INFLUENZA

INFLUENZA 

Definition

Influenza is an acute respiratory infection caused by influenza viruses, characterized by abrupt onset of fever, headache, myalgia, malaise, cough, sore throat and respiratory symptoms.

It is important in critical care because influenza can cause:

• Viral pneumonia
• Primary influenza viral pneumonia
• Secondary bacterial pneumonia
• Acute hypoxemic respiratory failure
• ARDS
• Sepsis/septic shock
• Myocarditis
• Encephalitis/encephalopathy
• Myositis/rhabdomyolysis
• Multiorgan failure
• Exacerbation of COPD/asthma/heart failure

Influenza Viruses

Influenza A → pandemics

Examples:

• H1N1 — 2009 pandemic
• H3N2 — major seasonal strain
• H5N1 — avian influenza
• H7N9 — avian influenza

Viral Proteins

Two surface glycoproteins are particularly important:

Hemagglutinin — HA

HA:

• Binds to sialic acid receptors on respiratory epithelial cells.
• Mediates viral attachment.
• Facilitates entry into the host cell.
• Major target of neutralizing antibodies.
• Determines the H designation of influenza A.

Neuraminidase — NA

NA:

• Cleaves sialic acid.
• Facilitates release of newly formed virions from infected cells.
• Allows spread of virus through respiratory epithelium.
• Target of neuraminidase inhibitors.

Examples:

• H1N1 → HA type 1 + NA type 1
• H3N2 → HA type 3 + NA type 2

Other Important Viral Proteins

Antigenic Variation

Two mechanisms are classically tested:

A. Antigenic Drift

Small, gradual mutations

Occurs because influenza RNA polymerase lacks proofreading.

Results in:

• New variants
• Seasonal epidemics
• Need for periodic vaccine updating

Occurs in:Influenza A and B

B. Antigenic Shift

Major abrupt change in HA and/or NA

• Occurs mainly through genetic reassortment because the genome is segmented.

Classically occurs when:

• Two different influenza A viruses infect the same host cell → genome segments reassort → novel virus emerges.
• This can produce a virus against which humans have little pre-existing immunity.

Consequence Pandemic—Classic example 2009:H1N1 pandemic influenza

Drift vs Shift

Reservoir

Influenza A

• Has extensive animal reservoirs:Wild aquatic birds,Poultry,Pigs,Horses,Dogs,Other mammals.
• Aquatic birds are an important natural reservoir.

Influenza B

Primarily human.

Transmission

• Mainly:Respiratory droplets Produced during:Coughing,Sneezing,Talking
• Also:Aerosol transmission

Especially in:

• Crowded indoor environments
• Poor ventilation
• Aerosol-generating procedures

Fomites

Possible but generally less important than respiratory transmission.

Incubation Period

• Usually:~2 days
• Typical range:1–4 days

Infectious Period

Adults can transmit influenza approximately:1 day before symptom onset → ~5–7 days after onset

Patients may remain infectious longer if:

• Young children
• Immunocompromised
• Severe illness

Important

Maximum infectiousness is generally around the first 3 days of illness.

High-Risk Groups

Severe influenza is more likely in:

Age

• <5 years, especially <2 years
• ≥65 years

Pregnancy

Especially important.

Pregnancy increases risk of severe influenza because of:

• Physiologic respiratory changes
• Cardiovascular changes
• Altered immune response

Medical conditions

• Chronic pulmonary disease
• Asthma
• COPD
• Cardiovascular disease
• Diabetes mellitus
• Chronic kidney disease
• Chronic liver disease
• Neurologic disorders
• Hematologic disorders
• Immunosuppression
• Morbid obesity

Clinical Features

Classic influenza has:Abrupt onset + systemic symptoms

Typical symptoms

• Fever
• Chills
• Headache
• Myalgia
• Malaise
• Dry cough
• Sore throat
• Nasal congestion
• Rhinorrhea

Compared with common cold

Influenza is generally:

• More abrupt
• More systemic
• More febrile
• More myalgic
• More likely to cause severe lower respiratory disease

Classic Influenza Syndrome

Think:Fever + headache + severe myalgia + dry cough + profound malaise

The cough may persist for weeks even after other symptoms resolve.

GI Symptoms

Especially in children:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain

GI manifestations can occasionally occur in adults as well.

Physical Examination

May show:

• Fever
• Tachycardia
• Pharyngeal erythema
• Cervical lymphadenopathy occasionally
• Dry cough
• Wheezing
• Hypoxemia in pneumonia

Uncomplicated influenza often has relatively few pulmonary examination findings.

Influenza Pneumonia

Two major patterns should be distinguished.

A. Primary influenza viral pneumonia

Virus directly causes lower respiratory tract disease.

Typical:

• High fever
• Severe cough
• Dyspnea
• Hypoxemia
• Diffuse pulmonary infiltrates
• Rapid progression

Can progress to:ARDS → respiratory failure → death

B. Secondary bacterial pneumonia

Influenza damages respiratory epithelium and impairs host defenses.Typical pathogens:

• Streptococcus pneumoniae
• Staphylococcus aureus Including:MRSA

Also:

• Streptococcus pyogenes
• Haemophilus influenzae
• Other respiratory bacteria

Influenza → Secondary Bacterial Pneumonia

Classic clinical pattern:

Phase 1

Influenza:Fever,Myalgia,Cough.

Phase 2

Initial improvement

Phase 3

Sudden deterioration:

• Recurrent fever
• Purulent sputum
• Worsening cough
• Dyspnea
• New infiltrates(dense lobar consolidation or cavitation)
• Sepsis

This biphasic illness strongly suggests secondary bacterial infection.

Necrotizing Pneumonia

Influenza-associated S. aureus, particularly MRSA, can produce:

• Severe necrotizing pneumonia
• Cavitation
• Hemoptysis
• Leukopenia
• Shock
• Rapid respiratory deterioration

PVL-producing strains have historically been associated with severe necrotizing disease.

Extrapulmonary Complications

Influenza is not only a respiratory disease.

Neurologic

• Encephalopathy
• Encephalitis
• Seizures
• Febrile seizures in children
• ADEM
• Guillain-Barré syndrome
• Meningitis rarely
• Acute necrotizing encephalopathy

Acute necrotizing encephalopathy

Classically associated with influenza in children.

May show:

• Altered consciousness
• Seizures
• Rapid neurologic deterioration
• Bilateral thalamic lesions

Cardiac Complications

Myocarditis

Influenza can cause:

• Myocarditis
• Myopericarditis
• Arrhythmias
• Acute LV dysfunction
• Cardiogenic shock

Severe myocarditis may require:

• Vasopressors
• Inotropes
• Mechanical circulatory support
• VA-ECMO in selected cases

Musculoskeletal Complications

Influenza-associated myositis can produce:

• Severe muscle pain
• Weakness
• Markedly elevated CK

Rarely:Rhabdomyolysis

Potential complications:Hyperkalemia,AKI,Metabolic acidosis.

Renal Complications

• AKI
• Rhabdomyolysis-associated AKI
• Hemolytic uremic syndrome rarely
• Acute tubular injury
• Multiorgan failure in severe infection

Other Complications

• Otitis media
• Sinusitis
• Croup
• Exacerbation of asthma
• COPD exacerbation
• Decompensated heart failure
• Secondary bacterial sepsis
• Myocardial infarction
• Febrile seizures

Diagnosis

Diagnosis can be:

• Clinical
• Molecular
• Antigen-based
• Serologic

For hospitalized/severe disease:Molecular testing is preferred.

RT-PCR-Preferred diagnostic test

Nucleic acid amplification testing (NAAT), usually RT-PCR

Advantages:

• High sensitivity
• High specificity
• Rapid
• Can distinguish influenza A/B
• Some assays identify specific subtypes

Rapid Influenza Diagnostic Tests — RIDTs

• Detect viral antigen.
• Advantages:Rapid,Point-of-care.
• Disadvantages:Lower sensitivity than molecular tests
• Therefore:A negative rapid antigen test does NOT reliably exclude influenza, especially when clinical suspicion is high.

Rapid Molecular Assays

Provide:

• High sensitivity
• High specificity
• Faster results than conventional laboratory PCR

Very useful in emergency/ICU settings.

Viral Culture

Can identify influenza but is:

• Slow
• Not ideal for routine acute clinical decision-making

More useful for:

• Surveillance
• Public health
• Characterization of unusual strains

Serology

Not useful for routine diagnosis of acute influenza.

Requires:

• Acute serum
• Convalescent serum

Mainly useful for epidemiologic/research purposes.

Specimen Collection

For uncomplicated upper respiratory infection:Nasopharyngeal swab/aspirate 

• If a nasopharyngeal PCR is negative and yet suspicion for influenza remains:For a non-intubated patient, it may be reasonable to repeat the nasopharyngeal PCR
• In severe lower respiratory tract disease:If upper respiratory sample is negative but suspicion remains high:

Obtain a lower respiratory tract specimen(gold-standard investigation)

• Endotracheal aspirate
• BAL

This is particularly important in mechanically ventilated patients.

• Blood cultures.
• Sputum for Gram stain & culture.

Imaging

Chest X-ray

May show:

• Bilateral infiltrates
• Patchy opacities
• Interstitial infiltrates
• Consolidation

CT

May show:

• Ground-glass opacities
• Multifocal consolidation
• Interlobular septal thickening
• Bilateral diffuse disease

Imaging is not specific for influenza.

Laboratory Findings

• Leukopenia
• Lymphopenia
• Leukocytosis
• Thrombocytopenia
• Elevated CRP
• Elevated ferritin
• Elevated LDH
• Elevated CK
• Elevated AST/ALT
• Elevated lactate in shock
• AKI

No routine laboratory abnormality is diagnostic.

Influenza vs COVID-19

Clinical features overlap considerably.

Therefore:Clinical features alone cannot reliably distinguish influenza from COVID-19.

During periods of circulation, consider testing for:

• Influenza
• SARS-CoV-2

Multiplex molecular respiratory panels can detect both.

Management

Fluid Management in Influenza Pneumonia

Patients with severe influenza pneumonia may develop ARDS, and excessive fluid administration can worsen pulmonary edema and oxygenation.

• Avoid unnecessary fluid loading, particularly once adequate perfusion has been established.
• In a patient with mild hypotension without clear evidence of hypovolemia, early vasopressor support may be preferable to repeated large-volume fluid boluses.
• In a normotensive patient without evidence of hypoperfusion or hypovolemia, routine administration of a 30 mL/kg fluid bolus is not indicated.
• Lactate should be interpreted in clinical context rather than used as an automatic trigger for fluid administration. Lactate may be elevated from increased work of breathing, adrenergic stimulation, β₂-agonists, or other causes and does not by itself establish fluid responsiveness.
• When fluid resuscitation is required, use small, reassessed boluses and evaluate fluid responsiveness rather than administering fluids empirically.
• Once shock has resolved, a conservative fluid strategy may help minimize pulmonary edema and facilitate recovery from ARDS.

Antiviral Therapy

• Treat suspected or confirmed influenza in patients who are hospitalized, severely ill, or at high risk for complications.
• Do not wait for laboratory confirmation in such patients if clinical suspicion is significant.

Neuraminidase Inhibitors

• Oseltamivir(Oral)
• Zanamivir(Inhaled)
• Peramivir(IV)

Oseltamivir

• Most commonly used systemic antiviral.
• Adult treatment—75 mg orally twice daily for 5 days
• ESRD with GFR <10 ml/min: relative contraindication
• Oseltamivir is considered safe during pregnancy.

Adverse Effects

Common:

• Nausea and vomiting — the most characteristic adverse effects; taking the drug with food may improve tolerability.
• Headache.

Less common/rare:

• Neuropsychiatric events: delirium, agitation, abnormal behavior, anxiety, hallucinations, nightmares, or seizures. Causality is uncertain because influenza itself can cause neurologic and neuropsychiatric manifestations.
• Bradycardia — reported, but uncommon.
• Serious hypersensitivity reactions: anaphylaxis, angioedema.
• Severe cutaneous reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
• Thrombocytopenia.
• Hepatotoxicity/hepatitis and elevated transaminases — uncommon.

Timing of Antiviral Therapy

Best benefit:Within 48 hours of symptom onset

Treatment in Critically Ill Patients(Controversial)

The recent REMAP-CAP Influenza Antiviral Domain randomized trial found that oseltamivir was associated with higher 90-day mortality compared with no antiviral therapy in critically ill patients ≥12 years with laboratory-confirmed influenza.

Zanamivir

Inhaled neuraminidase inhibitor.

Typical treatment:10 mg inhaled twice daily for 5 days

Avoid/caution in patients with:

• Asthma
• COPD
• Reactive airway disease

because bronchospasm may occur.

Not preferred for patients who cannot reliably inhale the medication.

Peramivir

IV neuraminidase inhibitor.GFR >50 ml/min: a single dose of 600 mg IV is used.

Useful when:

• Oral/enteral administration is difficult
• Patient cannot absorb enteral medication

However, routine use of IV peramivir instead of enteral oseltamivir has not demonstrated clear superiority in severe influenza.ESRD with GFR <10 ml/min: relative contraindication

Common:

• Diarrhea
• Nausea
• Vomiting is less frequent.

Less common/rare:

• Neutropenia
• Neuropsychiatric events: insomnia, hallucinations, delirium, abnormal behavior.
• Elevated transaminases.
• Hyperglycemia.
• Elevated creatine kinase.
• Serious hypersensitivity reactions, including anaphylaxis.
• Severe cutaneous reactions, including Stevens–Johnson syndrome and erythema multiforme.

Baloxavir

A newer antiviral.

Mechanism:Cap-dependent endonuclease inhibitor

It inhibits viral mRNA synthesis.

Advantages

• Single oral dose
• Different mechanism from neuraminidase inhibitors

Important limitation

For severe hospitalized influenza, oseltamivir remains the standard preferred antiviral approach; baloxavir is not routinely used as monotherapy for critically ill hospitalized patients.

Bacterial Coinfection

Consider bacterial superinfection when there is:

• Clinical deterioration after initial improvement
• Persistent/recurrent fever
• Purulent sputum
• New focal consolidation
• Leukocytosis
• Shock
• Rising inflammatory markers
• Positive cultures

Common organisms:

1. S. pneumoniae
2. S. aureus
3. MRSA
4. S. pyogenes
5. H. influenzae

Procalcitonin cannot reliably exclude bacterial coinfection by itself.

Use clinical assessment + microbiology + imaging.

Antibiotics in Influenza

• Uncomplicated influenza—No antibiotics.
• In severe influenza pneumonia:Antiviral + empiric antibacterial therapy may be appropriate when bacterial coinfection cannot be excluded.

Consider MRSA coverage when clinically indicated.

• Biphasic illness: initial influenza-like illness followed by partial improvement and then sudden clinical deterioration, suggesting secondary bacterial pneumonia.
• Purulent sputum or hemoptysis, particularly when accompanied by severe pneumonia; however, a dry cough does notexclude MRSA.
• Previous MRSA colonization or infection.
• Skin or soft-tissue findings suggestive of staphylococcal infection, such as pustules or abscesses.
• Cavitary or necrotizing pulmonary lesions on imaging.
• Other risk factors for MRSA colonization/acquisition, such as recent hospitalization, recent antibiotics, residence in a healthcare facility, or chronic hemodialysis.
• Severe rapidly progressive pneumonia, particularly with leukopenia, hemoptysis, shock, or respiratory failure, should raise concern for influenza-associated necrotizing S. aureus pneumonia.

Corticosteroids

Routine corticosteroids are NOT recommended solely for treatment of influenza pneumonia.

Observational studies have generally associated corticosteroid use in severe influenza with:

• Increased mortality
• Secondary infection
• Prolonged viral shedding

Exception

Give corticosteroids when there is another clear indication, such as:

• Refractory septic shock requiring corticosteroids
• Asthma exacerbation
• COPD exacerbation
• Adrenal insufficiency
• Early ARDS
• Virus-associated hemophagocytic syndrome

ICU Management For severe influenza:

Respiratory failure

• HFNC
• NIV in carefully selected patients
• Intubation when indicated
• Lung-protective mechanical ventilation in ARDS

Infection Control

• Hospitalized patients with influenza should generally receive:Standard precautions PLUS Droplet precautions
• Use appropriate PPE.
• For aerosol-generating procedures:Appropriate airborne/respiratory protection should be used according to institutional infection-control policy.

Vaccination

Vaccination is the most important preventive strategy.

Influenza vaccines are updated periodically because of:Antigenic drift

Types of Influenza Vaccine

Depending on country/product availability:

• Inactivated influenza vaccine(Usually IM)
• Live attenuated influenza vaccine(Intranasal)
• Recombinant influenza vaccine

Uses recombinant HA technology.

Who Should Be Vaccinated?

Broadly:Annual influenza vaccination is recommended for almost everyone ≥6 months of age who does not have a contraindication.

Especially important in:

• Elderly
• Pregnant women
• Healthcare workers
• Children
• Chronic cardiopulmonary disease
• Diabetes
• Immunocompromised individuals

Pregnancy

Inactivated influenza vaccine can be given during pregnancy.

It protects:

• Mother
• Infant during early life through passive antibody transfer

Live attenuated influenza vaccine is generally not recommended during pregnancy.

Vaccine Contraindications

Severe allergic reaction to a previous dose or vaccine component

Precautions vary by product.

Egg allergy is not generally a reason to withhold influenza vaccination under current recommendations.

Antiviral Chemoprophylaxis

• Used in selected high-risk exposure situations.
• Oseltamivir Commonly used.
• Typical adult regimen:75 mg once daily
• Duration depends on exposure setting and public-health guidance.

Post-Exposure Prophylaxis

Consider especially for:

• High-risk individuals
• Institutional outbreaks
• Certain healthcare exposures
• Immunocompromised persons who may respond poorly to vaccine

Vaccination remains the principal preventive strategy.

Influenza in Healthcare Workers

Healthcare workers should receive annual influenza vaccination because vaccination:

• Reduces healthcare-associated transmission
• Protects vulnerable patients
• Reduces staff absenteeism

Severe Influenza in Children

Potential complications:

• Pneumonia
• Otitis media
• Croup
• Febrile seizures
• Encephalitis
• Myositis
• Rhabdomyolysis
• Multiorgan failure

Children can shed virus longer than adults.

Influenza-Associated Encephalopathy

Particularly important in pediatrics.

May present with:

• Altered consciousness
• Seizures
• Cerebral edema
• Neurologic deterioration

A particularly severe form:Acute necrotizing encephalopathy

with characteristic deep gray matter involvement, especially thalami.

Influenza-Associated Myositis

More commonly recognized in children.

Typical:

• Calf pain
• Difficulty walking
• Elevated CK

Rarely progresses to:Rhabdomyolysis → AKI

Influenza and Cardiovascular Disease

Influenza infection can precipitate:

• Acute coronary syndrome
• Arrhythmia
• Heart failure
• Myocarditis

Inflammation and increased physiologic stress may contribute to cardiovascular events.

This is one reason vaccination is especially important in cardiovascular disease.

H5N1 

H5N1 is an avian influenza A virus.Human infection can produce:

• Severe pneumonia
• ARDS
• Shock
• Multiorgan dysfunction

Exposure history is extremely important:

• Sick/dead poultry
• Infected birds
• Contaminated environments
• Infected mammals in some settings

Management requires:

• Urgent public-health notification
• Infection-control precautions
• Molecular testing
• Antiviral therapy
• Specialist/public-health involvement