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Summary Table

Domain	Details
Risk Factors	Direct contact with infected poultry (live or dead), work on poultry/dairy farms, exposure to live bird markets, handling of infected carcasses, consumption of raw or undercooked poultry or unpasteurized dairy, close unprotected contact with an infected human (rare). Most cases occur in Southeast Asia, the Middle East, and Africa. Children and young adults have been disproportionately affected in historical outbreaks.
Etiology	Influenza A virus, subtype H5N1 (hemagglutinin type 5, neuraminidase type 1), belonging to the Orthomyxoviridae family. The currently dominant strain worldwide is clade 2.3.4.4b. The virus is a segmented, negative-sense, single-stranded RNA virus with 8 gene segments.
Patient Presentation	High fever, cough, dyspnea, sore throat, myalgia. Atypical features include diarrhea, vomiting, abdominal pain (sometimes preceding respiratory symptoms), conjunctivitis. Rapid progression to severe pneumonia and ARDS is a hallmark.
Classic Physical Exam	Fever (often >38.5 C), tachypnea, diffuse bilateral crackles, signs of respiratory distress, conjunctival injection (especially in occupational dairy cow exposure). Absence of upper respiratory catarrhal signs (runny nose, sneezing) early on is notable.
Key Diagnostic Results	Leukopenia with lymphopenia, thrombocytopenia, elevated aminotransferases, elevated LDH and creatinine. CXR: bilateral patchy infiltrates or consolidation progressing to diffuse ground-glass opacities (ARDS pattern). Real-time RT-PCR for influenza A/H5 is the confirmatory test.
Management	Empiric oseltamivir 75 mg PO BID for 5 days (start immediately; do not wait for lab confirmation). Hospitalized/severe cases: consider combination therapy (oseltamivir + baloxavir), extended treatment (up to 10 days), and IV peramivir if oral route is unavailable. Supportive ICU care for ARDS. Adamantanes (amantadine, rimantadine) are NOT effective.
Keywords	"Poultry worker with severe pneumonia," "rapidly progressive bilateral pneumonia + lymphopenia," "contact with sick birds," "influenza A unsubtypeable by standard assay," "conjunctivitis + respiratory illness after farm exposure," "diarrhea preceding respiratory failure," "cytokine storm."

1. Pathophysiology

Avian influenza A (H5N1) is one of the most virulent influenza subtypes affecting humans. The virus belongs to the Orthomyxoviridae family and is classified by two surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). There are 16 known HA subtypes and 9 NA subtypes circulating in birds. Of these, the H5 and H7 subtypes carry the potential for high pathogenicity. Subtypes confirmed to cause human infection include H5N1, H7N9, H5N6, H10N8, H9N2, H7N7, H7N2, and H7N3, but H5N1 stands out for its strong infectivity and high case fatality rate.

The key to understanding why H5N1 causes such severe disease lies in receptor tropism and cytokine dysregulation. Human seasonal influenza viruses preferentially bind to sialic acid alpha-2,6-galactose receptors found in the upper respiratory tract. H5N1, by contrast, preferentially binds to sialic acid alpha-2,3-galactose receptors, which are concentrated on type II pneumocytes and alveolar macrophages in the lower respiratory tract. This explains two critical exam-testable facts. First, H5N1 causes severe lower respiratory tract disease (pneumonia and ARDS) rather than typical upper respiratory symptoms. Second, throat swabs and lower respiratory samples offer more sensitive diagnostic yields than nasal swabs, which is the opposite of seasonal influenza.

Once the virus infects alveolar epithelial cells and macrophages, it triggers a profound pro-inflammatory cytokine response commonly termed the "cytokine storm." This dysregulated immune response involves excessive levels of TNF-alpha, IL-6, IL-8, MCP-1, and other mediators, leading to diffuse alveolar damage, capillary leak, and multi-organ failure. Apoptosis of alveolar epithelial cells destroys the respiratory epithelium and is considered a primary mechanism of H5N1 pneumonia. Additionally, apoptosis of leukocytes in the lungs, coupled with systemic cytokine-mediated destruction of lymphocytes in lymphoid organs, produces the characteristic leukopenia and lymphopenia observed on laboratory testing.

H5N1 infection is a systemic process, not purely a respiratory one. Autopsy studies have demonstrated viral RNA in the lungs, brain, intestines, kidneys, and liver. This explains why patients develop gastrointestinal symptoms (diarrhea, vomiting, abdominal pain), encephalopathy, elevated transaminases, and renal failure in addition to respiratory distress.

The reason sustained human-to-human transmission has not yet occurred is that the alpha-2,3 receptors needed for H5N1 binding are deep in the lower airways, making aerosolization and efficient person-to-person spread far less likely than with seasonal influenza. The virus does not currently transmit easily between humans, and sustained human-to-human transmission has not been documented. This is a central point tested in public health questions on the topic.

2. Classification and Clinical Manifestation

Classification of Avian Influenza Viruses Relevant to Human Disease

Feature	Highly Pathogenic AI (HPAI)	Low Pathogenic AI (LPAI)
Subtypes involved	H5N1, H5N6, H7N9 (some strains), H7N3, H7N7	H9N2, most H6 subtypes, some H7 subtypes
Poultry mortality	Up to 100% within 48 hours	Mild illness, reduced egg production
Cleavage site of HA	Multibasic cleavage site (cleaved by ubiquitous intracellular proteases, allowing systemic spread)	Monobasic cleavage site (cleaved only by trypsin-like proteases in respiratory/GI tract)
Human disease severity	Severe pneumonia, ARDS, multi-organ failure; case fatality rate up to 50%	Usually mild conjunctivitis or upper respiratory illness
Pandemic risk	High concern	Lower concern, but potential reassortment risk

Clinical Spectrum of H5N1 in Humans

Severity	Presentation	Typical Timeline
Mild / Subclinical	Conjunctivitis alone, mild ILI (influenza-like illness); increasingly recognized with clade 2.3.4.4b dairy-cow exposure cases	Within 1-3 days of exposure
Moderate	Fever, cough, sore throat, myalgia; may include diarrhea, vomiting, abdominal pain. Abnormal CXR with focal consolidation.	Days 2-5 after symptom onset
Severe / Fatal	Rapidly progressive bilateral pneumonia, ARDS, respiratory failure, multi-organ dysfunction (renal failure, hepatic injury, DIC, encephalopathy). Complications include pulmonary hemorrhage, pneumothorax, and pancytopenia.	Days 6-10; median time to death ~9-10 days from onset

Key Clinical Features by Organ System

System	Findings
Respiratory	Cough, dyspnea, hemoptysis, tachypnea, bilateral crackles, ARDS
Gastrointestinal	Watery diarrhea, vomiting, abdominal pain (may precede respiratory symptoms by 1-2 days)
Ocular	Conjunctivitis (especially with dairy cattle exposure; less common in poultry-related cases)
Neurologic	Encephalopathy, seizures (more common in children)
Hepatorenal	Elevated AST/ALT, elevated creatinine, acute kidney injury
Hematologic	Leukopenia, lymphopenia, thrombocytopenia, DIC in severe cases

3. Diagnostic Workup

Test	Role	Key Points
Rapid influenza antigen test (RIDT)	Screening (low sensitivity)	May detect influenza A but cannot distinguish H5N1 from seasonal strains. Poor negative predictive value. A negative RIDT does NOT rule out H5N1.
Influenza A RT-PCR (matrix gene)	Best initial test (in practice)	Detects influenza A broadly. If positive but the specimen cannot be subtyped to H1 or H3 ("unsubtypeable influenza A"), suspect a novel subtype and refer immediately.
H5-subtype real-time RT-PCR	Confirmatory / most accurate test	Performed at public health reference laboratories. Targets the H5 hemagglutinin gene. This is how a case is confirmed.
Viral culture	Gold standard (reference only)	Performed under BSL-3 enhanced conditions using embryonated chicken eggs. Not used clinically due to biosafety constraints and turnaround time, but remains the definitive method for isolation and characterization.
Microneutralization / HI assay	Serologic confirmation	A four-fold or greater rise in H5N1-neutralizing antibody titers between acute and convalescent sera confirms past infection. Used epidemiologically, not for acute clinical decision-making.
CBC, CMP, LDH	Supportive labs	Leukopenia (especially lymphopenia), thrombocytopenia, elevated transaminases, elevated LDH and creatinine
Chest radiography / CT	Imaging	Bilateral patchy infiltrates, consolidation, air bronchograms, ground-glass opacities. Rapid progression to diffuse bilateral disease consistent with ARDS.

The diagnostic approach begins with clinical suspicion. The most critical step is the exposure history. Clinicians should consider H5N1 in any patient with acute respiratory illness or conjunctivitis and a relevant epidemiologic exposure, including work on poultry or dairy farms with confirmed or suspected infection. Without this exposure link, the diagnosis is nearly impossible to make on clinical grounds alone, because the initial symptoms mimic ordinary influenza or community-acquired pneumonia.

When clinical suspicion is raised, the best initial test in most clinical settings is a standard influenza A RT-PCR targeting the conserved matrix (M) gene. This will confirm whether the patient has influenza A at all. The critical clue is when the specimen tests positive for influenza A but cannot be subtyped to H1 or H3 by routine assays. This "unsubtypeable influenza A" result is the laboratory red flag that mandates immediate referral of the specimen to a public health reference laboratory for H5-subtype-targeted RT-PCR.

For patients with conjunctivitis and acute respiratory illness, conjunctival, nasopharyngeal, and combination nasal-oropharyngeal swabs should be collected. For patients with only conjunctivitis, conjunctival and nasopharyngeal swabs are recommended. Recall that throat swabs are preferred over nasal swabs for H5N1 because viral titers are higher in the lower respiratory tract.

A confirmed case requires laboratory evidence of H5N1 by viral isolation, by RT-PCR from respiratory specimens, or by a four-fold or greater rise in H5N1-specific antibody titer between paired sera.

A crucial testing pearl: rapid antigen tests (RIDTs) have poor sensitivity for H5N1 and should never be used to rule out the diagnosis. Confirmatory diagnosis requires sophisticated laboratory support, and commercial rapid antigen tests are insensitive. A negative RIDT in a patient with exposure history and compatible symptoms should lead to immediate RT-PCR testing and empiric antiviral treatment.

On imaging, findings progress rapidly. Early CXR may show unilateral focal consolidation or patchy infiltrates, but within days the disease typically evolves into bilateral diffuse opacities with air bronchograms and ground-glass changes, reflecting ARDS. CT chest may show bilateral ground-glass opacities, consolidation, and air bronchograms.

4. Management and Treatment

Setting	Drug	Dose (Adults)	Duration	Notes
Outpatient (confirmed, probable, or suspected)	Oseltamivir	75 mg PO BID	5 days	Start empirically; do NOT wait for lab results. Best outcomes when started within 48 hours of symptom onset.
Hospitalized (severe / complicated)	Oseltamivir	75 mg PO/NG BID	5-10 days (consider extended 10-day course)	Consider longer duration for severe or critically ill patients.
Hospitalized (combination therapy)	Oseltamivir + Baloxavir	Oseltamivir 75 mg BID + Baloxavir single dose (weight-based: 40 mg if 40-80 kg; 80 mg if >80 kg)	Oseltamivir for up to 10 days	Combination may reduce risk of resistance emergence.
Parenteral (unable to take PO)	Peramivir IV	600 mg IV once daily	Minimum 5 days	Unlike seasonal influenza (single dose), H5N1 requires a multi-day course.
Post-exposure prophylaxis (PEP)	Oseltamivir	75 mg PO BID (treatment dosing, NOT once-daily prophylaxis dosing)	5 days (limited exposure) or 10 days (ongoing exposure)	PEP at twice-daily dosing, not the standard once-daily PEP used for seasonal flu.
Contraindicated	Amantadine / Rimantadine	N/A	N/A	Adamantanes are NOT effective; H5N1 viruses are resistant.

Treatment with oseltamivir should begin as soon as possible. An observational registry study showed that oseltamivir initiated within 2 days of symptom onset in patients without respiratory failure was significantly associated with survival. The principle is: treat empirically before confirmation. Antiviral treatment should never be delayed while awaiting laboratory results.

For outpatients with suspected H5N1, the standard dose of oseltamivir for adolescents and adults is 75 mg twice daily for 5 days. Pediatric dosing is weight-based per standard guidelines.

For hospitalized patients, particularly those with severe pneumonia or respiratory failure, three modifications apply. First, treatment duration may be extended to 10 days for severely ill hospitalized patients. Second, combination antiviral therapy with oseltamivir plus baloxavir can be considered because H5N1 strains may develop resistance to neuraminidase inhibitors when used alone. Third, in patients who cannot tolerate oral medication, IV peramivir at 600 mg once daily for a minimum of 5 days is recommended, which differs from the single-dose regimen used for uncomplicated seasonal influenza.

Most H5N1, H5N6, and H7N9 viruses are susceptible to neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) and baloxavir, but are often resistant to adamantanes (amantadine and rimantadine). This means adamantanes are NOT recommended under any circumstance.

For post-exposure prophylaxis (PEP), the dosing is notably different from standard seasonal flu PEP. Oseltamivir PEP is given at treatment-frequency dosing (twice daily), not the once-daily prophylaxis regimen used for seasonal influenza. Duration is 5 days for time-limited exposures or 10 days if exposure is ongoing.

Supportive care for severe cases includes ICU admission, mechanical ventilation with lung-protective strategies for ARDS ($V_T$ 6 mL/kg predicted body weight, plateau pressure <30 cmH2O), prone positioning, ECMO when available, and management of multi-organ failure. Corticosteroids are generally avoided or used with caution, as they have not been shown to improve outcomes in H5N1 and may prolong viral shedding.

Infection control is an important management consideration: patients should be placed on airborne precautions (negative pressure room, N95 respirator) plus contact precautions, in contrast to standard seasonal influenza which requires only droplet precautions.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Seasonal Influenza (H1N1, H3N2)	Fever, cough, myalgia, positive influenza A test	Seasonal influenza subtypes to H1 or H3 on routine PCR. No exposure to poultry or dairy farms. Rarely causes lymphopenia this profound. Does not typically progress to rapid bilateral ARDS in healthy individuals.
COVID-19 (SARS-CoV-2)	Fever, cough, dyspnea, bilateral GGOs on imaging, lymphopenia, ARDS	No poultry/farm exposure. SARS-CoV-2 PCR positive, influenza A PCR negative. COVID often has anosmia/ageusia (not seen in H5N1). Chest CT may show peripheral predominant GGOs rather than the rapid central consolidation of H5N1.
*Severe Community-Acquired Pneumonia (bacterial, e.g., S. pneumoniae, Legionella)*	Fever, cough, dyspnea, consolidation on CXR	Bacterial pneumonia typically shows leukocytosis with left shift (not leukopenia/lymphopenia). Responds to antibiotics. No exposure history. Procalcitonin elevated. Sputum culture or urinary antigen positive.
SARS (SARS-CoV-1)	Rapidly progressive atypical pneumonia, lymphopenia, elevated LDH, similar CXR pattern	SARS has not circulated since 2004. Exposure history differs (healthcare/nosocomial setting, no poultry link). SARS-CoV-1 testing distinguishes.
MERS-CoV	Severe pneumonia, high mortality, zoonotic exposure	Exposure to dromedary camels in the Middle East, not poultry. MERS-CoV PCR positive. Often includes renal failure early.
Hantavirus Pulmonary Syndrome	Rapid respiratory failure, bilateral pulmonary edema, thrombocytopenia, leukocytosis with left shift (immunoblasts)	Exposure to rodent droppings, not poultry. Characteristic hemoconcentration and immunoblasts on peripheral smear. No influenza A on PCR.
Pneumocystis Pneumonia (PCP)	Bilateral GGOs, dyspnea, hypoxemia, elevated LDH	Occurs in severely immunocompromised patients (HIV with CD4 <200). Insidious onset over weeks, not days. No poultry exposure. Methenamine silver stain or beta-D-glucan positive.

6. Traps and High-Yield Pearls

The single most common trap with avian influenza questions is failing to connect the exposure history to the diagnosis. A vignette will describe a patient with severe, rapidly progressive bilateral pneumonia and lymphopenia. The clinical picture alone overlaps heavily with COVID-19, SARS, or severe bacterial pneumonia. The test-writer places the answer in the stem: a single sentence about the patient working on a poultry farm, visiting a live bird market, or handling sick chickens. If you skip over that exposure detail, you will pick the wrong diagnosis.

A second frequent trap involves the rapid antigen test result. A vignette may describe a patient with textbook H5N1 features whose rapid influenza test returns negative. The wrong answer is to stop the workup. The correct next step is to order RT-PCR and start empiric oseltamivir immediately. Remember: rapid antigen tests have poor sensitivity for H5N1, and a negative result does not exclude the diagnosis.

Third, students frequently confuse PEP dosing for H5N1 with PEP dosing for seasonal influenza. For seasonal flu, oseltamivir prophylaxis is once daily. For H5N1, PEP uses treatment-frequency dosing (twice daily). This distinction is a favorite tested detail.

Fourth, understand that adamantanes are always wrong for avian influenza. If amantadine or rimantadine appears as an answer choice for treatment of H5N1, it is a distractor.

Fifth, remember the specimen collection nuance: for H5N1, throat swabs and lower respiratory samples outperform nasal swabs. This is the opposite of seasonal influenza, where nasal specimens are standard.

Finally, the core competency being tested in avian influenza questions is your ability to integrate epidemiologic context (exposure to poultry, farm work, travel to endemic regions) with atypical clinical features (GI symptoms preceding respiratory failure, conjunctivitis, lymphopenia out of proportion to the rest of the CBC) and then execute the correct empiric management (oseltamivir without waiting for confirmatory results). The vignette tests whether you can recognize a rare but high-stakes diagnosis that hides behind an ordinary-looking respiratory illness.

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