Influenza¶

Chapter 206 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 206

Key Clinical Points¶

Incubation period is very short: 48–72 hours.
Neuraminidase inhibitors (e.g., oseltamivir, zanamivir) are most effective if administered within 48 hours of symptom onset.
Pooled efficacy of inactivated influenza vaccines is approximately 59% in adults 18–65 years.
High-risk groups for prioritized vaccination include children 6–59 months, adults ≥50 years, pregnant women, and those with chronic cardiopulmonary/renal/met1abolic disorders.
The 1918 H1N1 pandemic was unique for its high mortality among young adults (25–34 years) due to a 'cytokine storm'.
Swine influenza viruses act as 'mixing vessels' because they possess both α-2,6- and α-2,3-galactose receptors on respiratory epithelial cells.
LAIV is not licensed for children <2 years old due to risks of wheezing and hospitalization.
Egg allergy alone does not require additional safety measures for vaccine administration.
Secondary bacterial pneumonia risk is highest in elderly patients and those with COPD.
Vaccine types include inactivated (trivalent/quadrivalent), high-dose, recombinant, and adjuvanted formulations.

1. DEFINITION & OVERVIEW¶

Influenza is a respiratory illness caused by orthomyxoviruses (types A, B, and C), characterized by systemic symptoms (fever, myalgia) and seasonal outbreaks.

• Clinical Characteristics: Systemic symptoms, winter seasonality in temperate climates (mirror-image season in the antipodes), and rapid transmission among close contacts.

• Surveillance & Monitoring: - CDC tracks influenza-like illness (ILI), virologically confirmed cases, and excess pneumonia/influenza mortality. - Annual vaccine reformulation is required due to antigenic drift; H3N2 strains show the greatest variability. - Vaccine availability typically occurs in August/September; composition decisions are made ~10 months before the seasonal peak.

• Outbreak Dynamics: - Outbreaks typically last 4–5 weeks but can have prolonged national impact. - Epidemic classification occurs when activity exceeds baseline thresholds.

Definition (Harrison's 22e): The influenza virus causes outbreaks during the cooler months of the year and thus has a mirror-image season in the antipodes compared with that in the Northern Hemisphere.

• Impact: Significant contribution to increased absenteeism, ED visits, and hospitalizations (especially in elderly and those with cardiopulmonary disease).

1.1 Surveillance & Classification¶

Global surveillance by WHO and CDC informs vaccine composition and epidemic severity.

• Factors Influencing Severity: Viral transmissibility, virulence, population susceptibility, and antigenic match to vaccines.

• Vaccine Evolution: - Requirement for annual reformulation due to antigenic drift (H3N2 strains show greatest variability). - 2024–2025 season reverted to trivalent due to the absence of B/Yamagata circulation. - Mismatch between predicted and circulating strains may reduce vaccine efficacy.

2. EPIDEMIOLOGY¶

Influenza circulates seasonally in temperate regions with mirror-image patterns in the Southern Hemisphere.

• Recent Trends: - 2020–2021 season showed suppressed activity due to pandemic mitigation (travel restrictions, masking). - Annual excess mortality: 4900–51,000 deaths from 2010–2023. - Post-pandemic pediatric mortality: 184/138 deaths in 2022–2023 (requires laboratory confirmation).

• Mortality Metrics: - 2023–2024 calculation shifted to focus on death certificate listings rather than excess mortality estimates.

• Transmission Dynamics: - Route: Respiratory droplets and aerosols, modulated by temperature/humidity. - Source: Often initiated by preschool/school-aged children. - Zoonotic Risk: Bird migration facilitates global spread; avian H5/H7 strains cause poultry outbreaks with limited human-to-human transmission. Human infection occurs via direct contact with infected birds or live-bird markets.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

Influenza A, B, and C viruses cause disease; Influenza A is the most clinically significant.

• Viral Structure: - Size: 80–120 nm diameter. - Composition: Lipid envelope with hemagglutinin (H) and neuraminidase (N) spikes. - Mechanism: H binds to sialic acid receptors; N cleaves virus from cell membrane.

• Genetics & Evolution: - Influenza A: Segmented RNA genome enables antigenic drift (epitope changes) and shift (reassortment). - Pandemic triggers: Occur after antigenic shifts (e.g., 1918 H1N1, 2009 H1N1pdm).

Definition (Harrison's 22e): Influenza A viruses have eight single-strand negative-sense RNA segments in their genomes that encode hemagglutinin and neuraminidase as well as internal genes, including polymerase, matrix, nucleoprotein, and nonstructural genes.

• Strain Specifics: - Influenza B: Two lineages (Yamagata/Victoria) with limited antigenic variability. - Influenza C: Causes mild, intermittent disease; limited clinical data.

• Swine Influenza: - Role: Act as "mixing vessels" for avian/human influenza reassortment. - Mechanism: Dual α-2,6- and α-2,3-galactose receptors on respiratory epithelium enable interspecies transmission. - 2009 H1N1pdm was a reassorted virus with avian, human, and swine gene segments.

• Pathogenesis: - Target: Ciliated cells in the upper respiratory tract; epithelial denudation contributes to symptoms and secondary bacterial infections. - Incubation Period: 48–72 hours (short for a viral illness). - Systemic Symptoms: Linked to cytokine release (especially in H5N1 infections). - Immunity: Targets H/N epitopes; HAI antibodies correlate with protection. Research focuses on broadly neutralizing antibodies targeting hemagglutinin stalk regions.

3.1 Influenza A Viruses¶

Pandemics occur when new hemagglutinin/neuraminidase subtypes emerge from animal reservoirs.

• Historical Pandemic Timeline: - 1889–1890: H2N8 (Severe) - 1918–1919: H1N1 (Severe; caused 'cytokine storm' in young adults) - 1957–1958: H2N2 - 1968–1969: H3N2 - 2009–2010: H1N1pdm

• Emerging Threats: - H5N1: High pathogenicity but poor human-to-human transmission. - 2024 dairy cow outbreak of H5 avian influenza highlights zoonotic risks. - Sporadic infections in mammals (sea lions, goats) and humans via animal exposure.

3.2 Swine Influenza Viruses¶

Swine act as "mixing vessels" for avian/human influenza reassortment due to the presence of both α-2,6- and α-2,3-galactose receptors on respiratory epithelial cells.

4. CLINICAL FEATURES¶

Influenza presents with sudden onset of fever, chills, myalgia, and respiratory symptoms.

• Clinical Course: - Systemic Symptoms: 2–5 days duration. - Respiratory Symptoms: May persist longer (recurrent cough). - Post-infectious Effects: Fatigue and reduced pulmonary function may last weeks/months.

• Patient Variation: - Elderly patients: Often present with non-specific symptoms (fatigue, anorexia) rather than respiratory signs.

• Physical Examination Findings: - General: Ill appearance with sweating and coughing. - Mucosae: Nonpurulent conjunctivitis and diffuse pharyngeal erythema. - Pulmonary: Scattered rales, rhonchi, wheezes (lower respiratory involvement). - Musculoskeletal: Muscle pain elicited by pressure (calves/thighs). - Note: No rash associated with influenza.

5. DIFFERENTIAL DIAGNOSIS¶

Influenza must be differentiated from other viral illnesses with overlapping symptoms.

• Respiratory Syncytial Virus (RSV): - Children: Causes bronchiolitis. - Elderly: Nonspecific respiratory illness.

• SARS-CoV-2: - Overlap: Fever, cough, fatigue, muscle aches, congestion/rhinorrhea. - Distinction: Anosmia/ageusia (present in minority of cases).

• Co-infection: Consider both viruses during co-circulation periods.

6. INVESTIGATIONS & DIAGNOSIS¶

Microbiologic diagnosis is critical for individual management and public health surveillance.

Specimen Collection:
Nasopharyngeal specimens are optimal for viral recovery.
Diagnostic Modalities:
Rapid influenza diagnostic tests (RIDTs): Detect antigens; results in 10–15 minutes.
Rapid molecular assays (NAATs): Detect viral RNA; available for home use.
RT-PCR and viral culture: Used in specialized labs (Note: Culture is not suitable for initial diagnosis due to delayed results).
Multiplex tests: Panel of respiratory pathogens (influenza, RSV, parainfluenza, coronaviruses).
Serology:
Requires paired serum samples (convalescent phase at 2 weeks post-infection).
Laboratory Findings:
Leukopenia: Common finding.
Bacterial Infection Indicator: WBC >15,000/μL suggests secondary bacterial infection.

7. MANAGEMENT & TREATMENT¶

Vaccination is the primary prevention strategy; antiviral therapy is indicated for high-risk patients.

Vaccination Strategy:
Inactivated Vaccines: Trivalent or quadrivalent (egg or cell-based).
High-dose Inactivated: For patients ≥65 years.
Recombinant & Adjuvanted: Additional inactivated options.
Live-attenuated Intranasal Vaccine (LAIV):
Not licensed for children <2 years due to risk of wheezing and hospitalization.
Efficacy: Approximately 59% in adults 18–65 years.
Antiviral Therapy:
Neuraminidase Inhibitors (Oseltamivir, Zanamivir):
Timing: Most effective if administered within 48 hours of symptom onset.
Indications: Hospitalized patients, immunocompromised individuals, and those with comorbidities.
Special Considerations:
Egg Allergy: No additional safety measures required beyond standard protocols.
Anaphylaxis: History of severe allergic reaction to any vaccine component is an absolute contraindication.

8. PROGNOSIS & COMPLICATIONS¶

Complications are more common in high-risk groups (elderly, children, pregnant women, immunosuppressed).

• Secondary Bacterial Pneumonia: - Highest risk: Elderly patients and those with COPD.

• Extrapulmonary Complications: - Myocarditis, encephalitis, sepsis.

• Mortality Patterns: - 1918 H1N1: High mortality in young adults (25–34 years) due to cytokine storm.

9. SPECIAL CONSIDERATIONS¶

High-priority groups for vaccination and treatment include:

• Pediatric: - Children 6–59 months. - Children/adolescents (6 months to 18 years) at risk for Reye syndrome (receiving aspirin/salicylates).

• Geriatric & High Risk: - Adults ≥50 years. - Residents of nursing homes and long-term-care facilities. - Individuals with BMI ≥40.

• Medical Conditions: - Chronic pulmonary (including asthma), cardiovascular (except isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus). - Immunocompromised individuals (any cause, including medications or HIV infection).

• Pregnancy: - Women who are or plan to be pregnant during the influenza season.

• Contacts and Caregivers: - Healthcare personnel in inpatient/outpatient settings. - Medical emergency-response workers, autopsy personnel. - Household contacts of children ≤59 months and adults ≥50 years.

10. KEY PEARLS & CLINICAL TRAPS¶

• Timing is Critical: Neuraminidase inhibitors must be started within 48 hours of symptom onset for maximum efficacy.

• Vaccine Efficacy: Approximately 59% in adults 18–65 years; varies by age and health status.

• Age-Specific Risks: - <2 years: LAIV contraindicated due to wheezing risk. - ≥65 years: High-dose inactivated vaccines available.

• Pathogen Differentiation: Influenza A is the primary driver of pandemics; Swine viruses are key "mixing vessels" for reassortment.

• Clinical Distinction: Sudden onset and systemic symptoms (myalgia, fever) distinguish influenza from many other respiratory infections.

• Bacterial Risk: WBC >15,000/μL is a key indicator of secondary bacterial infection.

Reference Tables¶

TABLE 206-1 Emergence of Antigenic Subtypes of Influenza A Virus Associated with Pandemic or Epidemic Disease YEARS…¶

Harrison's 22e, p.1545

YEARS SUBTYPE	EXTENT OF OUTBREAK
1889–1890 H2N8a	Severe pandemic
1918–1919 H1N1b (formerly HswN	1) Severe pandemic
1946–1947 H1N1	Mild epidemic
1968–1969 H3N2	Moderate pandemic
2009–2010d H1N1	Pandemic

TABLE 206-2 High-Risk Groups Who Should Be Assigned a High Priority for Influenza Immunization and Treatment a…¶

Harrison's 22e, p.1546

High-Risk Group
Children 6–59 months of age
Adults ≥50 years of age
Persons with chronic pulmonary (including asthma), cardiovascular (except
isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic
disorders (including diabetes mellitus)
Persons who are immunocompromised (any cause, including medications or HIV
infection)
Women who are or plan to be pregnant during the influenza season
Children and adolescents (6 months through 18 years of age) who are receiving
aspirin- or salicylate-containing medications and who might be at risk for Reye
syndrome
Residents of nursing homes and other long-term-care facilities
American Indians/Alaska Natives
Persons who are extremely obese (body mass index ≥40)
Contacts and Caregivers
Caregivers and contacts of those at risk: health care personnel in inpatient and
outpatient care settings who have the potential for exposure to patients or to
infectious materials, medical emergency-response workers, autopsy personnel,
employees of nursing home and long-term-care facilities who have contact with
patients or residents, and students and trainees in these professions who have
contact with patients
Household contacts and caregivers of children ≤59 months (i.e., <5 years) of age
(particularly contacts of infants <6 months old) and adults ≥50 years of age
Household contacts (including children) and caregivers of persons who are in a
high-risk group

TABLE 206-3 Categories of Vaccines Licensed for Prevention of Seasonal Influenza, United States Route Approved ages HA…¶

Harrison's 22e, p.1548

	LIVE ATTENUATED	NONREPLICATING VACCINES
		STANDARD INACTIVATED	HIGH-DOSE INACTIVATED	RECOMBINANT	ADJUVANTED INACTIVATED
Route	Intranasal	Intramuscular	Intramuscular	Intramuscular	Intramuscular
	2–49 years	≥6 months	≥65 years	≥18 years
HAa	15	15	60	45	15
	Eggs	Eggs/cell culture	Eggs	Cell culture
Number of strains	3	3	3	3	3