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Summary Table

Feature	Detail
Risk Factors	Age extremes (children <5, adults ≥65), pregnancy, immunosuppression, chronic cardiopulmonary disease (COPD, asthma, heart failure), obesity (BMI ≥40), nursing home residents, healthcare workers
Etiology	Influenza A or B virus (orthomyxovirus family); transmitted via respiratory droplets and fomites; Influenza A is responsible for pandemics due to antigenic shift
Patient Presentation	Abrupt onset of high fever, myalgia, headache, dry cough, sore throat, and malaise; often described as "sudden-onset flu-like illness during winter months"
Classic Physical Exam	Febrile, ill-appearing, diffuse myalgia, pharyngeal erythema without exudate, clear lungs on auscultation (unless complicated by pneumonia)
Key Diagnostic Results	Rapid influenza diagnostic test (RIDT) for screening; RT-PCR for confirmation; chest X-ray if pneumonia suspected (bilateral interstitial infiltrates in primary viral pneumonia)
Management	Oseltamivir (oral) within 48 hours of symptom onset; supportive care; annual vaccination for prevention
Keywords	"Abrupt onset," "myalgia," "winter season," "dry cough and high fever," "sick contacts," "antigenic shift vs. drift"

1. Pathophysiology

Influenza virus belongs to the Orthomyxoviridae family and contains a segmented, single-stranded, negative-sense RNA genome. The two surface glycoproteins that drive both pathogenesis and immune evasion are hemagglutinin (HA) and neuraminidase (NA).

Hemagglutinin binds to sialic acid residues on respiratory epithelial cells, allowing the virus to attach and enter the host cell. This is the primary target of neutralizing antibodies and the key antigen in influenza vaccines. Once the virus replicates inside the cell, neuraminidase cleaves sialic acid on the host cell surface, releasing newly formed virions to infect neighboring cells. This is the enzymatic target of oseltamivir and zanamivir.

The virus causes direct cytopathic damage to the respiratory epithelium, leading to cell death and denudation of the mucosal surface. This explains the dry, nonproductive cough and sore throat. The denuded epithelium also creates a vulnerability to secondary bacterial infection, most commonly by Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.

The systemic symptoms (high fever, myalgia, headache, profound malaise) are driven by a robust cytokine response, particularly IL-6, TNF-alpha, and interferons. This is why influenza feels disproportionately severe compared to other upper respiratory infections. The abrupt, dramatic onset of systemic symptoms is the hallmark that distinguishes influenza from the common cold.

Understanding the segmented genome is critical for exam purposes. Because the genome is divided into 8 segments, reassortment can occur when two different influenza strains co-infect the same cell (commonly in pigs or birds). This produces a completely novel HA or NA subtype, which the population has no pre-existing immunity against. This is called antigenic shift and is responsible for pandemics. In contrast, antigenic drift refers to gradual point mutations in HA and NA genes during normal replication, producing minor antigenic changes that cause seasonal epidemics and necessitate annual vaccine reformulation.

2. Classification and Clinical Manifestation

Influenza Virus Types

Type	Reservoir	Epidemiologic Significance	Antigenic Variation
A	Humans, birds, pigs, horses	Causes both epidemics and pandemics	Both antigenic shift and drift
B	Humans only	Causes seasonal epidemics only	Antigenic drift only (no animal reservoir for reassortment)
C	Humans	Causes mild upper respiratory illness; not clinically significant for exams	Minimal antigenic change

Clinical Manifestation Spectrum

Category	Presentation	Key Features
Uncomplicated influenza	Fever, cough, myalgia, headache, malaise, sore throat	Self-limited; resolves in 5 to 7 days; cough may persist up to 2 weeks
Primary viral pneumonia	Progressive dyspnea, persistent fever, bilateral infiltrates on CXR	Occurs within days of symptom onset; most common fatal complication; high mortality
Secondary bacterial pneumonia	Initial improvement followed by recurrence of fever, productive cough, consolidation on CXR	Classically presents as a biphasic illness; think S. aureus or S. pneumoniae
Myocarditis / Pericarditis	Chest pain, arrhythmia, heart failure symptoms	Rare but testable complication
Encephalitis	Altered mental status, seizures	More common in children; associated with Influenza A
Reye syndrome	Hepatic encephalopathy in children given aspirin during viral illness	Classic association: influenza or varicella + aspirin use in children
Myositis / Rhabdomyolysis	Severe muscle pain, elevated CK, dark urine	More common in children with Influenza B

3. Diagnostic Workup

Test	Role	Sensitivity	Turnaround Time	Notes
Rapid Influenza Diagnostic Test (RIDT)	Best initial test (point-of-care screening)	50 to 70%	15 to 30 minutes	High false-negative rate; a negative result does NOT rule out influenza
Rapid molecular assay (e.g., ID NOW)	Improved point-of-care testing	~95%	15 to 30 minutes	Increasingly used in clinical practice
RT-PCR	Most accurate / confirmatory test (gold standard)	>99%	1 to 6 hours	Detects viral RNA; differentiates influenza A vs. B and subtypes
Viral culture	Historical gold standard; now mainly for surveillance	High	3 to 7 days	Too slow for clinical decision-making
Chest X-ray	Indicated only when pneumonia is suspected	N/A	Immediate	Bilateral interstitial infiltrates in viral pneumonia; lobar consolidation suggests bacterial superinfection

In most outpatient settings during influenza season, the diagnosis is clinical. A patient presenting with abrupt onset of fever, myalgia, and cough during a known influenza outbreak does not routinely require laboratory confirmation to initiate treatment.

However, when testing is needed (hospitalized patients, immunocompromised hosts, atypical presentations, or infection control purposes), the approach is as follows:

The RIDT is the best initial test because it is fast and widely available at the point of care. It detects viral nucleoprotein antigens via immunoassay. The key limitation to remember is its low sensitivity (50 to 70%), meaning a negative RIDT cannot be used to exclude influenza. If clinical suspicion remains high despite a negative RIDT, proceed to RT-PCR.

RT-PCR is the most accurate test and serves as the gold standard for confirmation. It detects viral RNA with greater than 99% sensitivity and can subtype influenza A (e.g., H1N1, H3N2). This is the preferred test for hospitalized patients and outbreak investigations.

Viral culture is no longer used for clinical diagnosis due to slow turnaround but remains important for public health surveillance and antiviral resistance testing.

Obtain a chest X-ray only when you suspect a complication such as pneumonia. In primary viral pneumonia, expect bilateral diffuse interstitial or ground-glass infiltrates. In secondary bacterial pneumonia, expect focal lobar consolidation, often appearing after a brief period of clinical improvement (the "biphasic pattern").

4. Management and Treatment

Scenario	Agent	Dose (Adults)	Route	Duration	Notes
Standard treatment	Oseltamivir	75 mg twice daily	Oral	5 days	Most tested drug on exams; must start within 48 hours of symptoms
Alternative (inhaled)	Zanamivir	10 mg (2 inhalations) twice daily	Inhaled	5 days	Contraindicated in patients with underlying airway disease (asthma, COPD)
Single-dose option	Baloxavir marboxil	Weight-based single dose	Oral	Single dose	Cap-dependent endonuclease inhibitor; approved for ages ≥5 and high-risk patients
IV option (hospitalized)	Peremivir	600 mg single dose	IV	Single dose	For patients unable to take oral or inhaled medications
Chemoprophylaxis	Oseltamivir	75 mg once daily	Oral	Duration of exposure or 7 days post-exposure	For unvaccinated high-risk contacts during outbreaks
Prevention	Inactivated influenza vaccine (IIV) or live attenuated (LAIV)	Annual	IM (IIV) or intranasal (LAIV)	Yearly	LAIV contraindicated in pregnancy, immunosuppression, age <2, and asthma in children

Acute Stabilization

For uncomplicated influenza, the mainstay of treatment is oseltamivir 75 mg orally twice daily for 5 days, ideally initiated within 48 hours of symptom onset. The 48-hour window is the most commonly tested concept. Oseltamivir is a neuraminidase inhibitor that prevents release of new virions from infected cells, thereby limiting viral spread.

However, for hospitalized patients, severely ill patients, or those with progressive disease, antiviral therapy should be initiated regardless of the duration of symptoms. Do not withhold treatment in a critically ill patient simply because more than 48 hours have passed.

Zanamivir is an inhaled neuraminidase inhibitor and serves as an alternative. The key contraindication to remember is underlying airway disease (asthma or COPD), because the inhaled formulation can trigger bronchospasm.

Baloxavir marboxil is a newer agent that inhibits the cap-dependent endonuclease, blocking viral mRNA synthesis. It is given as a single oral dose and is approved for uncomplicated influenza in patients aged 5 and older, or for high-risk patients aged 12 and older. This is increasingly appearing on exams as an alternative option.

Supportive care includes antipyretics (acetaminophen or ibuprofen), adequate hydration, and rest. In children with influenza, avoid aspirin due to the risk of Reye syndrome.

Secondary Bacterial Pneumonia Management

If a patient with influenza develops a biphasic illness with recurrence of fever and new productive cough with lobar consolidation, treat for secondary bacterial pneumonia. Empiric coverage should target S. aureus (including MRSA in high-risk settings), S. pneumoniae, and H. influenzae. This typically requires a beta-lactam plus coverage for MRSA if risk factors are present (e.g., vancomycin or linezolid).

Prevention

Annual influenza vaccination is the single most important preventive measure. The inactivated influenza vaccine (IIV) is recommended for all individuals aged 6 months and older, including pregnant women. The live attenuated influenza vaccine (LAIV), given intranasally, is contraindicated in pregnancy, immunocompromised patients, children younger than 2 years, and children with asthma or wheezing.

Post-exposure chemoprophylaxis with oseltamivir (75 mg once daily for the duration of exposure or at least 7 days) is indicated for unvaccinated high-risk individuals exposed to a confirmed case.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Common cold (rhinovirus)	Both cause cough, sore throat, and nasal congestion	Common cold has gradual onset, predominant nasal symptoms, and no or minimal fever; influenza has abrupt onset with high fever and prominent myalgia
COVID-19	Fever, cough, myalgia, respiratory distress	COVID-19 more commonly features anosmia/ageusia, may have a longer incubation period (2 to 14 days vs. 1 to 4 days), and is confirmed by SARS-CoV-2 RT-PCR
Streptococcal pharyngitis	Fever, sore throat, malaise	Strep pharyngitis presents with tonsillar exudate, anterior cervical lymphadenopathy, and absence of cough (Centor criteria); influenza has prominent cough and myalgia
Infectious mononucleosis (EBV)	Fever, pharyngitis, malaise, fatigue	Mono presents with posterior cervical lymphadenopathy, splenomegaly, and atypical lymphocytes on smear; course is more prolonged (weeks)
Bacterial pneumonia	Fever, cough, dyspnea	Bacterial pneumonia typically shows focal lobar consolidation with productive purulent sputum and elevated WBC with left shift; influenza pneumonia is diffuse and bilateral
Mycoplasma pneumonia	Dry cough, low-grade fever, young patient	Mycoplasma has a more insidious onset, walking pneumonia pattern, and bullous myringitis may be present; lacks the acute systemic toxicity of influenza
Acute HIV seroconversion	Fever, myalgia, pharyngitis, rash, malaise	History of recent high-risk sexual exposure, presence of diffuse maculopapular rash, and mucosal ulcers distinguish this; confirmed by HIV RNA viral load

6. Traps and High-Yield Pearls

The single most common way students miss influenza questions is by not recognizing the clinical scenario as influenza at all. Test-writers rarely hand you the word "flu." Instead, they describe a patient with abrupt-onset fever, severe myalgia, dry cough, and headache during December or January, and expect you to connect that pattern to influenza without being told the diagnosis.

The second major trap is the 48-hour treatment window. Many students know oseltamivir must be started within 48 hours but then incorrectly withhold it in a hospitalized or severely ill patient who presents beyond that window. The guideline is clear: for hospitalized patients and those with severe or progressive illness, start antiviral therapy at any time point regardless of symptom duration.

A classic distractor involves zanamivir. When the vignette mentions a patient with asthma or COPD who needs antiviral therapy, zanamivir will appear as an answer choice. The correct answer is oseltamivir (oral), because zanamivir (inhaled) is contraindicated in patients with reactive airway disease.

Another high-yield trap involves children. If a child with a viral illness is given aspirin and subsequently develops vomiting, hepatomegaly, and altered mental status, this is Reye syndrome, not worsening influenza.

Finally, be sure you understand the distinction between antigenic shift and antigenic drift. Drift causes seasonal epidemics and is the reason for annual vaccine updates. Shift causes pandemics and involves reassortment of genome segments between different influenza A subtypes, typically involving an animal reservoir. Influenza B does not undergo antigenic shift because it lacks a significant animal reservoir. This is a foundational virology concept that appears repeatedly across different question formats.

The core competency being tested across all influenza questions is the ability to recognize the classic acute presentation, initiate timely antiviral therapy, and identify complications (especially secondary bacterial pneumonia with its biphasic course) before they progress.

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