worsening respiratory symptoms, including exacerbation of congestive heart failure or altered mental status, with or without fever 
  4. Outpatient immunocompromised persons of any age presenting with febrile respiratory symptoms, irrespective of time from illness onset, because immunocompromised persons can shed influenza viruses for weeks to months. 
Clinical Features: 
The typical incubation period for influenza is 1-4days (average two days). The time between onset of illness among household contacts among whom transmission has occurred (termed the serial interval) is 3-4 days. 
 
The classic clinical symptoms of influenza are fever, myalgia, sore throat, and nonproductive cough. Clinical complications associated with influenza include exacerbation of underlying chronic disease, viral pneumonitis/pneumonia/respiratory failure/ARDS and croup/bronchiolitis in infants, bronchospasm, secondary bacterial pneumonia; 
 
Extra pulmonary complications inlcude vasopressor-dependent shock; Encephalomyelitis, transverse myelitis, Guillain-Barré syndrome, aseptic meningitis, and encephalitis; myocarditis/pericarditis; myositis/rhabdomyolysis; AKI, HUS; hepatitis, portal vein thrombosis ; leukopenia, DIC, pancytopenia, TTP and HLH syndrome.  
 
Influenza infections can also present as a typical community acquired pneumonia with fever, cough, bilateral interstitial infiltrates, hypoxemia, and leucopenia.  
 
Secondary bacterial pneumonia— Secondary bacterial pneumonia is an important complication of influenza. The hallmark of the clinical presentation in patients with secondary bacterial pneumonia is the exacerbation of fever and respiratory symptoms after initial improvement in the symptoms of acute influenza. The most common organisms isolated from sputum are Streptococcus pneumoniae, Staphylococcus aureus (including community-acquired meticillin-resistant S aureus), Haemophilus influenzae, other Streptococcus species, and other Gram-negative rods.
 
Diagnosis

For influenza testing, RT-PCR is recommended; antigen detection tests such as rapid influenza diagnostic tests and Immunofluorescence assays (DFA) lack sensitivity and false negative results are common. So, a negative result does not rule out influenza virus infection; repeat by RT-PCR assay if influenza is still suspected. 
  1. RT-PCR. This is currently the most sensitive and specific of testing modalities for influenza, with results available within 4–6 h after specimen submission. RT-PCR shows greater sensitivity than viral culture, may be used as a confirmatory test, and is useful for quickly differentiating between influenza types and subtypes. 
  2.  Immunofluorescence. Direct fluorescent antibody or indirect fluorescent antibody staining for influenza antigen detection is used as screening tests. Immunofluorescence exhibits slightly lower sensitivity and specificity than viral isolation in cell culture, but results are available within hours after specimen submission. Performance of these assays depends heavily on laboratory expertise and the quality of the specimen collected. There can be false negative tests. 
  3.  Commercial rapid influenza diagnostic tests.  Given the lower sensitivity of Immunofluorescence and commercial rapid tests, follow-up testing with RT-PCR and/or viral culture should be considered to confirm negative test results.
Respiratory tract specimens should be obtained as close to illness onset as possible, preferably within 5 days after illness onset. Collection of specimens 15 days after illness onset may result in false-negative results because of substantially decreased viral shedding. However, keep in mind that influenza virus infection may shed influenza viruses for weeks to months, even without fever or respiratory symptoms. 
 
Collect both upper and lower respiratory tract specimens for influenza testing in hospitalized patients with suspected influenza – if ventilated, endotracheal aspirate specimens should be sent unless a BAL is done for other diagnostic reasons. Lower respiratory tract specimens can yield the diagnosis when influenza viral shedding is no longer detectable in the upper respiratory tract. Therefore negative influenza testing results on an upper respiratory tract specimen in a critically ill patient with lower respiratory tract disease does not exclude influenza. 
 
Clinicians should also consider that a positive influenza test result does not exclude bacterial co infection and evaluation for the potential need for antibiotics. 
 
Who should be treated? 
Persons with laboratory-confirmed or highly suspected influenza virus infection at high risk of developing complications, within 48 h after symptom onset. Fewer data is available by which to make recommendations regarding treatment of persons >48 h after symptom onset. However, persons who require hospitalization for influenza diagnosed >48 h after the onset of illness may also benefit from treatment. Hence, treatment is usually recommended regardless of influenza vaccination status and regardless of severity of illness. 
 
Treatment: 
 
Currently, two classes of antiviral medications, the adamantanes and the neuraminidase inhibitors, are approved for treatment. The adamantanes are only effective against influenza A viruses, as they inhibit the M2 protein, which is not coded by influenza B. In the US, there are currently two NAIs – oseltamivir (Tamiflu) and zanamivir.
 
Empiric antiviral treatment with oral/enteric oseltamivir should be started ASAP on any hospitalized patient with suspected influenza, no need to wait for influenza testing results – the greatest clinical benefit is when antiviral treatment is started as soon as possible, ideally closest to illness onset, but observational studies indicate clinical benefit of reducing complications and increasing survival even when antiviral treatment is started late.  
  1. Oseltamivir: Oseltamivir was developed based on the structure of the active site of zanamivir and is administered as a prodrug that is converted by the liver into its active form. Unlike zanamivir, treatment and prophylaxis dosages are based both on weight and renal function. Treatment is 75mg PO BID for five days. Consider longer duration for critically ill patients, and higher dosing (limited data). Tamiflu is active against both Influenza A&B. It is also available for intravenous administration in patients who cannot tolerate oral dosing. Oral oseltamivir is frequently associated with nausea and emesis. It is also the drug of choice in pregnancy.
  2. Zanamivir: A 10 mg dose is inhaled twice daily for 5 days, whereas prophylaxis is given once daily for 10 days, although it can be administered for up to 28 days. After inhalation, 15% of the drug deposits within the lower respiratory tract. Therefore, it can precipitate bronchospasm in patients with pulmonary disease and cannot be used in patients who require mechanical ventilation. It is also available in an intravenous (IV) form for compassionate use. Intravenous zanamivir can treat oseltamivir-resistant influenza A (H1N1) virus infection.
  3. Amantadine/Rimantadine, 200mg per day in 1-2 divided doses, can be used for Influenza-A. 
  4. Combination therapies: Given that there is increasing concern for resistance, the use of combination therapy is promising as it raises the potential of decreasing emerging resistance and increasing efficacy of therapy. These include oseltamivir + zanamivir, NAIs + adamantanes and ribavirin. Ribavirin is an RNA polymerase inhibitor and is more commonly used for the treatment of respiratory syncytial virus and hepatitis C virus infections.
Do not expect quick clinical improvement once antiviral treatment is started.  
 
For patients with community-acquired pneumonia during influenza season, consider influenza and co-infection with MSSA, MRSA, Streptococcus pneumoniae, or Group A Streptococcus (e.g. Consider antibiotic coverage for MRSA initially until microbiological results are back and then deescalate antibiotics); 
 
Avoid high-dose systemic corticosteroids for treatment of influenza except for patients on chronic treatment when treating the underlying chronic disease exacerbation (e.g. COPD, asthma exacerbation) because high-dose corticosteroids may prolong influenza viral shedding and increase the risk for VAP and death.  
 
Patients with respiratory failure can have prolonged influenza viral replication in the lower respiratory tract (weeks), and immuncompromised patients can shed influenza viruses for weeks to months – there is a risk for emergence of oseltamivir resistance.  
 
 
Chemoprophylaxis
Antiviral chemoprophylaxis use for appropriate persons within households should be initiated when 1 family member develops suspected or confirmed influenza and any other family member is at high risk of complications secondary to infection. In this setting, all noninfected family members should receive antiviral chemoprophylaxis. Ideally, all eligible family members in such settings should be vaccinated, making chemoprophylaxis unnecessary. 
 
For household or other close contact postexposure prophylaxis within the US, oseltamivir is approved for adults and children older than 13 years and is dosed at 75 mg orally twice daily for 10 days. Zanamivir is approved for prophylaxis in adults and children older than 5 years, and is dosed at 10 mg inhaled daily for 10 days.
 
Infection prevention and control for influenza is an essential part of clinical management for influenza patients, including prevention of nosocomial influenza. All healthcare personnel should receive influenza vaccination this season. Influenza patients should be isolated or cohorted if isolation is not possible. Standard, contact, and droplet precautions should be implemented for influenza patients. For aerosol-generating procedures, N95 respirator or higher level of respiratory protection is indicated.  
 
Steroids in Influenza: There is no sufficient evidence to suggest that steroids are helpful in influenza. Infact, there is some evidence to suggest that steroids might worsen the mortality rates in influenza.
 
References:
 
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