Influenza (Seasonal & Pandemic)

Meet the patient

A 34-year-old previously well nurse phones in at the start of the winter surge: she can date the illness to the hour — fever to 39 degC, rigors, aching calves and back, a dry cough, and she cannot get out of bed. She is 24 weeks pregnant.^[1][7]

Three exam questions are now live: is this influenza (and not a cold, COVID-19 or dengue)?, does she need an antiviral and does she need admission?, and what complication should I watch for next? The suddenness of the onset is the single feature that separates influenza from every common-cold mimic — patients can usually name the hour it began.^[1]

Hold those three questions and the rest of the topic slots into place. The two non-negotiables to carry through: pregnant, immunocompromised, hospitalised, or high-risk patients get oseltamivir at any time after onset — never wait for confirmation — and no child with a fever receives aspirin, ever, because of Reye syndrome.^[1][7]

What influenza is — and why it keeps coming back

Influenza is an acute, febrile, highly contagious viral infection of the respiratory tract caused by influenza viruses A, B and (rarely) C, members of the Orthomyxoviridae family. Influenza A and B cause the substantial burden of human seasonal disease; influenza C produces only mild, sporadic upper-respiratory illness and is not included in routine vaccines.^[2]

What makes influenza a perpetual global threat — and a perpetual exam favourite — is the antigenic mutability of its surface glycoproteins: minor point mutations (antigenic drift) accumulate continuously and force annual vaccine reformulation and seasonal epidemics, while major gene-segment reassortment (antigenic shift) periodically produces a wholly novel subtype to which the population has little immunity, igniting a pandemic. The 1918 'Spanish flu' (H1N1) killed an estimated 50–100 million people worldwide; the 2009 H1N1pdm09 pandemic was the first influenza pandemic of the 21st century.^[9]

The clinical task is three-fold: (1) recognise influenza early in the febrile patient during season, (2) identify who needs antivirals and who needs admission (the high-risk groups for whom influenza is lethal), and (3) anticipate the complications — viral pneumonitis, secondary bacterial pneumonia, myocarditis, encephalitis, and the multi-organ syndromes that follow.^[1]

Classification

Influenza viruses are classified by type, by subtype (A only), and — at the public-health level — by lineage (B) and clade. The classification is not merely taxonomic: it dictates vaccine composition, antiviral susceptibility, and pandemic risk.^[2][4]

By type: ^[1]

• Influenza A — infects humans, pigs, horses, birds (the natural reservoir, especially aquatic wild birds). Subtyped by H (1–18) and N (1–11). Causes pandemics (because of its broad animal reservoir allowing reassortment). Currently circulating human strains: A/H1N1pdm09 and A/H3N2.
• Influenza B — almost exclusively human. No subtypes; divided into two antigenically distinct lineages — Victoria and Yamagata (Yamagata not detected globally since 2020, likely extinct). Causes seasonal epidemics but not pandemics (no animal reservoir for reassortment).
• Influenza C — causes mild sporadic illness; not vaccine-targeted.
• Influenza D — primarily cattle; not a human pathogen of consequence. ^[1]

Subtyping of influenza A — the H and N nomenclature (high-yield):^[2]

• Haemagglutinin (H or HA) — 18 subtypes; mediates receptor binding and viral entry by binding sialic-acid receptors on respiratory epithelium. Antibody to HA is neutralising and protective. The haemagglutinin is the basis of subtyping.
• Neuraminidase (N or NA) — 11 subtypes; cleaves sialic acid to release progeny virions from the host cell (otherwise they remain tethered). The drug class neuraminidase inhibitors — oseltamivir, zanamivir, peramivir, laninamivir — target N.
• Only a small subset of H and N combinations circulate in humans: H1N1, H2N2 (1957–68), H3N2. Avian subtypes H5N1, H5N6, H7N9, H9N2 cause zoonotic human disease with very high mortality but very limited human-to-human transmission. ^[1]

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Epidemiology & Risk Factors

Influenza is one of the most significant infectious diseases of humans. Globally, modelling studies estimate that seasonal influenza causes approximately 1 billion infections, 3–5 million severe cases, and 290,000–650,000 respiratory deaths annually, the vast majority in adults aged over 65 and in low- and middle-income countries.^[10]

Seasonality: in temperate climates, influenza circulates in discrete winter epidemics (December–March in the Northern Hemisphere, May–August in the Southern). In tropical and subtropical regions (including much of India), influenza can circulate year-round or with semi-annual peaks linked to monsoon — this regional pattern influences both vaccination timing and the differential diagnosis of a febrile illness. ^[1]

Pandemic epidemiology — landmarks every candidate must know:^[9]

Risk groups for severe or complicated influenza (these define who gets priority vaccination, who gets antivirals regardless of duration of illness, and who needs a low threshold to admit):^[1][5]

• Age — children under 5 years (especially under 2) and adults aged 65 and over (blunted immunity, declining respiratory reserve).
• Pregnancy (and up to 2 weeks postpartum) — particularly the 2nd and 3rd trimesters; physiological immune modulation and reduced functional residual capacity.
• Chronic respiratory disease — COPD, asthma, cystic fibrosis, bronchiectasis.
• Cardiovascular disease — heart failure, ischaemic heart disease (influenza triggers acute coronary events).
• Chronic metabolic disease — diabetes mellitus, chronic kidney disease, chronic liver disease.
• Immunocompromise — HIV, haematological malignancy, chemotherapy, transplant, splenectomy, prolonged corticosteroid.
• Neurological/neuromuscular disease (often overlooked) — cerebral palsy, stroke, muscular dystrophy; impair swallowing and cough.
• Extreme obesity (BMI 40 or more) — emerged as a risk factor in 2009 H1N1; restrictive lung physiology and chronic inflammation.
• Residents of long-term care / nursing homes — explosive outbreaks.
• Healthcare workers — both at risk and a vector for vulnerable patients.
• Indigenous and certain ethnic populations (e.g. American Indian, Australian Aboriginal) — disproportionate mortality. ^[1]

Key zoonotic avian influenza (high-yield exam point): H5N1 (highly pathogenic avian influenza) has a case fatality rate approaching 60% in confirmed human cases, but sustained human-to-human transmission has not occurred. Risk factor: direct contact with sick or dead poultry.^[8] H7N9 (China) and H5N6 are other notable zoonotic threats. All suspected avian influenza must be notified to public health.

Pathophysiology

Influenza virus is transmitted from person to person mainly by large respiratory droplets (over 5 micrometres, travel up to 1–2 metres) generated by coughing and sneezing, and to a lesser extent by aerosols (smaller particles that travel further and linger) and by contact with contaminated surfaces (fomites) followed by self-inoculation of mucous membranes.^[2]

Incubation period is 1–4 days (average 2). Patients are contagious from 1 day before symptoms until 5–7 days after onset (longer in children and the immunocompromised). ^[1]

The molecular cascade of infection and inflammation: ^[1]

1. Receptor binding and entry. The viral haemagglutinin (HA) binds to sialic-acid receptors (alpha-2,6-linked in humans; alpha-2,3-linked in birds — the receptor difference explains species tropism and the swine 'mixing vessel', which has both linkage types) on ciliated columnar epithelial cells of the nose, trachea and bronchi. The virus is internalised by receptor-mediated endocytosis.
2. Replication. The virus is an enveloped, negative-sense, single-stranded RNA virus with a genome of 8 segments (each encoding one or two proteins). The viral RNA-dependent RNA polymerase (PB1, PB2, PA) — which lacks proof-reading and so accumulates errors (drift) — replicates in the host-cell nucleus. Newly synthesised HA and NA are inserted into the host cell membrane.
3. Release. Neuraminidase cleaves sialic-acid residues on the cell surface, releasing new virions. This is the drug target of oseltamivir/zanamivir — without NA, virions remain tethered to the dying cell and cannot spread.
4. Cellular destruction and inflammation. Viral replication lyses the ciliated epithelial cells, stripping the mucociliary escalator and exposing the basal epithelium. Release of virions and intracellular contents activates macrophages and dendritic cells, which release a cytokine storm (interferon-alpha/beta, TNF-alpha, IL-1, IL-6, IL-8, CXCL10). These cytokines — not the virus itself — produce the systemic 'flu' symptoms of fever, headache, myalgia, fatigue and anorexia.
5. Impaired defence and secondary invasion. Loss of the mucociliary barrier plus impaired neutrophil/macrophage function (transient post-influenzal immune paralysis) creates a fertile field for secondary bacterial infection — classically Strep pneumoniae, Staphylococcus aureus (especially the post-influenza necrotising pneumonia) and Haemophilus influenzae. This is why the second-spike of fever a few days into recovery is the cardinal sign of secondary bacterial pneumonia.
6. Resolution. In the uncomplicated case, cytotoxic CD8+ T cells clear infected cells, and HA-specific neutralising IgA (mucosal) and IgG (systemic) antibody develops, providing strain-specific immunity that lasts years against the same strain but does not protect against drifted strains — the rationale for annual vaccination. ^[1]

Why pandemics occur (mechanism of shift): when a host cell is co-infected by two different influenza A viruses (e.g. an avian and a human strain, often in a pig that has both alpha-2,3 and alpha-2,6 sialic-acid receptors), the 8 genome segments can reassort like a deck of cards, producing a progeny virus with a novel combination of H and N to which the human population has no antibody. This reassortment, plus the segmented genome, is the molecular basis of pandemics.^[2][4]

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Clinical Presentation

The hallmark of influenza is its suddenness. Patients can usually state the exact hour the illness began — this is the single feature that most reliably distinguishes influenza from the common cold.^[1]

Classic uncomplicated influenza (adult): abrupt onset of: ^[1]

• Fever (typically 38–40 degC) with rigors or chills — near-universal; may be absent in the elderly.
• Headache — often severe, frontal or retro-orbital.
• Diffuse myalgia — most severe in back and legs; incapacitating.
• Marked fatigue and weakness — out of proportion to the fever; can persist for 2–3 weeks.
• Dry (non-productive) cough — usually develops early and worsens.
• Sore throat.
• Anorexia, malaise.
• Nasal congestion, sneezing, lacrimation — present but milder than in the cold.
• Sometimes N/V and diarrhoea — more common in children and in H1N1pdm09 / avian strains than in classic seasonal influenza. ^[1]

The classic triad of "flu" = fever + cough + acute onset. Sensitivity of this triad in season for influenza approaches 80%; specificity around 60–80%. ^[1]

Differentiating influenza from the common cold (high-yield bedside exam):^[1]

Signs on examination (uncomplicated): febrile, flushed, conjunctival injection, mild pharyngeal erythema, cervical lymphadenopathy, and a clear chest or a few scattered wheezes/ronchi. Chest signs beyond this in the first 48 hours suggest viral pneumonitis or bacterial co-infection. ^[1]

Influenza in specific populations — the atypical presentations every candidate must know: ^[1]

• Elderly (over 65): atypical presentation — fever may be absent or low-grade; presenting features may be confusion, falls, anorexia, weakness, failure to cope, or functional decline. A high index of suspicion in winter is essential; morbidity and mortality are markedly higher.
• Neonates and infants: may present as sepsis-like illness, apnoea, poor feeding, irritability, or febrile seizures; cough may be absent.
• Young children (under 5): high fever, croup (laryngotracheobronchitis), bronchiolitis, otitis media; influenza is a leading cause of paediatric hospitalisation. Reye syndrome is the feared complication in children given aspirin.
• Pregnant women: particularly in the 2nd/3rd trimester and up to 2 weeks postpartum, influenza carries a markedly increased risk of severe pneumonitis, ARDS, ICU admission, miscarriage, preterm delivery, and fetal demise; the 2009 pandemic demonstrated this dramatically.^[7]
• Immunocompromised: may have prolonged viral shedding (weeks), atypical or absent fever, and higher rates of lower-respiratory involvement and resistance.
• Severe / fulminant influenza: rapid progression to primary viral pneumonia — dyspnoea, hypoxia, bilateral infiltrates, ARDS within 24–72 hours of onset; this is most common in pregnancy, immunocompromise, and extreme obesity.

Differential Diagnosis

A wide range of pathogens produce an influenza-like illness (ILI). The WHO defines ILI as measured fever of 38 degC or over AND cough, with onset within the last 10 days. The task is to recognise when it is NOT influenza and when to escalate.^[1]

The most dangerous pitfall is the febrile patient returning from an endemic area: in tropical and subtropical India, dengue, malaria, leptospirosis, scrub typhus and enteric fever must be considered alongside influenza in any acute undifferentiated fever. ^[1]

Clinical & Bedside Assessment

ABCDE first. Vital signs drive severity and disposition:^[1]

• Respiratory rate — the most sensitive single sign of lower-respiratory compromise; RR over 30/min suggests pneumonitis, pneumonia or ARDS.
• Oxygen saturation — target SpO2 94–98% (88–92% in COPD/CO2 retainers); hypoxia is a red flag.
• Temperature — high fever is expected, but hypothermia in the elderly is ominous.
• Heart rate, blood pressure — tachycardia, hypotension, and cool peripheries / prolonged capillary refill suggest sepsis.
• Conscious level — confusion, drowsiness, or seizures suggest hypoxia, encephalitis, or septic/metabolic encephalopathy.
• Hydration, urine output. ^[1]

Focused respiratory examination — most uncomplicated influenza has a clear chest; the finding of focal crackles, bronchial breath sounds, dullness to percussion, or pleural rub indicates viral pneumonitis or secondary bacterial pneumonia and warrants urgent CXR. ^[1]

Bedside tests: ^[1]

• Pulse oximetry — for every patient.
• Capillary glucose — in pregnancy, diabetes, the elderly, and any drowsy patient.
• Urinalysis — to exclude UTI as the source of fever. ^[1]

Assess for complications: otitis media (otoscopy in children), sinus tenderness, new murmur (myocarditis/endocarditis), rash (petechial — consider meningococcaemia), muscle tenderness with dark urine (rhabdomyolysis). ^[1]

Investigations

The decision to test depends on whether the result will change management. In a healthy ambulatory patient during a confirmed influenza season, the diagnosis is clinical. Testing is recommended for hospitalised patients, immunocompromised, pregnant, and any patient in whom the result will alter antiviral use, infection control, or antibiotic stewardship.^[1]

Diagnostic tests, in order of utility:^[1][2]

Sampling pearl: the nasopharyngeal swab (inserted through the nostril into the nasopharynx, rotated, withdrawn) is the specimen of choice; throat swabs have lower yield. Lower respiratory samples (BAL, sputum) should be sent in intubated patients or those with pneumonitis — upper-airway samples may become negative as disease descends. ^[1]

Admission bloods (when hospitalised or severe): ^[1]

• Full blood count — usually leukopenia with relative lymphopenia; a neutrophilic leucocytosis suggests secondary bacterial infection; thrombocytopenia in severe disease.
• CRP — often mildly to moderately raised; very high CRP suggests bacterial co-infection.
• U&E, LFTs — AKI, transaminitis (mild) common in severe influenza; raised CK suggests myositis/rhabdomyolysis.
• Lactate — for sepsis; elevated lactate with hypoxia is a poor sign.
• Chest X-ray — for any hypoxic, dyspnoeic, or focal-sign patient; bilateral interstitial or patchy infiltrates suggest viral pneumonitis; lobar consolidation suggests bacterial; multilobar is severe.
• ABG — if hypoxic, for the P/F ratio to grade ARDS severity.
• Blood cultures, sputum culture and Gram stain — before antibiotics in suspected secondary bacterial pneumonia.
• ECG — myocarditis, pericarditis; troponin if suspected.
• LP / neuroimaging — for any patient with altered mentation, seizure, or focal neurology (exclude influenza encephalitis, aseptic meningitis). ^[1]

Severity stratification for influenza (no single named score as for pneumonia — apply clinical judgement with these triggers): ^[1]

• Admit if: hypoxia (SpO2 under 92%), RR over 30, dehydration, altered mentation, haemodynamic instability, suspected complication, OR any high-risk group with significant symptoms (pregnancy, immunocompromise, chronic disease, age over 65).
• ICU if: ARDS (P/F ratio under 300), septic shock, respiratory failure needing ventilatory support, multi-organ failure. ^[1]

Management — Resuscitation

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ABCDE. Most uncomplicated influenza is managed at home with supportive care. The resuscitation priorities apply to the severe or deteriorating patient.^[1]

• Oxygen — target normal arterial oxygenation; hypoxia is a red flag for lower-respiratory involvement.
• Fluids — give cautiously with reassessment, because severe influenza can progress to ARDS with non-cardiogenic pulmonary oedema.
• Paracetamol or ibuprofen for fever and myalgia. AVOID aspirin in children and teenagers with viral illness — salicylate use in influenza or varicella under 18 years is linked to Reye syndrome, and national warnings against it collapsed the incidence.^[24]
• Hydration and rest — the supportive bedrock.
• Isolation and infection control — single room or cohorting with droplet precautions per local policy.
• Empirical antiviral therapy — START EARLY in suspected influenza among persons with severe, complicated or progressive illness or who require hospitalisation; the ACIP recommendation is to treat on clinical suspicion without waiting for confirmation.^[5]
• If septic — follow the local sepsis bundle: cultures, lactate, early antibiotics and circulatory support.

Management — Definitive & Stepwise

The two pillars are (1) antiviral therapy for those who need it, and (2) prevention by vaccination. Antibiotics are added only for documented or suspected secondary bacterial infection — never routinely.^[1][5]

Antiviral therapy — neuraminidase inhibitors (first line)

Oseltamivir (Tamiflu) — oral; the workhorse in adults and children. ^[1]

Paediatric oseltamivir dosing:^[12]

• Infants under 1 yr: studied twice-daily weight-based dosing of 3 mg/kg/dose (infants 91–364 days); younger neonates and young infants received 2–2.5 mg/kg/dose in the same trial, and 2–3 mg/kg twice daily achieved therapeutic exposure with an adequate safety margin.
• Older infants and children: dosing is weight-based per the national formulary and product label — always confirm the band against the current paediatric dosing schedule before prescribing.^[12]

Timing: best within 48 hours of symptom onset for uncomplicated disease — reduces duration by about 1 day and reduces complications/hospitalisation.^[3] For hospitalised, immunocompromised, pregnant, or severe disease — start at ANY time after onset, even beyond 48 hours; benefit persists and mortality is reduced.

Other neuraminidase inhibitors: ^[20]

• Zanamivir — an inhaled neuraminidase inhibitor for treatment and chemoprophylaxis; randomised trials of inhaled zanamivir contributed to the evidence that the class reduces time to symptom resolution and complications.^[20]
• Peramivir — intravenous; in previously healthy adults with uncomplicated influenza, a single 600 mg infusion significantly shortened time to symptom resolution versus placebo and was non-inferior to oral oseltamivir. Licensed for uncomplicated influenza in adults and children from 2 years.^[13]
• Laninamivir octanoate — single-inhalation, long-acting neuraminidase inhibitor; in a randomised non-inferiority trial a single inhaled dose matched oseltamivir 75 mg orally twice daily for 5 days for time to illness alleviation.^[19]

Cap-dependent endonuclease inhibitor (cap-snatch blocker)

Baloxavir marboxil (Xofluza) — first-in-class selective inhibitor of influenza cap-dependent endonuclease. Given as single, weight-based oral doses (40 or 80 mg) in patients 12 to 64 years with acute uncomplicated influenza: time to alleviation of symptoms was superior to placebo and similar to oseltamivir, with a greater reduction in viral load 1 day after starting treatment than either oseltamivir or placebo.^[6] In high-risk adolescents and adults (age over 65 or other risk factors), single-dose baloxavir was superior to placebo and similar to oseltamivir for symptom alleviation, and the trial stratified patients by weight (under 80 kg vs 80 kg or over).^[11]

M2 ion-channel inhibitors — historical and now obsolete

Amantadine and rimantadine block the M2 ion channel of influenza A (only). Resistance in circulating A/H1N1pdm09 and A/H3N2 is essentially universal — they are NOT recommended for treatment or prophylaxis. Mention only as an exam footnote and for the mechanism (block uncoating). ^[1]

Adjunctive therapy in severe influenza

• Corticosteroids — NOT recommended routinely in influenza-related severe pneumonia or ARDS: a meta-analysis of 19 studies found corticosteroid therapy associated with significantly higher mortality (OR 1.53) and more nosocomial infection (OR 3.15).^[16] Reserve steroids for a concomitant indication (e.g. septic shock, asthma/COPD exacerbation) per local ICU policy.
• Antibiotics for secondary bacterial pneumonia — most influenza fatalities historically resulted from secondary bacterial pneumonia with common upper-respiratory-tract bacteria; send cultures and treat guided by microbiology and local policy.^[23]
• Respiratory support escalation — high-flow nasal cannula → non-invasive ventilation → intubation with lung-protective ventilation (tidal volume 6 mL/kg of predicted body weight, end-inspiratory plateau pressure limit 30 cm of water), then proning and ECMO referral for refractory ARDS in a specialist centre.^[18]

Infection control and public-health actions

• Isolation and droplet precautions — follow local infection-control policy for suspected influenza in hospital.
• Notify the public-health authority of any suspected novel or avian influenza (e.g. H5N1, H7N9) — these are notifiable zoonotic infections in most jurisdictions.
• Antiviral post-exposure prophylaxis (PEP) — in a household randomised controlled trial, contacts taking oseltamivir 75 mg once daily for 7 days, started within 48 hours of symptom onset in the index case, had 89% protection against clinical influenza; it prevented outbreaks within households.^[14]

Stepwise care ladder (escalation triggers)

1. Mild uncomplicated influenza, low-risk patient — home, supportive care, fluids, safety-net advice.
2. Symptomatic high-risk patient, or anyone with severe, complicated or progressive illness — early antiviral treatment on clinical suspicion (oseltamivir 75 mg twice daily for 5 days in adults), regardless of rapid-test result.^[5][19]
3. Hypoxia, dehydration, dyspnoea, or any red flag — admit, oxygen, fluids, antivirals, CXR, bloods.
4. Severe disease / pneumonitis / ARDS / shock — ICU: antivirals plus lung-protective ventilation (6 mL/kg predicted body weight, plateau limit 30 cm water) with proning, vasopressors and ECMO referral as needed.^[18]
5. Immunocompromised host / persistent shedding — watch for emergence of oseltamivir resistance (the H275Y neuraminidase substitution), which oseltamivir therapy can rapidly select in A(H1N1)pdm09.^[17]

Specific Subtypes & Scenarios

• Seasonal H1N1pdm09 — the 2009 pandemic virus infected pregnant women disproportionately severely: in the first month of the US outbreak, 32% of reported pregnant cases were hospitalised and six pregnant women died, all after pneumonia progressing to ARDS requiring mechanical ventilation.^[7]
• Avian influenza A/H5N1 — zoonotic, with very high mortality where it occurs: in Indonesia's 2005–08 case series, 103 of 127 confirmed cases (81%) died; median time from onset to oseltamivir was 7 days, and earlier oseltamivir treatment was associated with survival.^[8]
• Institutional outbreak (nursing home, dormitory, barracks) — the IDSA guidance specifically addresses institutional outbreak management alongside treatment and chemoprophylaxis: isolate, test, treat cases and offer prophylaxis to residents and staff per public-health direction.^[1]
• Immunocompromised host — risk of emergence of oseltamivir resistance (H275Y) during therapy; in a stem-cell transplant recipient the substitution dominated the viral population after 15 days of oseltamivir.^[17]

Complications & Pitfalls

Pulmonary: ^[1]

• Primary viral pneumonia — direct viral damage; bilateral interstitial infiltrates, rapid hypoxia, ARDS; highest in pregnancy, immunocompromise, obesity, native populations.
• Secondary bacterial pneumonia — second fever spike after initial improvement; purulent sputum, lobar consolidation. Strep pneumoniae, Staph aureus (necrotising), Haemophilus influenzae. Post-influenza Staph aureus pneumonia is the classic exam association.
• Exacerbation of underlying COPD/asthma/cystic fibrosis — the most common complication of influenza in chronic lung disease.
• Bronchiolitis (children), croup, otitis media (especially paediatric), sinusitis, epiglottitis (rare). ^[1]

Cardiac: ^[1]

• Myocarditis — chest pain, dyspnoea, raised troponin, new arrhythmia, cardiogenic shock; can be fulminant.
• Pericarditis.
• Exacerbation of heart failure and acute coronary syndrome — influenza triggers plaque rupture; vaccination reduces major adverse cardiac events. ^[1]

Neurological: ^[1]

• Influenza-associated encephalitis/encephalopathy (IAE) — especially in children (H1N1pdm09); altered consciousness, seizures, focal neurology; MRI T2/FLAIR hyperintensities; high mortality.
• Guillain–Barre syndrome (GBS) — within 1–6 weeks of influenza; classically ascending flaccid paralysis with areflexia; treat with IVIG or plasmapheresis. (Also historically associated with the 1976 swine flu vaccine — the basis of GBS surveillance for every influenza vaccine campaign.)
• Transverse myelitis, ADEM, febrile seizures. ^[1]

Musculoskeletal: ^[1]

• Myositis and rhabdomyolysis — calf pain, raised serum CK, dark (myoglobinuric) urine, AKI; more common in children and H1N1/H3N2.
• Reactive arthritis (rare). ^[1]

Renal: AKI from rhabdomyolysis, sepsis, or myocarditis. ^[1]

Haematological: thrombocytopenia, disseminated intravascular coagulation (rare), haemophagocytic lymphohistiocytosis (HLH). ^[1]

Metabolic / hepatic: ^[1]

• Reye syndrome — classically in children given aspirin during a viral (influenza, VZV) illness — mitochondrial hepatopathy: vomiting, hepatomegaly, hypoglycaemia, altered consciousness, microvesicular steatosis, raised ammonia with normal/mild LFTs. NEVER give aspirin to a child with a fever — this is the single exam point. Mortality 20–40%. ^[1]

Toxic shock from superantigen-producing Staph/Strep co-infection. ^[1]

Classic pitfalls: ^[1]

• Over-reliance on a negative RIDT — repeat with PCR or treat empirically if clinical suspicion is high.
• Delaying antivirals waiting for confirmation in a hospitalised or high-risk patient.
• Failing to recognise the atypical presentation in the elderly (no fever; presenting as confusion or falls).
• Missing pregnancy as a high-risk group.
• Giving aspirin to a febrile child.
• Routine corticosteroids for influenza pneumonitis (harm).
• Forgetting the second fever spike = secondary bacterial pneumonia.
• Not testing for SARS-CoV-2 in any ILI during COVID circulation. ^[1]

Prognosis & Disposition

Most uncomplicated influenza resolves in 3–7 days, though cough and fatigue may persist for 2–3 weeks. The cough and post-viral asthenia are the patient's main complaints.^[1]

Predictors of poor outcome: age over 65, pregnancy, BMI 40 or more, immunocompromise, chronic cardiopulmonary/renal/hepatic/metabolic disease, delayed antiviral therapy, viral pneumonitis/ARDS, bacterial co-infection, MMT/ICU admission, neutrophilia, raised lactate, raised CK. ^[1]

Global mortality: seasonal influenza causes an estimated 290,000–650,000 respiratory deaths and up to 1 million total deaths annually; over 90% occur in adults over 65.^[10]

Disposition: ^[1]

• Home — uncomplicated, low-risk, improving; safety-net for return if breathless, drowsy, unable to keep fluids down, or fever recurs.
• Hospital (ward) — hypoxia, dehydration, secondary pneumonia, pregnancy with significant symptoms, immunocompromise, any high-risk group not improving.
• ICU — ARDS, septic shock, respiratory failure, multi-organ failure.
• Follow-up — review at 48–72 hours; follow-up CXR not routinely needed unless complicated. ^[1]

Special Populations

• Pregnancy. 2009 H1N1pdm09 was markedly more severe in pregnant women — higher hospitalisation rates than the general population, and every reported maternal death followed pneumonia with ARDS on mechanical ventilation — which is why guidance is to treat pregnant women with influenza promptly with anti-influenza drugs.^[7] Influenza vaccination during pregnancy protects the baby as well: infants born to vaccinated mothers had 41% lower influenza hospitalisation in the first 6 months of life in a national cohort.^[22]
• Children. Oseltamivir is dosed by weight (infants under 1 yr have studied dosing of 3 mg/kg twice daily).^[12] Never give aspirin to children or teenagers with influenza or varicella — salicylate warnings were issued in 1980 after the association with Reye syndrome, and reported cases collapsed thereafter.^[24]
• Severe or hospitalised influenza. ACIP recommends early antiviral treatment of suspected or confirmed influenza in anyone with severe, complicated or progressive illness or requiring hospitalisation.^[5]
• Immunocompromised. Prolonged shedding and atypical presentation; monitor for emergence of oseltamivir resistance (H275Y) during therapy.^[17]

Evidence, Guidelines & Regional Differences

Landmark evidence

• Dobson 2015 (Lancet, individual-patient-data meta-analysis of 9 RCTs) — oseltamivir in adults reduced symptom duration by about 1 day (from 122 to 98 h) and halved hospitalisations in high-risk adults.^[3]
• Hayden 2018 NEJM (CAPSTONE-1) — baloxavir marboxil was non-inferior to oseltamivir for symptom alleviation and reduced viral shedding faster.^[6]
• Ison 2020 (CAPSTONE-2, Lancet Infect Dis) — baloxavir in high-risk adolescents and adults reduced complications and time to alleviation.^[11]
• Iuliano 2018 (Lancet, global mortality model) — redefined the global burden at 290,000–650,000 respiratory deaths/year.^[10]
• Taubenberger 2020 (CSH Perspect Med) — definitive account of the 1918 pandemic and its scientific legacy.^[9]

Guidelines

• IDSA 2018 (Uyeki et al.) — the global reference for diagnosis, treatment, chemoprophylaxis and outbreak management.^[1]
• CDC ACIP — annual updates to vaccination recommendations, strains, and indication list.^[5]
• WHO Global Influenza Surveillance and Response System (GISRS) — global strain surveillance and the body that announces twice-yearly vaccine composition (February for Northern Hemisphere, September for Southern).

Regional differences

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Controversies

• Cochrane reviews (Jefferson/Demicheli) on oseltamivir — questioned the magnitude of benefit and highlighted publication bias; mainstream guidance still endorses oseltamivir for high-risk and severe disease based on individual-patient data.
• Routine corticosteroids for influenza pneumonitis — harm in observational data, but still used in some settings for septic shock; guideline: avoid unless indicated for another reason.
• Universal influenza vaccine — the holy grail; targets the conserved stalk of HA, the M2e ion channel, or the conserved NA; would eliminate the need for annual reformulation and seasonal strain prediction.^[4]

Prevention — vaccination (cornerstone)

Annual quadrivalent inactivated influenza vaccine (QIV) — the single most important intervention. The composition is updated twice yearly by WHO; a typical Northern Hemisphere season includes A/Victoria/H1N1pdm09-like, A/Darwin/H3N2-like, B/Victoria-lineage, and B/Yamagata-lineage strains.^[4]

Indications (CDC/ACIP: everyone 6 months and over; high-priority groups):^[5]

• All children 6 months to 5 yr (and their household contacts).
• All adults over 50 or 65 (depends on country; US over 50, UK over 65).
• Pregnant women at any gestation.
• Chronic pulmonary, cardiac (excluding isolated hypertension), renal, hepatic, neurological, haematological, metabolic (including diabetes) disease.
• Immunocompromised (including HIV).
• Residents of long-term care / nursing homes.
• Healthcare workers and household contacts of high-risk persons.
• Extreme obesity (BMI 40 or more).
• Children 6 months to 18 yr on long-term aspirin (to prevent Reye syndrome if they acquire influenza). ^[1]

Doses: single annual IM dose (deltoid); children 6 months–8 yr receiving influenza vaccine for the first time need TWO doses, 4 weeks apart. High-dose, adjuvanted (MF59), or recombinant vaccines are preferred for adults over 65 (improve immunogenicity). ^[1]

Contraindications/precautions: severe allergic reaction (e.g. anaphylaxis) to a previous dose or component; severe egg allergy (recombinant cell-based vaccines are egg-free; in most modern guidelines mild egg allergy is no longer a contraindication — observe for 30 min); history of GBS within 6 weeks of a previous influenza vaccine (precaution); moderate-to-severe acute illness (defer). Live attenuated intranasal vaccine (LAIV) has additional contraindications: immunocompromise, pregnancy, severe asthma, salicylate therapy in children, age under 2 or over 49. ^[1]

Vaccine effectiveness (VE): typically 40–60% in the well-matched years; lower (10–40%) against H3N2 due to rapid drift, egg-adaptation mutations, and immunosenescence. Even when VE against infection is low, vaccination reduces severe disease, hospitalisation, ICU admission, and death. ^[1]

Exam Pearls

• Two surface antigens — haemagglutinin (HA) and neuraminidase (NA): antibodies to HA and NA confer substantial protection; NA is the target of the neuraminidase inhibitors (oseltamivir, zanamivir, peramivir).^[20]
• Antigenic drift drives yearly vaccine reformulation and annual seasonal epidemics; pandemics arise from influenza A strains of zoonotic origin.^[2]
• Receptor binding: human influenza HA prefers α-2,6-linked sialic-acid receptors on airway epithelium.^[21]
• Antivirals — oseltamivir 75 mg BD x 5 days in adults; shortens symptom duration and reduces lower-respiratory complications and hospitalisation.^[3][19]
• Baloxavir = single-dose cap-dependent endonuclease inhibitor; superior to placebo, similar to oseltamivir for symptom alleviation.^[6]
• Pandemic mnemonic — 'SpHAN': Spanish 1918 H1N1; Hong Kong 1968 H3N2; Asian 1957 H2N2; Novel 2009 H1N1pdm09. The 1918 pandemic killed an estimated 50–100 million people.^[9]
• NO aspirin in children or teenagers with influenza/varicella → Reye syndrome — salicylate warnings date from 1980, after which reported cases fell sharply.^[24]
• Secondary bacterial pneumonia killed most 1918 victims — common upper-respiratory-tract bacteria; the "second fever spike" in recovery is the classic sign.^[23]
• Pregnancy is high-risk with influenza — treat pregnant women promptly with anti-influenza drugs.^[7]
• H5N1 (avian) — zoonotic with very high mortality: 81% (103/127) died in Indonesia's 2005–08 series; earlier oseltamivir was associated with survival.^[8]
• Negative RIDT does NOT exclude influenza — traditional RIDTs had pooled sensitivity of only 54% for A and 53% for B versus RT-PCR.^[15]

^{[10] [19] [15] [14] [16] [18]}

Ward-round test — three stems, thirty seconds each

Stem 1 — the pregnant nurse from the opening vignette (answer)ShowHide

The 24-weeks-pregnant nurse with abrupt fever, myalgia and dry cough at the start of the winter surge. Rapid influenza diagnostic test (RIDT) is negative. What do you do? Model: Start antiviral treatment now — oseltamivir 75 mg PO twice daily for 5 days — without waiting for confirmation.^[19] Do not be deterred by the negative RIDT: pooled sensitivity versus RT-PCR is only about 54% for influenza A.^[15] Pregnancy was a high-risk state in the 2009 pandemic — higher hospitalisation rates than the general population, and every reported maternal death followed pneumonia with ARDS on mechanical ventilation — so pregnant women with influenza should be treated promptly with anti-influenza drugs.^[7] Confirm with RT-PCR, isolate per local policy, and admit if there is dyspnoea, hypoxia, dehydration or obstetric concern; her own influenza vaccination in pregnancy also protects her baby (41% fewer infant influenza admissions to 6 months).^[22]

Stem 2 — the second fever spike (answer)ShowHide

A 68-year-old man is on day 5 of recovery from a PCR-confirmed influenza A illness. His fever had settled, then returned today at 39 degC with purulent rust-coloured sputum, pleuritic pain and a rising CRP. What happened, and what is the organism to cover? Model: This is the classic second fever spike of secondary bacterial pneumonia. Autopsy data from 1918–19 and the subsequent pandemics show that secondary bacterial pneumonia with common upper-respiratory-tract bacteria caused most influenza fatalities — viral damage to the airway plus post-influenzal immune paralysis opens the door to invasion.^[23] Send blood and sputum cultures, and start empirical antibiotics covering the common respiratory pathogens per local policy, targeting Staphylococcus aureus where suspected (the classic post-influenza necrotising pneumonia). Continue antiviral therapy while viral shedding is ongoing.

Stem 3 — the child given aspirin (answer)ShowHide

A 6-year-old is recovering from an influenza-like illness. Three days after being given aspirin for the fever, he develops vomiting, becomes drowsy and hypoglycaemic, and is found to have hepatomegaly. What is the diagnosis, and what is the rule? Model: This is Reye syndrome — a mitochondrial hepatopathy triggered by aspirin during a viral illness (influenza, varicella). The triad is vomiting with altered consciousness, hypoglycaemia and microvesicular hepatic steatosis with a raised ammonia and only mildly deranged LFTs. Stop the aspirin, give glucose, support ventilation and intracranial pressure, and refer to PICU; mortality is 20 to 40 percent. The rule that prevents it: never give aspirin to a child or teenager with a febrile viral illness — use paracetamol or ibuprofen instead.^[1]

References24ShowHide

1. [1]Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa Clin Infect Dis, 2019.PMID 30566567
2. [2]Krammer F, Smith GJD, Fouchier RAM, Peiris M, Kedzierska K, Doherty PC, et al. Influenza Nat Rev Dis Primers, 2018.PMID 29955068
3. [3]Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials Lancet, 2015.PMID 25640810
4. [4]Paules C, Subbarao K. Chasing Seasonal Influenza - The Need for a Universal Influenza Vaccine N Engl J Med, 2018.PMID 29185857
5. [5]Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep, 2011.PMID 21248682
6. [6]Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents N Engl J Med, 2018.PMID 30184455
7. [7]Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA Lancet, 2009.PMID 19643469
8. [8]Kandun IN, Tresnaningsih E, Purba WH, Lee V, Samaan G, Harun S, et al. Factors associated with case fatality of human H5N1 virus infections in Indonesia: a case series Lancet, 2008.PMID 18706688
9. [9]Taubenberger JK, Morens DM. The 1918 Influenza Pandemic and Its Legacy Cold Spring Harb Perspect Med, 2020.PMID 31871232
10. [10]Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study Lancet, 2018.PMID 29248255
11. [11]Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, et al. Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial Lancet Infect Dis, 2020.PMID 32526195
12. [12]Rath BA, Brzostek J, Guillén S, et al. Safety, virology and pharmacokinetics of oseltamivir in infants with laboratory-confirmed influenza: a Phase I/II, prospective, open-label, multicentre clinical trial Antivir Ther, 2015.PMID 26015411
13. [13]Scott LJ. Peramivir: A Review in Uncomplicated Influenza Drugs, 2018.PMID 30196350
14. [14]Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial JAMA, 2001.PMID 11176912
15. [15]Merckx J, Wali R, Schiller I, et al. Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction: A Systematic Review and Meta-analysis Ann Intern Med, 2017.PMID 28869986
16. [16]Zhou Y, Fu X, Liu X, et al. Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis Sci Rep, 2020.PMID 32080223
17. [17]Abed Y, Schibler M, Checkmahomed L, et al. Molecular pathway of influenza pan-neuraminidase inhibitor resistance in an immunocompromised patient Antivir Ther, 2019.PMID 32031540
18. [18]Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome N Engl J Med, 2004.PMID 15269312
19. [19]Watanabe A, Chang SC, Kim MJ, et al. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: a double-blind, randomized, noninferiority clinical trial Clin Infect Dis, 2010.PMID 20936975
20. [20]Tejada S, Jansson M, Solé-Lleonart C, et al. Neuraminidase inhibitors are effective and safe in reducing influenza complications: meta-analysis of randomized controlled trials Eur J Intern Med, 2021.PMID 33358065
21. [21]Wu D, Huang W, Wang Y, et al. Gene silencing of β-galactosamide α-2,6-sialyltransferase 1 inhibits human influenza virus infection of airway epithelial cells BMC Microbiol, 2014.PMID 24670114
22. [22]Wee LE, Goh NS, Ho RW, et al. Vertical Vaccination Against Infant Influenza Hospitalization in a Tropical Setting JAMA Netw Open, 2026.PMID 42579278
23. [23]Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness J Infect Dis, 2008.PMID 18710327
24. [24]Belay ED, Bresee JS, Holman RC, et al. Reye's syndrome in the United States from 1981 through 1997 N Engl J Med, 1999.PMID 10228187