INFLUENZA

Katherine M. Tromp, PharmD • Hershey S. Bell, MD, MS, FAAFP

 BASICS

DESCRIPTION

•  Acute, typically self-limited, febrile infection caused by orthomyxovirus influenza types A and B

•  Marked by inflammation of nasal mucosa, pharynx, conjunctiva, and respiratory tract

•  Outbreaks have varying degrees of severity and generally peak in winter.

•  Influenza virus can undergo antigenic shift (abrupt change) leading to strains of virus to which little immunologic resistance exists in a population, potentially resulting in pandemic outbreak. Minor seasonal variations are called antigenic drift.

•  System(s) affected: typical cases: head/eyes/ears/nose/throat; pulmonary; complicated cases: cardiac and CNS involvement

•  Synonym(s): flu; grippe; acute catarrhal fever

EPIDEMIOLOGY

•  Predominant age: children (3 months to 16 years) and young adults

–  Morbidity: seasonal morbidity and rates of hospitalization highest in very young (preschool), elderly (>75 years of age), and individuals with comorbid illness (lung disease, malignancy)

•  Predominant sex: male = female

Incidence

•  Seasonal influenza in preuniversal vaccination: 95 million cases per year, typically fall/winter

•  Attack rates in healthy children: 10–40% each year, prior to routine influenza vaccination

•  Weekly reports are available: http://www.cdc.gov/flu/weekly

ETIOLOGY AND PATHOPHYSIOLOGY

Orthomyxovirus (influenza types A [majority] and B). Influenza A virus subtypes HxNx based on hemagglutinin and neuraminidase

•  Incubation is 1 to 4 days; infected persons are most contagious during peak symptoms.

•  Spread by aerosolized droplets or contact with respiratory secretions

•  Hemagglutinin binds to columnar respiratory epithelium where replication occurs, and neuraminidase protein facilitates spread along respiratory epithelium.

RISK FACTORS

•  For contracting disease

–  Crowded environments such as nursing homes, barracks, schools, and correctional facilities

•  For complications

–  Neonates, infants, elderly

–  Pregnancy, especially in 3rd trimester

–  Chronic pulmonary diseases

–  Cardiovascular diseases, including valvular problems and congestive heart failure (CHF)

–  Metabolic disease, morbid obesity

–  Hemoglobinopathies

–  Malignancy; immunosuppression

–  Neuromuscular diseases that limit respiratory function and ability to handle secretions

–  Patients <19 years of age who are on long-term aspirin therapy

GENERAL PREVENTION

•  Vaccination: All persons >6 months should be vaccinated annually, with few exceptions:

–  Inactivated influenza vaccine (IIV) is available with either 3 (IIV3) or 4 (IIV4) strains of influenza. IIV also is available as high-dose, intradermal, cell culture-based (ccIV3), MF59-adjuvanted (aIIV3), and recombinant hemagglutinin influenza vaccine (RIV3).

–  Live attenuated influenza vaccine (LAIV) is an intranasal quadrivalent vaccine.

•  IIV recommended annually for the following:

–  All persons aged ≥6 months

–  Vaccine should be administered annually as soon as the vaccine is available.

–  Protection occurs 1 to 2 weeks after immunization.

–  Typically mild side effects include low-grade fever and local reaction at vaccination site.

–  Inactivated IM dose: ≥3 years of age: 0.5 mL; children 6 to 35 months of age: 0.25 mL

–  Intradermal formulation for 18- to 64-year-olds uses a short 30-gauge needle in a single-use prefilled syringe with 0.1 mL vaccine; somewhat higher local reactions when given intradermal

–  Single dose every year except for children <9 years of age, who should receive 2 doses (4 weeks apart) the first year they receive influenza vaccine.

–  Vaccine contraindication: Severe allergy such as anaphylaxis to eggs or other IIV components; hives from eggs are not considered a contraindication to IIV due to very low ovalbumin dose in current IIV and good safety information; observe all patients for 15 minutes after vaccination; no skin testing with influenza vaccine is needed in egg-allergic patients. Egg allergy is a contraindication to LAIV. RIV is safe in patients with an egg allergy.

–  Precaution: Guillain-Barré syndrome within 6 weeks after a previous dose of influenza vaccine

•  LAIV is not recommended for the 2016 to 2017 influenza season.

•  IIV-HD: high-dose quadrivalent IIV

–  Contains 4 times the antigen concentration of IIV

–  Licensed for persons ≥65 years of age

–  Results in higher antibody levels but somewhat higher rates of local reactions

–  Advisory Committee on Immunization Practices does not express a preference for or against IIV-HD.

•  Antiviral prophylaxis depends on current resistance patterns each year; see http://www.cdc.gov/flu/ for current patterns or check with local health department.

–  In high-risk groups that have not been vaccinated or need additional control measures during epidemics. Not a substitute for vaccination unless vaccine is contraindicated (1)[A]

–  During influenza season, for those with contraindications to vaccine who have been exposed to the virus (1)[A]

–  For staff and residents in nursing home outbreaks

–  For immune-deficient persons who are expected not to respond to vaccination after exposure to the virus

Pediatric Considerations

•  Vaccinate children 6 to 23 months old with IIV.

•  Either IIV or LAIV in healthy children ages 2 to 18 years

•  For prophylaxis, oseltamivir dosage varies by weight and is recommended by the CDC for prophylaxis for children ≥3 months; zanamivir is approved for prophylaxis for children ≥5 years of age at a dosage of 2 inhalations per day. For prophylaxis, the dosage of amantadine and of rimantadine is 5 mg/kg/day up to 150 mg in 2 divided doses. Currently, amantadine and rimantadine are not recommended due to resistance.

Pregnancy Considerations

•  The CDC recommends vaccinating all women who will be pregnant during influenza season.

•  If unvaccinated at the time of flu season, pregnant women should receive IIV.

•  Oseltamivir, zanamivir, peramivir, rimantadine, and amantadine are pregnancy Category C.

COMMONLY ASSOCIATED CONDITIONS

Bacterial pneumonia

 DIAGNOSIS

Absence of the following to rule out influenza:

•  Systemic symptoms

•  Cough

•  Not being able to cope with daily activities

•  Being confined to bed

HISTORY

Sudden onset of the following:

•  Fever (37.7–40.0°C), especially if combined with presenting within 3 days of illness onset

•  Anorexia

•  Chills, sweats, malaise, myalgia, arthralgia

•  Headache

•  Sore throat/pharyngitis

•  Nonproductive cough

•  Rhinorrhea, nasal congestion

PHYSICAL EXAM

•  Physical exam is not specific for influenza.

•  Physical examination should exclude complications such as otitis media, pneumonia, sinusitis, and tracheobronchitis.

DIFFERENTIAL DIAGNOSIS

•  Respiratory viral infections including respiratory syncytial virus, parainfluenza, adenovirus, enterovirus (“influenza-like illness”)

•  Infectious mononucleosis

•  Coxsackievirus infections

•  Viral or streptococcal tonsillitis

•  Atypical mycoplasmal pneumonia

•  Chlamydia pneumoniae

•  Q fever

•  Less likely possibilities include severe acute respiratory syndrome, primary HIV infection, acute myeloid leukemia, tuberculosis, anthrax, and malaria.

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

•  During influenza season, diagnosis is based solely on clinical findings. If additional testing is needed

–  Reverse transcription polymerase reaction (RT-PCR) from nasopharyngeal swab or aspirate is the gold standard for diagnostic confirmation.

–  CBC: typically shows normal WBC count or mild leukopenia. Leukocytosis may indicate bacterial complications.

–  Direct fluorescent antibody or indirect fluorescent antibody staining for influenza antigen; results available in hours (dependent on lab expertise)

–  Commercial rapid enzyme-linked immunosorbent assay antigen tests are available. Some rapid tests diagnose influenza A, whereas others diagnose A and B. Sensitivity and specificity vary by manufacturer, strain of influenza, and age of patient. False-negative results are fairly common particularly during periods of peak influenza activity.

–  Viral isolation is not particularly useful except in periods of low influenza activity when making the correct diagnosis is critical.

•  Imaging

–  Chest x-ray if pneumonia is suspected

 TREATMENT

•  Symptomatic treatment is typically all that is required (saline nasal spray, analgesic gargle, antipyretics, analgesics).

•  Cool-mist or ultrasonic humidifier to increase moisture of inspired air

•  Droplet precautions: see http://www.cdc.gov/HAI/settings/outpatient/basic-infection-control-prevention-plan-2011/transmission-based-precautions.html#c

•  5 days is the average period of viral shedding in immunocompetent hosts.

•  Hospitalized patients may require oxygen or ventilatory support.

•  Tobacco cessation

MEDICATION

•  Antiviral treatment depends on yearly resistance patterns; check http://www.cdc.gov/flu/ or with local health department. Antivirals are most effective if administered within first 48 hours in laboratory-confirmed (or highly suspected based on clinical findings) influenza cases.

•  Antivirals within 48 hours of symptom onset are recommended for patients at risk of complications (i.e., diabetes, CHD, COPD, asthma, etc.) (1)[A].

•  Antivirals are recommended if hospitalized (2)[A].

•  Antivirals include amantadine, rimantadine, oseltamivir, zanamivir, and peramivir.

•  Antivirals may be considered for persons not at increased risk of complications from influenza whose onset of symptoms is within the past 48 hours and who wish to shorten the duration of illness and further reduce their relatively low risk of complications (1)[A].

•  Symptomatic treatment is preferred for those patients without risk factors and without signs of lower respiratory tract infection 2.

•  Effect is 24-hour reduction of symptoms and a reduction in complication rates.

–  Zanamivir dose: 2 inhalations BID for 5 days (age ≥7 years)

–  Rimantadine dose: 100 mg BID for ages 13 to 64 years; 100 mg/day for >65 years of age

–  Amantadine dose: 100 mg BID for ages 13 to 64 years; 100 mg/day for >65 years of age

–  Oseltamivir dose: 75 mg PO BID for 5 days (age ≤13 years)

–  If severe renal impairment, 75 mg/day PO

–  Oseltamivir for children ≥1 year of age

  <15 kg, 30 mg BID

  >15 to 23 kg, 45 mg BID

  >23 to 40 kg, 60 mg BID

  >40 kg, 75 mg BID

–  Oseltamivir for children <1 year of age: 3 mg/kg/dose BID

•  Peramivir dose: 600 mg IV infusion over 15 to 30 minutes for adults ≥18 years of age

•  Antipyretics

–  Acetaminophen: in children

•  Precautions

–  Zanamivir may cause bronchospasm if the patient has COPD or asthma; the patient should have a bronchodilator available.

–  Amantadine has anticholinergic properties and should be used with caution in those with psychiatric, addiction, or neurologic disorders, as it may increase risk for suicide attempts or increase neurologic symptoms.

–  Rimantadine may increase the risk of seizures in those with an underlying seizure disorder.

–  Oseltamivir may cause nausea and vomiting; may be less severe if taken with food

–  Peramivir may cause serious skin reactions.

•  Amantadine and rimantadine are currently not recommended due to resistance.

•  Decrease dose of certain antivirals if creatinine clearance <30 mL/min.

•  Ibuprofen or other NSAIDs for symptomatic relief

•  Aspirin: should not be used in children <16 years due to risk of Reye syndrome

•  Outpatient treatment is sufficient except for cases with severe complications or in high-risk groups.

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  Mild cases: Usually, no follow-up is required.

•  Moderate or severe cases: Follow up until symptoms and any secondary sequelae resolve.

DIET

Increase fluid intake.

PATIENT EDUCATION

CDC: http://www.cdc.gov/flu/

PROGNOSIS

Good

COMPLICATIONS

•  Otitis media

•  Acute sinusitis

•  Croup

•  Bronchitis

•  Pneumonia (primary viral or secondary bacterial)

•  Apnea in neonates

•  Reye syndrome

•  Rhabdomyolysis/myositis

•  Postinfluenza asthenia

•  COPD or CHF exacerbation

•  Encephalopathy, death

Geriatric Considerations

Complications are more likely in elderly who are also more likely to require hospitalization.

REFERENCES

1.  Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed October 7, 2016.

2.  Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8):1003–1032.

ADDITIONAL READING

•  Centers for Disease Control and Prevention. Influenza (flu). http://www.cdc.gov/flu/index.htm. Accessed October 14, 2016.

•  Ebell MH, White LL, Casault T. A systematic review of the history and physical examination to diagnose influenza. J Am Board Fam Pract. 2004;17(1):1–5.

•  Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2016–17 influenza season. MMWR Recomm Rep. 2016;65(5):1–54.

•  Osterholm MT, Kelley NS, Sommer A, et al. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(1):36–44.

 CODES

ICD10

•  J11.1 Influenza due to unidentified influenza virus with other respiratory manifestations

•  J10.1 Flu due to oth ident influenza virus w oth resp manifest

•  J11.00 Flu due to unidentified flu virus w unsp type of pneumonia

CLINICAL PEARLS

•  Influenza is an acute, (typically) self-limited, febrile infection caused by influenza virus types A and B.

•  With rare exceptions, all persons >6 months should be vaccinated against influenza on an annual basis.

•  Complications from influenza are most common in the very young, very old, and individuals with comorbid disease.

•  Hand hygiene either with soap and water (slightly superior) or with alcohol-based hand rubs and covering coughs are simple ways to reduce the spread of influenza.