• Over 770 million confirmed cases and 7 million deaths reported globally by WHO (as of late 2024/early 2025)
• Multiple waves driven by successive variants of concern (VOC): Alpha → Delta → Omicron (BA.1, BA.2, BA.5, XBB, JN.1, KP.2, etc.)
• Since 2023, the disease has transitioned to an endemic phase in most countries; WHO ended the PHEIC designation in May 2023
• Case fatality rate (CFR) has dropped significantly with vaccination, prior infection, and improved therapeutics — from ~2–3% in early pandemic to < 0.1% in vaccinated populations with Omicron

• Hong Kong experienced major waves: first wave (early 2020, imported), second wave (March 2020, returning residents), third wave (July 2020, community), fourth wave (Nov 2020 – Feb 2021), and the devastating fifth wave (Jan–May 2022, Omicron BA.2) which caused the majority of deaths in HK ^[1]
• Fifth wave: >1.2 million confirmed cases, >9,000 deaths (largely in unvaccinated elderly)
• HK's initial "dynamic zero-COVID" strategy shifted to "living with COVID" from late 2022
• Vaccine uptake was initially slow in the elderly, contributing to the catastrophic fifth-wave mortality
• HK used both BioNTech-Pfizer (Comirnaty/BNT162b2) and Sinovac (CoronaVac) vaccines

• COVID-19 co-circulates with influenza and RSV seasonally
• Updated (bivalent/monovalent XBB or JN.1-based) vaccines are recommended annually, particularly for high-risk groups
• Dominant circulating variants are Omicron sublineages (JN.1 descendants, KP.2/KP.3, LB.1, etc.)

• Institutionalized elderly (nursing homes) — close living quarters, frailty
• Healthcare workers — occupational exposure
• Lower socioeconomic status — crowded housing, delayed healthcare access

Risk factors for severe COVID-19: extremes of age (especially elderly), immunocompromised state, chronic medical conditions (DM, CKD, CLD, CVD, chronic lung disease), obesity, and pregnancy ^[1][2].

• Family: Coronaviridae, genus Betacoronavirus (same genus as SARS-CoV-1 and MERS-CoV)

• Genome: Single-stranded, positive-sense RNA virus (~30 kb — the largest RNA virus genome known)

  • Positive-sense means the RNA can be directly translated by host ribosomes (like an mRNA) → this explains the rapid replication cycle

• Structure:

  • Spike (S) protein — the key surface glycoprotein; mediates entry; target of vaccines and neutralizing antibodies
    • S1 subunit: contains the receptor-binding domain (RBD) that binds ACE2
    • S2 subunit: mediates membrane fusion
  • Envelope (E) protein — involved in viral assembly and release; also forms ion channels
  • Membrane (M) protein — most abundant structural protein; gives the virion its shape
  • Nucleocapsid (N) protein — packages the RNA genome; target of many rapid antigen tests

• Key receptor: ACE2 (Angiotensin-Converting Enzyme 2) — the functional receptor for viral entry

  • TMPRSS2 (Transmembrane Serine Protease 2) — primes the spike protein for membrane fusion
  • Some variants (Omicron) can also use the endosomal pathway (cathepsin-mediated) for entry

The distribution of ACE2 is essentially the map of COVID-19's organ involvement. This is why COVID-19 is NOT just a respiratory disease.

• Upper airway: Nasal cavity → pharynx → larynx — site of initial viral replication; explains early symptoms (sore throat, rhinorrhoea, anosmia)
• Lower airway: Trachea → bronchi → bronchioles → alveoli
  • Type II pneumocytes line the alveoli and produce surfactant (reduces surface tension, prevents alveolar collapse)
  • SARS-CoV-2 destroys Type II pneumocytes → surfactant deficiency → atelectasis → V/Q mismatch → hypoxaemia
  • Damaged alveolar-capillary barrier → protein-rich oedema fluid floods alveoli → hyaline membrane formation → diffuse alveolar damage (DAD) — the histopathological hallmark of COVID-19 ARDS

SARS-CoV-2 — a betacoronavirus of likely zoonotic origin (bat reservoir, with possible intermediate host — this remains debated between natural spillover vs. laboratory-related incident).

SARS-CoV-2 binds ACE2 receptor using its spike protein (S protein), with TMPRSS2 facilitating membrane fusion ^[1][2].

SARS-CoV-2 is transmitted primarily via: ^[1][2]

1. Respiratory droplets (> 5 μm) — close contact (< 1–2 metres), coughing, sneezing, talking, singing
2. Aerosols / airborne transmission (< 5 μm) — especially in poorly ventilated, enclosed spaces; prolonged exposure; aerosol-generating procedures (AGPs: intubation, bronchoscopy, CPR, nebulization, NIV)
3. Contact transmission — fomites (contaminated surfaces) → touching eyes, nose, mouth; considered less important than initially thought
4. Faecal-oral — possible but not a major route; SARS-CoV-2 RNA detected in stool

Aerosol-generating procedures (AGPs) carry high transmission risk; appropriate PPE (N95 respirator, eye protection, gown, gloves) is required ^[3][4].

• Mean incubation period: 2–5 days (Omicron shorter than Delta) ^[1]
• Range: 1–14 days (hence the historical 14-day quarantine)
• Omicron variants: median ~3 days

• Infectious period: typically from 2 days before symptom onset to ~7–10 days after symptom onset in immunocompetent individuals
• Peak infectivity is around the time of symptom onset (or 1 day before) — this is why COVID-19 is harder to contain than SARS-CoV-1 (which was most infectious later in the disease course)
• Immunocompromised patients may shed viable virus for weeks to months → important for infection control

Understanding variants is important because they explain changes in clinical behaviour over time:

• The shift toward upper respiratory tract tropism (rather than deep lung) with Omicron variants partly explains the milder clinical phenotype in many patients

1. Virus enters via nasal/oropharyngeal epithelium → binds ACE2 on epithelial cells
2. Viral RNA enters cell → hijacks ribosomes for replication
3. Local innate immune response: epithelial cells release interferons (IFN-α, IFN-β) and chemokines → recruit neutrophils, NK cells, monocytes
4. Upper respiratory symptoms predominate: sore throat, rhinorrhoea, cough
5. Anosmia/ageusia — virus infects sustentacular (supporting) cells of olfactory epithelium which express ACE2 (neurons themselves have less ACE2); local inflammation disrupts olfactory signalling
6. Viraemia may occur → systemic symptoms (fever, myalgia, fatigue)

Key point: In most immunocompetent, vaccinated individuals, the disease is contained at this phase. Antivirals (nirmatrelvir/ritonavir, remdesivir) work best here because they target viral replication.

1. In a subset of patients (especially unvaccinated elderly, immunocompromised), virus descends to lower respiratory tract
2. SARS-CoV-2 infects and destroys Type II pneumocytes →
   • Surfactant deficiency → atelectasis
   • Loss of alveolar-capillary barrier integrity → protein-rich oedema into alveoli
   • Hyaline membrane formation (fibrin + dead cells + protein) — hallmark of diffuse alveolar damage (DAD)
3. Inflammatory cell infiltration (macrophages, T cells) into lung parenchyma
4. Clinical correlate: bilateral ground-glass opacities (GGO) on CT/CXR, hypoxaemia, dyspnoea
5. Endothelial injury begins → microvascular thrombosis in pulmonary vasculature → further V/Q mismatch

Why do some COVID-19 patients have "silent hypoxia" (happy hypoxia)?

• Early in the pulmonary phase, lung compliance may still be preserved (unlike typical ARDS where lungs are stiff)
• Hypoxaemia is driven more by V/Q mismatch and shunt than by decreased compliance
• Patients don't feel as dyspnoeic as their SpO2 suggests because their work of breathing is not markedly increased (no stiff lungs yet)
• This can lead to delayed presentation

1. Dysregulated immune response with excessive release of pro-inflammatory cytokines — termed "cytokine storm" or macrophage activation syndrome (MAS)-like:
   • IL-6, IL-1β, TNF-α, IL-8, IL-18, IFN-γ
   • Marked elevation of inflammatory markers: CRP, ferritin, LDH, D-dimer, IL-6 ^[1][2]
2. ARDS develops — bilateral pulmonary infiltrates, severe hypoxaemia (PaO2/FiO2 < 300)
3. Endotheliitis and immunothrombosis — a distinctive feature of COVID-19:
   • Direct viral infection of endothelium + complement activation + NETosis (neutrophil extracellular traps) + platelet activation
   • → Microthrombi in pulmonary vasculature, kidneys, brain, heart
   • → Macrovascular events: DVT, PE, stroke, MI
4. Multi-organ dysfunction:
   • AKI — direct viral injury + haemodynamic instability + nephrotoxins
   • Myocardial injury — myocarditis, demand ischaemia, stress cardiomyopathy
   • Liver injury — direct viral effect, drug toxicity, hypoxic hepatitis
   • Neurological — encephalopathy, stroke, Guillain-Barré syndrome
   • Haematological — lymphopaenia (↓CD4+ and CD8+ T cells), DIC, thrombocytopaenia
5. Secondary infections (bacterial/fungal) may develop — COVID-associated pulmonary aspergillosis (CAPA), secondary bacterial pneumonia

The biphasic nature of COVID-19 is crucial for treatment timing: antivirals in early phase, anti-inflammatory/immunomodulatory therapy (dexamethasone, tocilizumab, baricitinib) in the hyperinflammatory phase ^[1][2].

• When SARS-CoV-2 binds ACE2, the receptor is internalized and downregulated
• Normal function of ACE2: converts Angiotensin II → Angiotensin 1-7 (which is vasodilatory, anti-inflammatory, anti-fibrotic)
• Loss of ACE2 → unopposed Angiotensin II accumulation →
  • Vasoconstriction
  • Pro-inflammatory signalling (via NF-κB)
  • Pro-thrombotic state
  • Increased vascular permeability
  • Pulmonary oedema
• This "RAAS imbalance" contributes to the multi-organ damage seen in severe COVID-19

This deserves special mention because it is a hallmark of severe disease:

• Mechanism: Immunothrombosis — the interplay between inflammation and coagulation
  1. Endothelial injury → tissue factor exposure → extrinsic coagulation pathway activation
  2. Complement activation (C3a, C5a) → further endothelial damage
  3. NETosis (neutrophils release DNA webs) → scaffold for thrombus formation
  4. Platelet activation and aggregation
  5. Impaired fibrinolysis (↑PAI-1)
• D-dimer is characteristically elevated (and is a prognostic marker)
• Clinical manifestations: PE, DVT, stroke, MI, limb ischaemia, renal infarction
• This is why prophylactic anticoagulation (LMWH) is standard of care in hospitalized COVID-19 patients

This classification directly guides management decisions:

Severity classification is essential for determining appropriate level of care and treatment (e.g., antivirals for mild-moderate in high-risk, dexamethasone for severe-critical) ^[1][2].

• A post-infectious hyperinflammatory condition in children/adolescents, typically 2–6 weeks after COVID-19
• Resembles Kawasaki disease and toxic shock syndrome — fever, mucocutaneous features, GI symptoms, shock, cardiac involvement (coronary aneurysms)
• Rare but important differential in a febrile child with multisystem involvement ^[5]

• May present atypically: falls, confusion/delirium (without fever), anorexia, functional decline
• Lower threshold for hypoxaemia due to reduced respiratory reserve
• Delirium may be the presenting feature — do not dismiss as "just dementia" ^[6]

• Generally milder disease than adults
• Can present with upper respiratory symptoms, fever, GI symptoms
• MIS-C (see above) is the major severe complication — usually presents 2–6 weeks post-infection with persistent high fever, GI symptoms, rash, conjunctivitis, and may progress to shock and cardiac dysfunction

• Higher risk of severe disease (especially 3rd trimester)
• Increased risk of preterm delivery and stillbirth
• Vaccination is recommended and safe in pregnancy

• Prolonged viral shedding (weeks to months)
• Higher risk of severe/critical disease
• May develop new variants during prolonged infection (evolutionary pressure from suboptimal immune response)
• Respond poorly to vaccination → may need prophylactic monoclonal antibodies (if available/effective against circulating variants)

For COVID-19: ^[3][4]

• Standard precautions (hand hygiene, respiratory hygiene/cough etiquette) for ALL patient encounters
• Droplet precautions: surgical mask, eye protection, within 1–2 m
• Airborne precautions: for AGPs — N95 respirator (fit-tested), eye protection, gown, gloves, negative pressure room if available
• Contact precautions: gown, gloves

1. Hand hygiene — the single most important measure to prevent healthcare-associated infection ^[4]
2. Appropriate PPE — based on risk of exposure (AGPs vs. routine care)
3. Environmental cleaning — regular disinfection of high-touch surfaces
4. Respiratory hygiene — mask-wearing by patients and HCWs
5. Isolation — airborne infection isolation room (AIIR) for AGPs; cohort isolation for confirmed cases
6. Vaccination of HCWs and patients

Diagnosis of infections: the clinical approach involves (1) clinical assessment, (2) appropriate specimen collection, (3) laboratory testing ^[3].

• Primary series + booster doses are recommended for all eligible individuals
• Updated (variant-matched) boosters are recommended annually (similar to influenza)
• High-risk groups should be prioritized: elderly, immunocompromised, healthcare workers, pregnant women
• Vaccination is safe in pregnancy — reduces risk of severe disease, preterm birth, and stillbirth
• Common side effects: injection site pain, fatigue, headache, myalgia, fever — these are expected immune responses
• Rare adverse events:
  • mRNA vaccines: myocarditis/pericarditis (mainly young males, 2nd dose; usually mild and self-limiting)
  • Inactivated vaccines: generally very safe; lower immunogenicity than mRNA
  • Very rare: anaphylaxis (observe for 15–30 minutes post-vaccination) — this is why post-COVID vaccine patients wait before leaving ^[7]

The observation period after COVID-19 vaccination (15–30 minutes) is to monitor for immediate Type 1 hypersensitivity reactions (anaphylaxis) mediated by IgE ^[5][7].

MIS-C is a critical DDx in a febrile child with multisystem involvement and recent/concurrent COVID-19. Key differentiators from Kawasaki disease: MIS-C patients are typically older (median age 8–9 years vs. < 5 years for KD), have more prominent GI symptoms and shock, and have evidence of recent SARS-CoV-2 infection/exposure ^[5][13].

In the immunocompromised host, the DDx of fever + pulmonary infiltrates is particularly broad: ^[9]

Travel history is essential. ^[10]

In any patient presenting with fever after travel, always take a detailed TOCC history (Travel, Occupation, Contact, Clustering). The differential includes COVID-19, malaria, dengue, typhoid, and other travel-related infections depending on the destination. ^[10]

Part of the diagnostic approach to any patient with fever and respiratory symptoms is to systematically exclude common differentials and detect co-infections: ^[3][10]

In Hong Kong, always consider TB in any patient with bilateral pulmonary infiltrates. TB and COVID-19 can coexist, and their CXR findings can overlap. Sputum AFB and Xpert MTB/RIF should be sent in at-risk patients. ^[3][10]

The following table organizes investigations by clinical priority:

A single negative PCR does NOT exclude COVID-19. Causes of false negatives include:

• Sampling error — swab not reaching the nasopharynx (most common cause!)
• Timing — testing too early (before sufficient viral replication) or too late (virus cleared from upper airway but still in lungs)
• Specimen handling — degradation of RNA during transport

If clinical suspicion remains high despite a negative NPS PCR: ^[3]

1. Repeat NPS PCR in 24–48 hours
2. Consider lower respiratory tract specimen (sputum, tracheal aspirate, BAL) — viral load in lower airway may be higher than upper airway in pneumonia phase
3. Consider CT chest — characteristic bilateral GGO supports a probable diagnosis even without PCR confirmation

• May have prolonged viral shedding — PCR can remain positive for weeks to months
• Ct values and clinical context must be integrated to distinguish active infection from residual shedding
• Viral culture (research labs) or subgenomic RNA detection can help determine if virus is still replicating

• Reinfection: new infection with a different variant, typically ≥ 90 days after initial infection, with new symptom onset and Ct value < 30
• Persistent positivity: PCR remains positive (high Ct) without new symptoms — usually non-infectious residual RNA
• Genomic sequencing can differentiate by identifying different viral lineages

• Patients with persistent symptoms > 4 weeks after acute infection should be assessed for Post-COVID-19 condition (Long COVID)
• Common symptoms: fatigue, cognitive dysfunction ("brain fog"), dyspnoea, chest pain, palpitations, joint pain
• No specific antiviral or anti-inflammatory treatment proven for Long COVID — management is supportive and multidisciplinary
• Investigations guided by symptoms: pulmonary function tests, echocardiography, cardiac MRI, neuropsychological assessment
• Graduated exercise rehabilitation; psychological support
• Vaccination has been associated with symptom improvement in some Long COVID patients

This is the most feared acute respiratory complication and the leading cause of death in COVID-19.

• Mechanism: SARS-CoV-2 destroys Type II pneumocytes (via ACE2) → loss of surfactant → alveolar collapse + disruption of alveolar-capillary barrier → protein-rich oedema floods alveoli → hyaline membrane formation = diffuse alveolar damage (DAD). The cytokine storm (Phase 3) amplifies this damage through massive inflammatory cell recruitment and microvascular thrombosis.

• Berlin Definition of ARDS applies:

  • Acute onset (within 1 week of known insult)
  • Bilateral opacities on CXR/CT (not fully explained by effusion, lobar collapse, or nodules)
  • Respiratory failure not fully explained by cardiac failure or fluid overload
  • PaO2/FiO2 ratio: Mild 200–300, Moderate 100–200, Severe < 100

• Clinical features: Progressive dyspnoea, tachypnoea, refractory hypoxaemia (requires escalating O2), bilateral crackles, cyanosis

• Management: Lung-protective ventilation (low tidal volume 6 mL/kg IBW, plateau pressure < 30 cmH2O), prone positioning ≥ 12–16 hours/day if PaO2/FiO2 < 150, PEEP optimization, dexamethasone, tocilizumab/baricitinib if rapidly deteriorating, ECMO for refractory cases ^[1][2]

• Prognosis: COVID-19 ARDS carries ~30–50% mortality in the ICU setting (pre-vaccine/early pandemic); lower with vaccination and current treatments

ARDS is the most common cause of death in severe COVID-19. The pathological hallmark is diffuse alveolar damage (DAD) with hyaline membrane formation. ^[1]

• Mechanism: Viral destruction of respiratory epithelium impairs mucociliary clearance and local immunity → breach in the airway's first-line defence → secondary bacterial colonization and infection. Additionally, dexamethasone and tocilizumab further immunosuppress the patient.

• Common pathogens: Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa (especially ventilator-associated pneumonia, VAP)

• Clinical clues: New fever after initial improvement, purulent sputum, rising WCC with neutrophilia, rising procalcitonin (key differentiator — procalcitonin is normally low in viral COVID-19; elevation suggests bacterial co-infection) ^[17], new lobar consolidation on CXR

• Management: Blood cultures + sputum culture → empirical antibiotics (guided by local antibiogram) → de-escalate based on culture results

• Mechanism: Severe COVID-19 + dexamethasone/tocilizumab-induced immunosuppression + damaged airway epithelium → creates a permissive environment for Aspergillus colonization and invasion. Similar to invasive pulmonary aspergillosis in neutropaenic patients.

• Risk factors: ICU admission, mechanical ventilation, prolonged corticosteroids, lymphopaenia

• Diagnosis: Serum/BAL galactomannan, BAL culture, CT findings (nodules, cavitation, halo sign — though classic halo sign is less common than in neutropaenic aspergillosis)

• Management: Voriconazole (first-line) or isavuconazole

Always consider fungal superinfection (especially CAPA) in a COVID-19 ICU patient who is not improving or deteriorating despite optimal antiviral and anti-inflammatory therapy. ^[9]

• Mechanism: The healing phase of DAD involves fibroblast proliferation and collagen deposition → in some patients, this fibrotic process is excessive and irreversible, leading to permanent lung scarring

  • Think of it as an exaggerated wound healing response in the lung

• Risk factors: Severity of initial pneumonia (especially if mechanical ventilation required), prolonged ICU stay, older age

• Clinical features: Persistent dyspnoea, reduced exercise tolerance, restrictive pattern on PFT (reduced FVC, reduced DLCO), reticular opacities / honeycombing / traction bronchiectasis on CT

• Management: Pulmonary rehabilitation; role of antifibrotics (nintedanib, pirfenidone) under investigation; no proven disease-modifying therapy yet

• Myocardial injury (elevated troponin) occurs in 20–30% of hospitalized COVID-19 patients and is an independent predictor of mortality

• Mechanisms:

  • Type 2 MI (demand ischaemia): Hypoxia + tachycardia + fever → myocardial oxygen demand exceeds supply → subendocardial ischaemia without plaque rupture. This is the most common mechanism.
  • Direct viral myocarditis: SARS-CoV-2 infects cardiomyocytes via ACE2 → inflammatory infiltrate → myocardial oedema and necrosis
  • Cytokine-mediated injury: Circulating cytokines (IL-6, TNF-α) directly damage cardiomyocytes
  • Stress (Takotsubo) cardiomyopathy: Catecholamine surge → apical ballooning

• Clinical features: Chest pain, dyspnoea, arrhythmias, new heart failure, cardiogenic shock (fulminant myocarditis)

• Investigations: Serial troponin, NT-proBNP, ECG (diffuse ST changes, low voltage), echocardiography (wall motion abnormalities, reduced EF), cardiac MRI (myocardial oedema on T2, subepicardial late gadolinium enhancement = LGE pattern of myocarditis) ^[18]

• Management: Supportive care for HF; immunosuppression NOT routinely recommended for viral myocarditis (unlike giant cell or autoimmune myocarditis); inotropes/ECMO for fulminant cases

• Mechanism: Myocardial injury, hypoxia, electrolyte disturbances (hypokalaemia, hypomagnesaemia from diarrhoea/diuretics), catecholamine surge, direct viral effect on cardiac conduction system, drug-related QTc prolongation

• Types: Sinus tachycardia (most common — from fever and sympathetic activation), atrial fibrillation, atrial flutter, ventricular tachycardia, heart block

• Management: Correct underlying cause (electrolytes, hypoxia); rate/rhythm control as per standard arrhythmia management; monitor QTc if on drugs that prolong it

• Mechanism: Can be from myocarditis, demand ischaemia, fluid overload (aggressive IV fluids), or pre-existing cardiac disease unmasked by the stress of acute illness

• Clinical features: Dyspnoea, orthopnoea, elevated JVP, bilateral crackles, peripheral oedema, elevated NT-proBNP

• Why it matters: Overlap with COVID-19 pneumonia makes diagnosis challenging — both cause bilateral CXR opacities and dyspnoea. NT-proBNP and echocardiography help differentiate.

• Incidence: VTE occurs in 10–30% of ICU COVID-19 patients even with prophylactic anticoagulation — dramatically higher than other ICU populations

• Mechanism: Immunothrombosis — the interplay of (1) endothelial injury via ACE2 + complement (C3a, C5a), (2) NETosis (neutrophil extracellular traps provide scaffolding for thrombi), (3) platelet activation and aggregation, (4) impaired fibrinolysis (↑PAI-1), (5) immobilization ^[11]

• Clinical features:

  • DVT: Unilateral leg swelling, warmth, tenderness, Homan's sign (unreliable)
  • PE: Sudden dyspnoea, pleuritic chest pain, haemoptysis, tachycardia, hypotension/shock (massive PE); sudden clinical deterioration in a previously stable COVID-19 patient should always raise suspicion for PE ^[11]

• Diagnosis: D-dimer (elevated in essentially all severe COVID-19 — so its specificity is low, but a markedly RISING D-dimer is concerning), CTPA for PE, Doppler USS for DVT

• Management: Therapeutic anticoagulation (LMWH or UFH → transition to DOAC or warfarin); thrombolysis for massive PE with haemodynamic instability; surgical or catheter-directed embolectomy for saddle PE ^[11]

COVID-19 is a strong independent risk factor for VTE. All hospitalized COVID-19 patients require prophylactic anticoagulation. A rising D-dimer or sudden deterioration should prompt investigation for PE. ^[2][11]

• Mechanism: Same immunothrombosis pathway, but affecting the arterial system

• Stroke: Both ischaemic (large vessel occlusion from hypercoagulable state or cardioembolism from arrhythmia) and haemorrhagic (from coagulopathy or anticoagulation complications). Young patients with COVID-19 can present with large vessel occlusion stroke — this was a striking early pandemic observation.

• Acute MI: Type 1 MI (plaque rupture from systemic inflammation destabilizing vulnerable plaques) or Type 2 MI (demand ischaemia from hypoxia/tachycardia)

• Limb ischaemia: Arterial thrombosis of peripheral vessels → acute limb ischaemia with pain, pallor, pulselessness

• Mechanism: Massive activation of coagulation cascade → consumption of clotting factors and platelets → simultaneous thrombosis AND bleeding

• Lab findings: ↑D-dimer, ↑PT/INR, ↓fibrinogen, ↓platelets, schistocytes on blood film

• Clinical features: Bleeding from venepuncture sites, mucosal bleeding, petechiae/purpura, combined with microvascular thrombosis (digital ischaemia, renal failure, hepatic failure)

• Management: Treat the underlying cause (COVID-19); supportive with platelet transfusion, FFP, cryoprecipitate as needed; consider heparin in DIC with predominant thrombosis

• Most common neurological complication of COVID-19 — especially in the elderly

• Mechanism: Multifactorial — systemic inflammation (cytokines crossing the blood-brain barrier → neuroinflammation), hypoxia, metabolic derangements (hyponatraemia from SIADH ^[16], uraemia, hepatic dysfunction), drugs (sedation, steroids), social isolation (ICU delirium)

• Always exclude other causes of confusion before attributing to COVID-19: metabolic (electrolytes, glucose, renal/hepatic failure), drugs, head injury, infections (meningitis), and structural causes (stroke) ^[12]

Confusion in any acutely unwell patient — including COVID-19 — requires a systematic workup. Do NOT assume it is just "COVID encephalopathy" without excluding treatable causes like hyponatraemia, drug effects, or stroke. ^[12]

• As discussed above — immunothrombosis can cause large vessel occlusion ischaemic stroke; anticoagulation complications or DIC can cause haemorrhagic stroke
• Notably affects younger patients without traditional cardiovascular risk factors — a distinctive feature of COVID-19
• Young patient + COVID-19 + focal neurological deficit = think stroke and get urgent CT/CTA

• Mechanism: Post-infectious autoimmune demyelination — molecular mimicry between SARS-CoV-2 antigens and peripheral nerve gangliosides → immune attack on peripheral nerves
• Clinical features: Ascending symmetric weakness, areflexia, sensory changes, potential respiratory failure (if phrenic nerve involved)
• Timing: Usually 1–3 weeks after COVID-19 infection
• Diagnosis: Clinical + CSF (albuminocytologic dissociation = ↑protein, normal WCC) + nerve conduction studies
• Management: IVIG or plasmapheresis; supportive care; monitor FVC for respiratory compromise

• Usually resolves within weeks to months, but can persist for > 6 months in some patients (part of Long COVID)
• Mechanism: Damage to sustentacular cells and local inflammation in olfactory epithelium → disrupted olfactory neuron signalling; in some cases, possible direct neuronal damage
• Management: Olfactory training (sniffing essential oils regularly); intranasal steroids (limited evidence); time and patience

• The hallmark haematological finding — occurs in ~80% of severe COVID-19
• Mechanism: Direct viral cytopathic effect on T cells (which express ACE2) + cytokine-induced apoptosis of lymphocytes (TNF-α, IL-6) + redistribution of lymphocytes to inflamed tissues (lungs)
• Clinical significance: Profound lymphopaenia (< 0.5 × 10⁹/L) correlates with disease severity and predicts ICU admission and mortality. It also reflects impaired adaptive immunity → higher susceptibility to secondary infections ^[1][2]

• Mechanism: Immune-mediated platelet destruction (similar to immune thrombocytopaenia, ITP), consumption in microthrombi (DIC), direct marrow suppression
• Vaccine-induced Immune Thrombocytopaenia and Thrombosis (VITT): A rare but important complication of adenoviral-vector COVID-19 vaccines (AstraZeneca, J&J — not used in HK, but historically relevant). Mechanism involves anti-PF4 antibodies → platelet activation → unusual-site thrombosis (cerebral venous sinus, splanchnic veins) + thrombocytopaenia. Treatment: avoid heparin (unlike typical HIT, use non-heparin anticoagulants + IVIG).

• A hyperinflammatory syndrome seen in a subset of severe COVID-19 patients
• Mechanism: Dysregulated macrophage activation → uncontrolled phagocytosis of blood cells and tissue destruction
• Clinical features: Persistent high fever, cytopaenias (especially ↓↓ferritin — paradoxically very high as a marker despite its name), hepatosplenomegaly, elevated triglycerides, elevated LDH, low fibrinogen
• HScore can help calculate probability of HLH
• Management: Treat underlying cause; dexamethasone; tocilizumab/baricitinib; in refractory cases, consider etoposide or anakinra (IL-1 receptor antagonist)

• Mechanism: (1) Direct viral infection of pancreatic islet cells (ACE2 expressed on beta cells) → beta cell destruction, (2) steroid-induced hyperglycaemia (dexamethasone increases gluconeogenesis and insulin resistance), (3) stress response (cortisol, catecholamines)
• Clinical significance: Hyperglycaemia is common in hospitalized COVID-19 patients and worsens outcomes; requires insulin management; some patients develop persistent diabetes after recovery

• Chest infection (including COVID-19) is a recognized respiratory cause of SIADH ^[16]
• Mechanism: Inflammatory cytokines and pulmonary disease trigger inappropriate ADH secretion → water retention → dilutional hyponatraemia
• Clinical features of hyponatraemia: Non-specific initially (malaise, lethargy, headache) → severe (confusion, convulsions, coma) — especially if acute (< 48 hours) ^[16]
• Management: Fluid restriction; address underlying cause; hypertonic saline only for severe symptomatic acute hyponatraemia (under experienced supervision; rate of correction must be < 0.5 mmol/L/hour or < 12 mmol/L/day for chronic hyponatraemia to avoid central pontine myelinolysis) ^[16]

Hyponatraemia from SIADH is a common but frequently overlooked complication of COVID-19 pneumonia. Always check sodium in hospitalized COVID-19 patients. SARS patients also commonly presented with very low sodium. ^[16]

• Rare but reported — bilateral adrenal haemorrhage/infarction from hypercoagulable state, or critical illness-related corticosteroid insufficiency
• Suspect if refractory hypotension despite vasopressors; random cortisol and ACTH help diagnose
• Treat with stress-dose hydrocortisone if suspected

• Timing: 2–6 weeks after SARS-CoV-2 infection (may not even have had symptomatic COVID-19)

• Mechanism: Post-infectious hyperinflammatory response — likely involves autoantibody formation and T-cell mediated tissue damage triggered by molecular mimicry with SARS-CoV-2 antigens

• Resembles Kawasaki disease and toxic shock syndrome ^[5][13]

• Clinical features:

  • Persistent fever ≥ 5 days
  • GI symptoms (abdominal pain, vomiting, diarrhoea — very prominent, can mimic surgical abdomen)
  • Mucocutaneous features (rash, conjunctivitis, oral changes — Kawasaki-like)
  • Cardiovascular (myocarditis, coronary artery aneurysms, reduced EF, shock requiring inotropes)
  • Haematological (elevated inflammatory markers — CRP, ferritin, D-dimer; thrombocytopaenia; elevated troponin)
  • BCG scar inflammation may be present ^[13]

• Diagnosis: Clinical criteria + evidence of recent SARS-CoV-2 infection or exposure + exclusion of other causes (sepsis, KD, toxic shock)

• Management: IVIG (first-line), corticosteroids, aspirin (for coronary involvement), biological agents (anakinra, infliximab) for refractory cases, inotropic support for shock, serial echocardiography for coronary surveillance ^[5]

• Rarer than MIS-C; similar pathophysiology
• Can present with myocarditis, shock, GI symptoms, rash, lymphopaenia
• Treatment: IVIG, steroids, biologics (as per MIS-C principles)