Respiratory

Influenza: diagnosis, antivirals, and post-exposure prophylaxis

Clinical Overview and When to Suspect Influenza

— Abrupt onset of fever (often 38.5–40°C), myalgias, headache, malaise

— Dry cough, sore throat, nasal congestion

— Symptom onset within 48–72 hours (rapid progression distinguishes flu from most colds)

— Elderly: low-grade or no fever, anorexia, altered mental status, falls, decompensation of CHF/COPD

— Infants: sepsis-like picture, apnea, poor feeding

— Immunocompromised: prolonged viral shedding, atypical pneumonia

Influenza is an acute respiratory viral illness caused by influenza A (H1N1, H3N2) and B viruses, circulating in the US predominantly October–May with peak activity December–February.

Disease burden in a typical season: 20–40 million infections, 200,000–700,000 hospitalizations, and 20,000–50,000 deaths, concentrated in adults ≥65, infants, pregnant patients, and those with chronic cardiopulmonary disease.

Suspect influenza in any patient presenting during local influenza activity with:

Atypical presentations the test will hide the diagnosis behind:

Transmission: large respiratory droplets and contact; incubation 1–4 days, infectious from 1 day before symptoms to ~5–7 days after (longer in children and immunocompromised).

Ambulatory Step 3 framing: during peak season, clinical diagnosis alone is appropriate for outpatients without high-risk features who present within 48 hours — testing is not required to start antivirals if it would delay therapy.

Step 3 management: In an outpatient with classic influenza-like illness during widespread community influenza activity, do not wait for confirmatory testing to start oseltamivir in high-risk patients — empiric treatment within 48 hours of onset has the strongest mortality and complication benefit.

Board pearl: Positive predictive value of "fever + cough" during peak season approaches 80%, but plummets in May–September — out-of-season "flu" should prompt consideration of COVID-19, RSV, parainfluenza, or adenovirus before anchoring.

Presentation Patterns and Key History

— Sudden onset ("I was fine at lunch, sick by dinner") vs gradual onset of viral URI

— Prominent systemic symptoms: myalgia (especially back/thighs), prostration, headache, chills

— Respiratory symptoms: nonproductive cough, pharyngitis, rhinorrhea (less dominant than systemic features)

— GI symptoms: nausea, vomiting, diarrhea — more common in children and with influenza B

— <48 hours: full benefit of neuraminidase inhibitors and baloxavir

— >48 hours: still treat if hospitalized, pregnant, immunocompromised, or with severe/progressive disease

— Household or workplace contacts with confirmed flu

— Long-term care facility residence or employment

— Recent travel, particularly with poultry/swine exposure (consider novel/zoonotic strains)

— Age <2 or ≥65, pregnancy/postpartum ≤2 weeks, BMI ≥40

— Asthma/COPD, CHF, CAD, CKD, DM, hemoglobinopathy, immunosuppression

— Nursing home residence, American Indian/Alaska Native heritage

Classic influenza-like illness (ILI) is defined by CDC as temperature ≥100°F (37.8°C) plus cough and/or sore throat without another known cause.

Hallmark history elements to elicit:

Time-from-onset is the single most important historical data point because it drives antiviral eligibility:

High-risk exposure history:

Vaccination history is essential but does not exclude flu — vaccine effectiveness varies 10–60% by season and strain match.

Comorbidity screen that changes management:

Key distinction: Influenza vs COVID-19 cannot be reliably separated by history alone — both cause fever, cough, myalgia; anosmia favors COVID but is not specific. Multiplex PCR is now standard of care when both are circulating because management diverges (Paxlovid vs oseltamivir).

Board pearl: A biphasic course — initial improvement at days 3–5 followed by recurrent fever, productive cough, and pleuritic pain — is the classic stem for secondary bacterial pneumonia, most often S. pneumoniae, S. aureus (including MRSA), or H. influenzae.

Physical Exam Findings and Severity Assessment

— Fever 38–40°C is typical; absence does not exclude flu, especially in elderly or after antipyretics

— Tachycardia proportional to fever; disproportionate tachycardia raises concern for myocarditis or sepsis

— Tachypnea (RR >24), SpO₂ <94% on room air, or hypotension → escalate

— Erythematous pharynx without exudate, nonpurulent conjunctival injection

— Cervical lymphadenopathy modest (prominent nodes suggest mononucleosis or strep)

— Lungs typically clear in uncomplicated flu; rales, focal consolidation, or egophony suggest pneumonia (primary viral or secondary bacterial)

— CURB-65 or PSI if pneumonia suspected

— qSOFA ≥2 (RR ≥22, SBP ≤100, altered mentation) suggests sepsis trajectory

Vital signs drive triage more than any single physical finding:

HEENT and respiratory exam:

Cardiovascular: listen for new murmurs, friction rub, S3 — myocarditis and pericarditis are recognized complications; JVD and crackles may indicate decompensated CHF triggered by flu.

Neurologic: assess mental status carefully in elderly; meningismus, focal deficits, or seizures warrant evaluation for encephalitis or influenza-associated encephalopathy (especially pediatric).

Hydration status: mucous membranes, capillary refill, skin turgor — vomiting/diarrhea plus poor intake commonly produce prerenal AKI.

Severity tools for outpatient disposition:

CCS pearl: In a simulated case, order vitals q4h, continuous pulse oximetry if SpO₂ ≤94%, and strict I/Os — early detection of declining oxygenation or oliguria is what advances the case toward correct ICU transfer or IV fluid orders.

Board pearl: Bilateral diffuse crackles with hypoxemia within the first 48 hours of flu onset in a young, otherwise healthy adult is the stem for primary influenza viral pneumonia — a rapidly progressive entity historically associated with H1N1 pandemic strains and pregnant patients. This requires inpatient oseltamivir (often 10-day course), oxygen, and ICU readiness rather than reassurance.

Diagnostic Workup — Initial Testing

— Hospitalized patients (all)

— High-risk outpatients where antiviral decision depends on confirmation

— Patients in congregate settings (LTCF, prisons) for outbreak control

— Pregnancy, immunocompromise, severe/progressive disease

— RT-PCR / NAAT (nucleic acid amplification): gold standard; sensitivity >95%, specificity >99%; differentiates A vs B and many subtypes; preferred for hospitalized patients

— Rapid molecular assays (e.g., ID NOW, Cepheid Xpert): point-of-care NAAT, sensitivity 90–95% — acceptable for outpatient and ED use

— Rapid influenza diagnostic tests (RIDTs, antigen-based): sensitivity only 50–70%, specificity ~98%; negative result does not rule out flu during high prevalence

— Viral culture and serology: epidemiologic/research use, not for clinical decisions

— Multiplex RT-PCR (flu A/B, SARS-CoV-2, RSV) is now standard in most US EDs and inpatient settings

— Order based on local epidemiology and CDC guidance

— CBC (often leukopenia or normal WBC; high WBC suggests bacterial superinfection)

— BMP (AKI, electrolytes from GI losses)

— LFTs, CK (rhabdomyolysis with severe myalgia), lactate if septic

— Procalcitonin can support but not exclude bacterial coinfection

Testing is not required for outpatients with classic ILI during peak local activity if the result will not change management — empiric treatment is acceptable.

Test when results will change management:

Available diagnostic tests, ranked by test characteristics:

Specimen of choice: nasopharyngeal swab > nasal swab > throat swab; for intubated patients use endotracheal aspirate or BAL (upper airway specimens may miss lower-tract infection).

Concurrent testing during co-circulation:

Adjunct labs in hospitalized or moderately ill patients:

Step 3 management: In a hospitalized patient with suspected influenza, send NAAT plus chest X-ray, CBC, BMP, and start empiric oseltamivir within 1 hour — do not wait for the PCR result before treating.

Board pearl: A negative RIDT in a symptomatic patient during peak season should be confirmed by RT-PCR before withholding antivirals or stopping isolation.

Advanced and Confirmatory Studies

— Chest X-ray first line — patterns include bilateral interstitial infiltrates (primary viral pneumonia), lobar consolidation (secondary bacterial), or mixed

— CT chest reserved for diagnostic uncertainty, immunocompromise, or progressive disease — may show ground-glass opacities, peribronchial thickening, or cavitation (suggests MRSA)

— Indicated for severe cases not responding to therapy, suspected zoonotic exposure (H5, H7), outbreaks, or surveillance

— Oseltamivir resistance is rare overall (<1%) but has emerged in H1N1pdm09 strains (H275Y mutation) — switch to zanamivir or baloxavir if suspected

— Troponin and ECG if chest pain, arrhythmia, or hemodynamic instability — myocarditis can present 1–2 weeks after illness

— Echocardiography for new heart failure or persistent troponin elevation

— LP for suspected encephalitis (CSF often normal or mild lymphocytic pleocytosis; PCR of CSF rarely positive — diagnosis often clinical)

— MRI brain for encephalopathy/encephalitis, especially acute necrotizing encephalopathy in children

Chest imaging when pneumonia is suspected:

Subtyping and resistance testing (public health, CDC, or reference lab):

Workup for complications:

Sputum/blood cultures before antibiotics in patients hospitalized with suspected bacterial superinfection.

ABG and lactate in severe respiratory distress or sepsis physiology.

CCS pearl: When the simulated case shows a flu patient deteriorating on day 5 with new fever and productive sputum, order CBC, blood cultures ×2, sputum Gram stain/culture, chest X-ray, lactate, and add empiric ceftriaxone + vancomycin (MRSA coverage) — continue oseltamivir; do not stop it.

Key distinction: Primary viral pneumonia appears within 1–3 days of flu onset with bilateral diffuse infiltrates and hypoxemia. Secondary bacterial pneumonia appears 4–14 days in with focal consolidation after initial improvement — both require antibiotics if any consolidative pattern is present, because differentiation is rarely clean.

Board pearl: A flu patient with cavitary lung lesions and rapid deterioration → MRSA pneumonia until proven otherwise; cover with vancomycin or linezolid (linezolid preferred if necrotizing toxin–mediated disease is suspected).

Risk Stratification and Treatment Decision Logic

— Age <2 or ≥65

— Pregnancy or ≤2 weeks postpartum

— BMI ≥40

— Chronic pulmonary (asthma, COPD), cardiac (not isolated HTN), renal, hepatic, hematologic, metabolic (DM), neurologic disease

— Immunosuppression (HIV, malignancy, chemotherapy, biologics, post-transplant)

— Long-term care facility residents

— American Indian/Alaska Native persons

— Children on chronic aspirin (Reye syndrome risk)

→ Treat regardless of symptom duration; greatest benefit within 48 hours.

— Hydration, rest, acetaminophen or ibuprofen for fever/myalgia

— Avoid aspirin in children/adolescents (Reye syndrome)

— Return precautions: worsening dyspnea, chest pain, persistent fever >3 days, confusion

Step 3 logic: every patient with confirmed or suspected influenza needs a treatment decision based on (1) severity, (2) risk category, and (3) time from symptom onset.

Tier 1 — Hospitalized or severe/progressive illness: treat with antivirals regardless of duration of symptoms. Oseltamivir is first line; can be started even >5 days into illness if still symptomatic.

Tier 2 — High-risk outpatients (any of):

Tier 3 — Healthy outpatients with uncomplicated illness, symptoms <48 hours: antiviral therapy is a shared decision — modest benefit (shortens illness ~1 day, may reduce complications); IDSA/CDC recommend offering treatment.

Tier 4 — Healthy outpatient, >48 hours from onset, improving: supportive care only — no antiviral benefit demonstrated.

Supportive care across all tiers:

Step 3 management: A 72-year-old with COPD presenting on day 3 of fever and cough during flu season → start oseltamivir now, even though >48 hours have elapsed; high-risk status overrides the 48-hour rule.

Board pearl: Antibiotics are not indicated in uncomplicated influenza — adding azithromycin "just in case" is a wrong answer unless there is evidence of bacterial superinfection (focal consolidation, persistent/biphasic fever, purulent sputum, marked leukocytosis).

Pharmacotherapy — First-Line Antivirals

— Adult treatment dose: 75 mg PO BID × 5 days

— Active against influenza A and B

— Approved from age ≥2 weeks; weight-based pediatric dosing

— Adverse effects: nausea/vomiting (take with food), rare neuropsychiatric events (especially in adolescents in Japan — counsel, don't withhold)

— Renal dose adjustment required (see chunk 9)

— 10 mg (two 5-mg inhalations) BID × 5 days

— Age ≥7 for treatment

— Contraindicated in asthma/COPD (bronchospasm risk) — major exam trap

— Useful when oseltamivir resistance suspected

— Single 600 mg IV dose over 15–30 min for adults ≥6 months

— Useful when oral/inhaled routes are not feasible (ICU, severe N/V)

— Hospitalized patients with severe disease often receive oseltamivir via NG tube rather than peramivir

— 40 mg (40–80 kg) or 80 mg (≥80 kg) PO ×1

— Approved age ≥5 for treatment (per current labeling)

— Not recommended in pregnancy, breastfeeding, hospitalized severely ill patients, or complicated influenza — limited data

— Avoid co-administration with dairy, calcium, iron, antacids (chelation)

— Rapid emergence of reduced-susceptibility variants (PA/I38) — single-agent use in immunocompromised discouraged

Four FDA-approved classes; neuraminidase inhibitors are workhorses; baloxavir is newer cap-dependent endonuclease inhibitor.

Oseltamivir (Tamiflu) — first line for nearly all patients:

Zanamivir (Relenza) — inhaled:

Peramivir (Rapivab) — IV:

Baloxavir marboxil (Xofluza) — oral, single dose:

Hospitalized/severe disease: oseltamivir 75 mg BID is standard; some experts use higher doses in obesity or critical illness, though evidence for benefit is limited. Duration may extend beyond 5 days if persistently positive or critically ill.

Adamantanes (amantadine, rimantadine): no longer recommended — universal resistance in circulating influenza A; inactive against B.

Step 3 management: Default antiviral is oseltamivir for treatment and post-exposure prophylaxis in nearly every Step 3 vignette — only deviate for specific contraindications.

Antiviral Timing, Duration, and Post-Exposure Prophylaxis

— Standard treatment: 5 days of oseltamivir (or single-dose baloxavir/peramivir)

— Severe/hospitalized or immunocompromised: extend to 10 days or until clinical improvement and viral clearance

— Indication: high-risk individuals with close contact (within 6 ft for prolonged time, household exposure) to a confirmed flu case, within the prior 48 hours, AND who are either unvaccinated, vaccinated <2 weeks ago, or with conditions limiting vaccine response

— Drug of choice: oseltamivir 75 mg PO once daily × 7 days after last known exposure (zanamivir 10 mg inhaled daily as alternative; baloxavir single dose is also FDA-approved for PEP ≥5 yo)

— Pre-emptive treatment dose (BID) is preferred over prophylactic dose if the contact develops symptoms — switch immediately

— Initiate facility-wide chemoprophylaxis for all residents (vaccinated or not) and unvaccinated staff at the earliest sign of an outbreak (≥2 cases within 72 hours)

— Continue for ≥14 days AND until 7 days after the last new case identified

— Vaccinate unvaccinated staff/residents concurrently

Timing principle: greatest benefit within 48 hours of symptom onset (reduces illness by ~1 day, decreases complications, hospitalization, and mortality in high-risk groups). Benefit persists in hospitalized/severe disease started up to 4–5 days in.

Duration:

Post-exposure prophylaxis (PEP) — high-yield Step 3 territory:

Institutional outbreaks (LTCF, hospitals):

Vaccination is not a substitute for PEP in already-exposed high-risk persons because immunity takes ~2 weeks to develop — give both.

Step 3 management: Healthy household member of a confirmed flu case with no risk factors → no chemoprophylaxis needed; recommend vaccination if not already done, monitor for symptoms, start early treatment if ILI develops.

Board pearl: In a nursing home with 2 confirmed influenza cases in 72 hours, start oseltamivir prophylaxis for all residents immediately, even those already vaccinated, and continue for at least 14 days and 7 days past the last case — this is the canonical USMLE outbreak-management answer.

CCS pearl: When closing a case involving an index flu patient with high-risk household contacts, order chemoprophylaxis prescriptions for the contacts as part of the disposition — failure to address contacts loses points.

Special Populations — Elderly and Renal/Hepatic Impairment

— Highest mortality group; account for ~70–85% of seasonal flu deaths

— Atypical presentation: low-grade or absent fever, confusion, falls, decompensated chronic disease

— Treat all symptomatic elderly with oseltamivir regardless of symptom duration

— Vaccination: prefer high-dose inactivated (Fluzone HD), adjuvanted (Fluad), or recombinant (Flublok) vaccine — ACIP gives a preferential recommendation for these higher-immunogenicity products in adults ≥65

— Monitor for drug interactions (warfarin INR may rise during acute illness; statins, antihypertensives may need adjustment during dehydration)

— CrCl >60: 75 mg BID (standard)

— CrCl 31–60: 30 mg BID

— CrCl 10–30: 30 mg once daily

— ESRD on hemodialysis: 30 mg after every other HD session (×5 days total, ~3 doses)

— ESRD on peritoneal dialysis: 30 mg once weekly

— For prophylaxis, halve the treatment frequency at each level

— Oseltamivir: minimal interactions; live attenuated flu vaccine (LAIV) is inactivated if given within 48 h before or 2 weeks after oseltamivir — reschedule vaccination

— Baloxavir: avoid with polyvalent cations (Ca, Mg, Fe, Al, dairy); reduces absorption

Elderly (≥65):

Renal impairment — oseltamivir dose adjustments (high-yield):

Peramivir also requires renal adjustment; baloxavir does not (no adjustment for CrCl ≥50; limited data below).

Hepatic impairment: no dose adjustment required for oseltamivir in mild-moderate; data limited in severe — use with monitoring.

Drug-drug interactions:

Step 3 management: Hospitalized 80-year-old with CrCl 25 mL/min and confirmed influenza → oseltamivir 30 mg once daily × 5 days; do not omit therapy due to renal disease — adjust the dose instead.

Board pearl: "Tamiflu doesn't work in the elderly" is a myth — observational data show reduced mortality and hospital length-of-stay even when started >48 h after onset in this group.

Key distinction: ACIP preferentially (not exclusively) recommends high-dose/adjuvanted/recombinant vaccines in ≥65; if unavailable, any age-appropriate inactivated vaccine is acceptable — never delay vaccination waiting for a "preferred" product.

Special Populations — Pregnancy, Pediatrics, and Immunocompromised

— Pregnant and ≤2 weeks postpartum patients are high-risk for severe influenza, ICU admission, and death (especially second/third trimester)

— Oseltamivir is the antiviral of choice in pregnancy — pregnancy category historical "C" but CDC and ACOG strongly recommend treatment as benefits clearly outweigh theoretical risks

— Treat empirically and immediately based on clinical suspicion — do not wait for confirmatory testing

— Standard dose 75 mg BID × 5 days; can extend if severe

— Avoid baloxavir (insufficient pregnancy data)

— Inactivated influenza vaccine recommended in any trimester; LAIV contraindicated in pregnancy

— Maternal vaccination protects infant for first 6 months (infants <6 months cannot be vaccinated)

— Children <5, especially <2, are at high risk for complications (otitis media, febrile seizures, pneumonia, myocarditis)

— Oseltamivir approved from 2 weeks of age; weight-based dosing:

– ≤15 kg: 30 mg BID

– 15–23 kg: 45 mg BID

– 23–40 kg: 60 mg BID

– >40 kg: 75 mg BID

— Baloxavir: ≥5 years for treatment and PEP

— Zanamivir: ≥7 years for treatment, ≥5 for PEP; avoid in reactive airways

— Aspirin is contraindicated (Reye syndrome — encephalopathy + hepatic failure)

— Annual vaccination from age 6 months; 2 doses ≥4 weeks apart for first-time vaccinees <9 years

— Prolonged viral shedding (weeks); higher resistance emergence on antivirals

— Treat early and longer (often 10 days); consider extended therapy guided by viral testing

— Combination therapy not routinely recommended; consult ID for severe/refractory cases

— Avoid LAIV entirely; give inactivated/recombinant vaccine

Pregnancy — high-yield, frequently tested:

Pediatrics:

Immunocompromised (HSCT, solid organ transplant, advanced HIV, B-cell depleting therapy):

Step 3 management: A 28-week-pregnant woman with 24 hours of fever, cough, myalgia in January → start oseltamivir 75 mg BID × 5 days immediately, send NP swab for confirmation, give acetaminophen for fever (avoid NSAIDs in 3rd trimester), counsel return precautions.

Board pearl: Untreated maternal hyperthermia in the first trimester is associated with neural tube defects — aggressive fever control with acetaminophen is part of flu management in pregnancy.

Complications and Adverse Outcomes

— Primary influenza viral pneumonia: occurs within 24–72 h of onset; bilateral diffuse infiltrates, hypoxemia, ARDS; young healthy adults, pregnant patients, cardiopulmonary comorbidities

— Secondary bacterial pneumonia: classic biphasic illness 4–14 days in; S. pneumoniae (most common), S. aureus including MRSA (often necrotizing/cavitary), H. influenzae, GAS

— Mixed viral-bacterial pneumonia frequent in severe disease

— Acute MI risk 6–10× higher in the 7 days following influenza infection (per NEJM 2018) — vaccination is a class I AHA/ACC cardiovascular prevention measure post-MI

— Myocarditis/pericarditis — chest pain, troponin elevation, arrhythmia; supportive care, restrict exercise

— Decompensation of CHF, atrial fibrillation

— Febrile seizures (children)

— Influenza-associated encephalopathy/encephalitis — confusion, seizures, coma; acute necrotizing encephalopathy in young children carries high mortality

— Guillain-Barré syndrome — rare post-infectious; far more often associated with the infection itself than with vaccination

— Transverse myelitis (rare)

Pulmonary complications — most common cause of flu-related death:

Cardiovascular:

Neurologic:

Musculoskeletal: myositis, rhabdomyolysis (calf pain in children, elevated CK, AKI risk) — more common with influenza B

Renal: AKI from dehydration, rhabdomyolysis, or sepsis

Hematologic: hemophagocytic lymphohistiocytosis (HLH) — rare but lethal

Otitis media, sinusitis — common in children

Reye syndrome: aspirin + viral illness (flu, varicella) → encephalopathy with fatty liver — never give aspirin to children with febrile illness

Pregnancy-specific: preterm labor, low birth weight, fetal loss with severe maternal illness

Step 3 management: Returning patient on day 6 of flu with new productive cough, fever rebound to 39.5°C, and focal right-lower-lobe rales → CXR, blood and sputum cultures, start ceftriaxone + azithromycin (community-acquired pneumonia regimen); add vancomycin/linezolid if severe, necrotizing/cavitary, or recent hospitalization.

Board pearl: A young athlete with recent flu who collapses during exercise — think myocarditis; restrict activity for 3–6 months after diagnosis pending cardiology clearance.

When to Escalate Care — Inpatient and ICU Triage

— SpO₂ <92–94% on room air or new oxygen requirement

— RR >24, HR >120 sustained, SBP <90, altered mental status

— Inability to tolerate oral intake; signs of dehydration with AKI

— Radiographic pneumonia plus comorbidity

— Pregnancy with moderate–severe illness

— Failure of outpatient therapy after 48–72 hours

— Social: unable to monitor at home, lives alone with frailty

— Need for mechanical ventilation or high-flow nasal cannula >6 L/min to maintain SpO₂ ≥92%

— Septic shock requiring vasopressors

— Severe ARDS (PaO₂/FiO₂ ≤200)

— Multiorgan failure, severe rhabdomyolysis with AKI, status epilepticus, severe myocarditis with arrhythmia

— Standard + droplet precautions until 24 hours after fever resolution (longer in immunocompromised, prolonged shedders)

— Private room; mask the patient during transport

— Consider airborne precautions during aerosol-generating procedures (intubation, bronchoscopy, BiPAP)

— Oseltamivir 75 mg BID (renal-adjusted) — start within 1 hour of suspicion, do not wait for PCR

— Supplemental O₂ to keep SpO₂ ≥92% (≥94% if pregnant)

— IV fluids judiciously (avoid volume overload in pneumonia/ARDS)

— CBC, BMP, LFTs, CK, lactate, troponin if cardiac concern

— CXR; consider POCUS lung; ABG if hypoxic

— VTE prophylaxis (enoxaparin 40 mg SC daily unless contraindicated)

— Acetaminophen scheduled for fever

— Infectious disease for immunocompromised, severe/refractory, suspected resistance, or novel strains

— Pulmonary/critical care for ARDS

— OB for pregnant patients (fetal monitoring after 23–24 weeks viability)

— Cardiology for suspected myocarditis or new HF

Outpatient → inpatient admission criteria (any of):

ICU criteria:

Infection control on admission:

Order set on admission:

Consults:

CCS pearl: In the simulated case, advance the clock 4–6 hours after starting oseltamivir and reassess SpO₂, RR, mental status; if worsening despite therapy, transfer to ICU, intubate for refractory hypoxemia, and add broad-spectrum antibiotics covering MRSA and S. pneumoniae. Order public health reporting if novel strain suspected.

Key Differentials — Same-Category Respiratory Viruses

— Overlapping symptoms; anosmia/ageusia more specific to COVID but not reliable

— Higher rate of dyspnea, longer incubation (2–14 days)

— Distinguish with multiplex NAAT — management diverges (nirmatrelvir-ritonavir, remdesivir vs oseltamivir)

— Coinfection ("flurona") possible — treat both

— Bronchiolitis/wheezing in infants and adults ≥65

— Often more wheezing and lower-tract findings than flu

— Confirmed by multiplex PCR

— No specific antiviral routinely used in immunocompetent adults; supportive care, nirsevimab for infants and RSV vaccine for ≥60 yo and pregnancy 32–36 weeks

— Croup in children (barking cough, stridor)

— Mild URI in adults; can cause LRTI in immunocompromised

— Pharyngoconjunctival fever, pneumonia in military recruits, gastroenteritis

— Can cause severe pneumonia in immunocompromised

— Common cold; gradual onset, prominent rhinorrhea, mild systemic symptoms, low/no fever

— Distinguishes from abrupt high-fever flu

— Indistinguishable from RSV clinically; multiplex PCR identifies

— Paroxysmal cough, post-tussive emesis, inspiratory whoop; prolonged (>2 weeks) cough; consider in unvaccinated/incomplete Tdap status

— Treat with macrolide (azithromycin)

— "Walking pneumonia" — gradual onset, low-grade fever, prolonged cough; treat with macrolide or doxycycline

COVID-19 (SARS-CoV-2):

RSV:

Parainfluenza:

Adenovirus:

Rhinovirus / coronaviruses (non-SARS):

Human metapneumovirus:

Bordetella pertussis:

Mycoplasma / Chlamydia pneumoniae:

Key distinction: Rhinovirus colds start gradually with sneezing and rhinorrhea, peak day 2–3, and rarely cause fever ≥38.5°C in adults. Influenza explodes onto the scene with fever, myalgia, and prostration first; respiratory symptoms follow.

Board pearl: When the vignette explicitly describes both flu and COVID circulating, multiplex PCR is the right test, and the right treatment depends on the result — don't anchor on flu.

Key Differentials — Other-Category Causes of Acute Febrile Illness

— Fever, sore throat, anterior cervical lymphadenopathy, tonsillar exudate, no cough (Centor criteria)

— Rapid strep / culture; treat with penicillin/amoxicillin

— Adolescent/young adult; posterior cervical lymphadenopathy, splenomegaly, pharyngitis, prolonged fatigue

— Heterophile (monospot) antibody; avoid contact sports for splenic rupture risk

— Fever, pharyngitis, mucocutaneous rash, lymphadenopathy 2–4 weeks post-exposure

— HIV RNA viral load is the diagnostic test (antibody may be negative); fourth-generation Ag/Ab combo helpful

— Pneumococcal: rust-colored sputum, lobar consolidation, single rigor

— Atypicals as above

— Subacute/chronic cough, hemoptysis, night sweats, weight loss; risk factors (endemic country, incarceration, HIV)

— CXR upper-lobe cavitation; respiratory isolation + IGRA/AFB sputum × 3

Bacterial pharyngitis (Group A Strep):

Infectious mononucleosis (EBV):

Acute HIV:

Early sepsis from any source: UTI/pyelonephritis, intra-abdominal, skin/soft tissue — check exam and history broadly; do not anchor on respiratory

Bacterial pneumonia without flu:

Tuberculosis:

PE: dyspnea + pleuritic chest pain + tachycardia, sometimes low-grade fever — D-dimer / CTPA; don't miss in postpartum, immobilized, or cancer patients with "flu-like" symptoms

Acute MI / myocarditis presenting as fatigue and dyspnea — check ECG/troponin if any red flags

Meningitis/encephalitis: fever + headache + altered mental status or meningismus → LP

Endocarditis: prolonged fever + IVDU/valvular disease + emboli; blood cultures ×3, TTE/TEE

Malaria, dengue, typhoid: returning traveler with fever — get travel history every time

Rocky Mountain spotted fever: fever, headache, rash starting wrists/ankles in endemic area summer; treat doxycycline empirically (don't wait for serology)

Key distinction: A "flu-like illness" with rash is rarely influenza — expand differential to acute HIV, RMSF, measles, parvovirus, meningococcemia, secondary syphilis.

Board pearl: The Step 3 trap is the "flu" vignette with subtle clues (travel, IVDU, rash, neck stiffness, tick exposure) — read every line; the right answer is usually not oseltamivir.

Secondary Prevention — Vaccination and Long-Term Plan

— Vaccinate by end of October ideally; continue offering through the season as long as virus circulates

— Don't vaccinate too early in adults ≥65 (Jul–Aug) — immunity may wane before season's end

— Inactivated influenza vaccine (IIV) — quadrivalent or trivalent (post-2024 ACIP shift to trivalent as B/Yamagata no longer circulating); IM

— Recombinant (RIV, Flublok) — egg-free; ≥18 yo; preferentially recommended in ≥65

— High-dose IIV (Fluzone HD) — ≥65; preferentially recommended

— Adjuvanted IIV (Fluad) — ≥65; preferentially recommended

— Live attenuated (LAIV, FluMist) — intranasal, age 2–49, healthy non-pregnant; FDA approved for at-home self-administration starting 2024–25 season

— Document flu episode in chart; confirm next-season vaccination plan

— Address comorbidity tune-up (asthma action plan, COPD inhaler review, CHF med titration)

— Pneumococcal vaccination if indicated (PCV20 or PCV15+PPSV23 in ≥65 or high-risk adults)

— Smoking cessation counseling (smokers have 2–4× flu hospitalization risk)

— Hand hygiene, cough etiquette

Annual influenza vaccination is recommended for everyone ≥6 months old without contraindication (CDC/ACIP).

Timing:

Vaccine options:

Contraindications to LAIV: pregnancy, immunocompromise, age <2 or ≥50, children on aspirin, asthma in age 2–4, anatomic/functional asplenia, CSF leak/cochlear implant, close contacts of severely immunocompromised

Egg allergy: ACIP (2023 update) — any vaccine appropriate for age can be given; no special precautions required regardless of severity of egg allergy

Coadministration: flu vaccine can be given same day as COVID-19, pneumococcal, Tdap, RSV, shingles, etc.

Post-flu discharge counseling:

Step 3 management: Patient discharged after flu pneumonia at age 67 — order PCV20 if pneumococcal-naïve, annual flu vaccine plan documented, RSV vaccine (shared decision-making ≥60 or routine ≥75 per latest ACIP), tobacco cessation, and follow-up CXR in 6–8 weeks to confirm resolution if infiltrate was present.

Board pearl: Vaccination reduces flu-associated MI by ~30%; AHA/ACC endorse annual flu vaccine as secondary CV prevention post-MI/CHF — a frequently tested high-yield association.

Follow-Up, Monitoring, and Counseling

— Telephone or telehealth check at 48–72 hours in high-risk patients to confirm clinical improvement

— Office visit at 5–7 days if not improving, or sooner with red flags

— Full recovery typically 7–14 days; cough/fatigue may persist 2–4 weeks

— Worsening shortness of breath or chest pain

— Persistent or recurrent fever after initial improvement (think bacterial superinfection)

— Confusion, severe lethargy, inability to keep fluids down

— In children: bluish color, not waking up, no tears when crying, decreased urine output, fever with rash

— In pregnancy: decreased fetal movement, vaginal bleeding, severe headache/visual changes

— Stay home until at least 24 hours after fever resolves without antipyretics

— Healthcare workers: per facility policy, generally same standard plus symptom resolution

— Primary care visit within 1–2 weeks of hospital discharge

— Repeat CXR at 6–8 weeks if pneumonia present, especially in smokers ≥40 (rule out underlying malignancy masked by post-pneumonic infiltrate)

— Repeat CBC and BMP if AKI or cytopenia during admission

— Cardiology follow-up if myocarditis (cardiac MRI at 3–6 months, exercise restriction)

— Resume held home medications; reassess diuretic dose post-volume status correction

— Confirm vaccine status updated at discharge

— Mark influenza in problem list with date and strain (A vs B) for surveillance and future history

— Note antiviral course completed

Outpatient follow-up cadence:

Return-precaution counseling (verbatim teach-back):

Work/school exclusion:

Post-discharge inpatient follow-up:

Medication reconciliation:

Documentation:

CCS pearl: When closing a hospitalized flu case, place orders for: PCP follow-up 1 week, flu vaccine before discharge if not given this season, smoking cessation counseling, PCV20 if eligible, and patient education on return precautions — these "discharge bundle" items frequently appear on the score sheet.

Board pearl: Influenza vaccination during the same hospitalization is acceptable and encouraged — do not defer to "outpatient follow-up"; missed opportunities are a Step 3 quality-of-care error.

Ethical, Legal, and Patient Safety Considerations

— Seasonal influenza is not universally reportable in adults, but pediatric influenza-associated deaths are nationally notifiable to CDC

— Novel influenza A (H5, H7, swine variants, any non-seasonal subtype) is immediately reportable to local/state health departments — Step 3 commonly tests this in poultry/swine exposure vignettes

— Outbreaks in LTCFs, schools, and healthcare settings require institutional and often public health reporting

— Strongly recommended; many institutions mandate with medical/religious exemptions

— Unvaccinated HCWs may be required to mask year-round or during outbreaks

— Ethically, HCWs have a duty to protect vulnerable patients — refusal is permissible but accommodations apply

— Vaccination consent includes discussion of common adverse effects (sore arm, low-grade fever), rare risks (GBS ~1 per million), and the VICP (Vaccine Injury Compensation Program) route for claims — flu vaccine is a covered vaccine

— Document refusal with reasons; offer at every subsequent encounter

— Prioritize high-risk patients during shortages

— Avoid over-prescribing baloxavir as single agent in immunocompromised (resistance emergence)

— Renal-adjusted oseltamivir dosing must be explicitly communicated to outpatient pharmacy and PCP — a frequent dosing error site

— Ensure household high-risk contacts get PEP prescriptions before index patient leaves the ED — failure here is a measurable safety lapse

— Droplet precautions are an institutional patient-safety mandate; lapses contribute to nosocomial outbreaks

— Cohort known flu patients if private rooms unavailable

— Document risks of untreated flu in pregnancy (preterm labor, ICU admission, death) when patient hesitates about oseltamivir — autonomy is respected, but informed refusal must be informed

— A patient refuses both vaccine and antivirals: respect autonomy if capacity intact; counsel about household contacts and isolation

— Pediatric vaccination refusal: most states allow exemptions; document, continue education, do not abandon care

Mandatory reporting:

Healthcare worker vaccination:

Informed consent:

Antiviral stewardship and shortages:

Transition-of-care safety:

Infection control compliance:

Pregnancy and shared decision-making:

Ethics edge cases:

Step 3 management: A poultry worker with severe pneumonia and confirmed influenza A unsubtypable by routine assay → place on airborne precautions, notify state/local public health within 24 hours, send specimen to public health lab for subtyping (H5 surveillance), continue oseltamivir while awaiting results. This is the canonical reportable-disease/novel-strain Step 3 question.

High-Yield Associations and Rapid-Fire Clinical Facts

— CrCl 31–60: 30 mg BID

— CrCl 10–30: 30 mg daily

— HD: 30 mg after every other session

Abrupt onset + fever + myalgia + dry cough in winter = influenza until proven otherwise

Biphasic fever 5–7 days after flu = secondary bacterial pneumonia (S. pneumoniae, S. aureus/MRSA, H. flu)

Cavitary pneumonia post-flu = MRSA — add vancomycin/linezolid

Reye syndrome = aspirin + viral illness (flu/varicella) in children → encephalopathy + hepatic steatosis; avoid aspirin <19 yo with febrile illness

Calf pain + dark urine in child after flu B = benign acute childhood myositis ± rhabdomyolysis

Acute necrotizing encephalopathy = young children, post-flu, bilateral thalamic lesions on MRI — high mortality

30% reduction in post-MI cardiovascular events with annual flu vaccine — class I AHA/ACC

6–10× MI risk in the week after lab-confirmed flu (NEJM 2018)

Pregnancy is a high-risk category: empiric oseltamivir, inactivated vaccine any trimester, no LAIV, no baloxavir

LAIV contraindications: pregnancy, immunocompromise, age <2 or ≥50, asthma 2–4, aspirin therapy, anatomic asplenia, close contact with severely immunocompromised in protective environment

Egg allergy is not a contraindication to any flu vaccine (ACIP 2023)

Oseltamivir renal dosing:

Zanamivir = avoid in asthma/COPD (bronchospasm)

Baloxavir = single dose, ≥5 yo, avoid in pregnancy/severe disease/immunocompromise; no dairy/cation co-administration

Adamantanes (amantadine/rimantadine) = not used — universal resistance

PEP duration: 7 days for community contact; ≥14 days and 7 days past last case for facility outbreaks

Outbreak definition: ≥2 cases in 72 hours in LTCF triggers facility-wide chemoprophylaxis

Pediatric influenza deaths are nationally notifiable; novel influenza A is immediately reportable

Droplet precautions until 24 hours afebrile; airborne for aerosol-generating procedures

Antigenic drift = small mutations, annual epidemics; antigenic shift = reassortment in animal reservoir, pandemic potential (1918 H1N1, 2009 H1N1pdm09)

Vaccine takes ~2 weeks to develop immunity — give PEP concurrently in exposed high-risk patients

CCS pearl: Reflex order whenever flu suspected hospitalized → NAAT + CXR + CBC/BMP + oseltamivir + droplet precautions + acetaminophen.

Board pearl: "Post-influenza" + young + cavitary + necrotizing pneumonia = MRSA; cover with linezolid or vancomycin plus standard CAP regimen.

Board Question Stem Patterns

72-year-old with COPD presents on day 3 of fever, myalgia, dry cough during January. SpO₂ 95%, RR 18.

→ Oseltamivir 75 mg BID × 5 days now (high-risk overrides 48-hour rule). Test is reasonable but should not delay therapy.

Three nursing home residents test positive for influenza A within 48 hours.

→ Oseltamivir prophylaxis (75 mg daily, renally adjusted) for all residents regardless of vaccination status; continue ≥14 days and 7 days past last new case; vaccinate unvaccinated staff.

29-week pregnant patient with 24 hours of fever, cough, myalgia.

→ Oseltamivir 75 mg BID × 5 days, acetaminophen for fever, return precautions; inactivated flu vaccine if not yet given this season.

Patient improving from flu has fever recurrence on day 6 with productive yellow sputum and right-lower-lobe consolidation.

→ CBC, blood/sputum cultures, start ceftriaxone + azithromycin (CAP); continue oseltamivir.

Previously healthy 24-year-old, 5 days into flu, now with hemoptysis and cavitary RUL lesion.

→ Add vancomycin or linezolid for MRSA; ICU evaluation.

Hospitalized patient with CrCl 25 mL/min, confirmed flu A.

→ Oseltamivir 30 mg PO daily × 5 days.

Healthy 30-year-old with 18 hours of fever, myalgia, cough.

→ Shared decision: oseltamivir may be offered to shorten illness; supportive care alone is also acceptable; return precautions mandatory.

Healthy 70-year-old presents in September for routine care.

→ High-dose, adjuvanted, or recombinant influenza vaccine preferred; if unavailable, give any age-appropriate vaccine — do not delay.

Healthy 8-year-old with asthma controlled on daily ICS.

→ Inactivated vaccine (LAIV avoided in asthma ≥5 if recent wheezing/severe asthma; safe ICS use in well-controlled is per provider judgment but IIV is the safer board answer).

Poultry farmer with severe pneumonia, flu A NAAT positive but unsubtypable.

→ Airborne + droplet precautions, report to public health within 24 hours, send specimen to state lab, oseltamivir.

Patient with history of anaphylaxis to eggs needs flu vaccine.

→ Any age-appropriate flu vaccine is acceptable (ACIP 2023) — egg allergy is not a contraindication; consider recombinant if available.

Stem 1 — Outpatient high-risk:

Stem 2 — LTCF outbreak:

Stem 3 — Pregnant patient:

Stem 4 — Biphasic illness:

Stem 5 — Necrotizing pneumonia post-flu:

Stem 6 — Renal dosing:

Stem 7 — Healthy young adult, day 1:

Stem 8 — Vaccine selection elderly:

Stem 9 — LAIV contraindication:

Stem 10 — Novel strain exposure:

Stem 11 — Egg allergy:

Board pearl: The most commonly correct Step 3 answer is "oseltamivir 75 mg BID × 5 days, started empirically" — when in doubt in a high-risk vignette, choose it.

One-Line Recap

Rapid recap bullets:

Bottom line: Influenza is a clinical diagnosis during peak season — treat all high-risk and hospitalized patients with empiric oseltamivir (renally dosed) within 48 hours, give post-exposure prophylaxis to exposed high-risk contacts and to entire LTCFs during outbreaks, vaccinate everyone ≥6 months annually, and watch for secondary bacterial (especially MRSA) pneumonia, myocarditis, and Reye syndrome as the highest-yield complications.

Treatment: oseltamivir 75 mg BID × 5 days first line; treat all hospitalized and high-risk patients regardless of symptom duration; treat healthy outpatients within 48 hours by shared decision. Renal dose adjustments mandatory (CrCl 31–60 → 30 mg BID; CrCl 10–30 → 30 mg daily; HD → 30 mg every other session). Avoid zanamivir in asthma/COPD; avoid baloxavir in pregnancy, severe disease, and immunocompromise.

PEP: oseltamivir 75 mg daily × 7 days for high-risk close contacts within 48 hours of exposure; LTCF outbreaks (≥2 cases in 72 hours) trigger facility-wide chemoprophylaxis × ≥14 days and 7 days past last case, regardless of vaccination status.

Vaccination: annual inactivated vaccine for everyone ≥6 months; high-dose/adjuvanted/recombinant preferentially recommended in ≥65; inactivated vaccine any trimester of pregnancy; LAIV contraindicated in pregnancy, immunocompromise, asthma in 2–4, age <2 or ≥50; egg allergy is not a contraindication.

Don't miss: biphasic fever = bacterial pneumonia (S. pneumoniae, MRSA if cavitary/necrotizing — add vancomycin/linezolid); aspirin + child + flu = Reye syndrome; chest pain or HF after flu = myocarditis; pediatric flu deaths and novel influenza A are reportable; renal-adjusted dosing and PEP for household contacts are the most commonly missed Step 3 transition-of-care safety steps.