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Dengue Fever - A Comprehensive Overview

Causative Agent & Classification

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Epidemiology

• Global burden: The WHO reports a 30-fold increase in dengue incidence over the past 30 years. An estimated 50 million+ cases occur annually, with 400,000 cases of dengue hemorrhagic fever (DHF). In 2024, the WHO recorded over 14 million cases - a historic high. A CDC report (2025) noted a 359% spike in US dengue incidence in 2024 (3,798 cases vs. an annual average of 828).
• Current outbreaks (2026): Sri Lanka is battling one of its worst outbreaks - over 44,000 cases and 28 deaths by mid-June 2026, with military drones now being deployed to detect mosquito breeding grounds.
• Endemic zones: Tropical and subtropical regions of Southeast Asia, the Pacific, Latin America, and the Caribbean. All four serotypes co-circulate in many areas.
• Vector: Primarily Aedes aegypti (day-biting mosquito); Aedes albopictus is a secondary vector. The mosquito breeds in clean, stagnant water in containers around human dwellings (endophagic and endophilic). It survives best at 16-30°C with 60-80% relative humidity.
• Transmission: Female mosquito acquires virus from a viremic human; extrinsic incubation period is 8-14 days, after which the mosquito remains infective for its lifetime (1-3 months). There is no person-to-person transmission except via blood transfusion and vertical (mother-to-child) transmission.
• Iceberg phenomenon: DF/DHF follows an "iceberg" or pyramid pattern - the majority of cases are asymptomatic at the base, followed by classical DF, DHF, and dengue shock syndrome (DSS) at the apex.

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Dengue Virus Infection - Classification

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Pathogenesis

• Infection with one serotype confers lifelong immunity to that serotype but only short-duration cross-protection against others.
• On secondary infection with a different serotype, pre-existing dengue antibodies form virus-antibody complexes. These non-neutralizing "enhancing" antibodies promote infection of a larger number of mononuclear cells.
• This triggers massive release of cytokines, vasoactive mediators, and procoagulants, leading to plasma leakage, thrombocytopenia, and disseminated intravascular coagulation (DIC) - the hallmarks of DHF.
• Cross-reactive T cell immune responses also contribute to the cytokine storm.
• Risk of DHF is ~0.2% in primary infection, but at least 10-fold higher with secondary infection by a different serotype. Co-circulation of all four serotypes (as seen in Panama in 2025) sharply increases severe case risk.

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Clinical Features

Incubation Period

Three Clinical Phases of DHF

Classical Dengue Fever (DF)

• Sudden onset with chills, high fever, intense headache, retro-orbital pain (worsened by eye movement), severe myalgia/arthralgia
• Biphasic fever curve (saddle-back): fever for ~3-4 days, brief remission, then a second febrile phase
• Rash: appears in ~80% of cases during remission or second febrile phase - maculopapular or scarlatiniform, starting on trunk/chest, spreading to extremities and face; may be accompanied by itching and hyperaesthesia
• Fine pale morbilliform rash on trunk spreading outward after defervescence
• Convalescence may be protracted; fatality is exceedingly low in classical DF
• Small children may present with only mild URTI symptoms

Dengue Haemorrhagic Fever (DHF) - WHO Criteria (all four required)

1. Acute fever lasting 2-7 days
2. Haemorrhagic manifestations: positive tourniquet test, petechiae, ecchymoses, purpura, or bleeding from mucosa/GI tract/injection sites
3. Platelet count ≤ 100,000 cells/mm³
4. Objective evidence of plasma leakage: haematocrit rise ≥20% from baseline, OR pleural effusion, ascites, hypoproteinaemia

Dengue Shock Syndrome (DSS) - DHF plus shock

• Tachycardia, cool extremities, delayed capillary refill, weak/thready pulse, lethargy or restlessness
• Pulse pressure ≤ 20 mmHg (e.g., 100/80 mmHg)
• Hypotension for age
• Mortality >10% if untreated; can be reduced to <1% with prompt treatment

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Grading of Dengue Infection (WHO)

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Diagnosis

Probable Diagnosis (clinical):

Confirmed Diagnosis (laboratory):

• Virus isolation from serum/CSF/autopsy tissue (within first 6 days of illness)
• Fourfold rise in IgG (HIA) or IgM seroconversion
• Detection of viral antigen/genome by ELISA, immunofluorescence, or RT-PCR
• NS1 antigen detection: ELISA or rapid test - detects antigen from Day 1 to Day 6 (earliest marker, does not differentiate serotype)
• IgM (MAC-ELISA): detectable after Day 5; remains positive for months

Diagnostic Test Timing Summary

Other Lab Findings

• Leukopenia (characteristic)
• Thrombocytopenia (progressive)
• Rising haematocrit (haemoconcentration from plasma leakage)
• Elevated liver enzymes (ALT/AST)
• Coagulopathy in DHF

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Differential Diagnosis

• Influenza, measles, rubella (similar fever + rash)
• Chikungunya (prominent arthralgia; rash similar)
• Zika virus (conjunctivitis more prominent; teratogenic risk)
• West Nile fever (causes lymphadenopathy - usually absent in dengue)
• Malaria (especially falciparum - must be excluded)
• Leptospirosis, rickettsial infections, meningococcemia (petechial rash overlap)
• Other viral haemorrhagic fevers (Ebola, Marburg, yellow fever)

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Management

Dengue Fever (DF - outpatient)

• Rest and adequate oral fluids (ORS, fruit juices, electrolyte-containing drinks)
• Paracetamol for fever and pain
• Avoid NSAIDs and aspirin - risk of bleeding due to thrombocytopenia and platelet dysfunction
• Monitor for warning signs (abdominal pain, persistent vomiting, bleeding, rapid breathing, postural hypotension, drop in platelet count)
• Return to hospital immediately if warning signs develop

DHF Grade I/II (hospital admission)

• IV fluid therapy if oral intake inadequate
• Monitor haematocrit, platelet count, and urine output closely
• Isotonic crystalloids (normal saline or Ringer's lactate)
• Critical phase fluid management: adjust rate based on haematocrit trends
• Watch for signs of over-hydration during recovery phase

DHF Grade III/IV - DSS (ICU)

• Aggressive IV fluid resuscitation (colloid if haematocrit does not improve)
• Oxygen and vital sign monitoring
• Blood product transfusions for significant haemorrhage (packed RBCs, fresh frozen plasma, platelets as needed)
• Organ support as required
• Steroids: several studies evaluated but evidence remains inconclusive - not currently recommended

Disposition

• DF: can be outpatient if tolerating oral fluids and no warning signs
• DHF: hospital admission for IV fluids and monitoring
• DSS: ICU admission

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Prevention & Control

Personal Protection

• Insect repellents (DEET, picaridin)
• Protective clothing (long sleeves, long trousers)
• Mosquito nets (especially for sleeping children/infants)
• Window and door screens

Vector Control

• Source reduction: eliminate stagnant water containers (flower pots, tyres, water tanks, coolers) - the cornerstone
• Larviciding: temephos in water containers
• Adult mosquito control: indoor residual spraying, space spraying (fogging)
• Biological control: Bacillus thuringiensis israelensis (Bti), larvivorous fish
• Novel approaches: Wolbachia-infected mosquitoes to suppress virus replication; sterile insect technique; genetically modified mosquitoes

Vaccination

• Dengvaxia (CYD-TDV) by Sanofi Pasteur: first licensed dengue vaccine; tetravalent; recommended only for seropositive individuals (prior dengue infection confirmed) aged 9-16 in endemic areas - risk of severe dengue in seronegative recipients
• TAK-003 (Qdenga) by Takeda: newer tetravalent live-attenuated vaccine; approved in EU, Indonesia, and several other countries; can be given regardless of prior serostatus in endemic regions

Surveillance (India - National Programme)

• 521 sentinel surveillance hospitals with lab support for endemic states
• 14 Apex Referral Laboratories linked to sentinel hospitals
• IgM capture ELISA kits provided free via National Institute of Virology, Pune
• NS1 ELISA kits introduced for early (Day 1) diagnosis
• Mid-term plan components: surveillance, case management, vector management, outbreak response, capacity building, IEC (Information, Education, Communication)

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Recent Evidence (2025)

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• 4 serotypes; secondary infection with a different serotype = risk of DHF via ADE
• Vector: Aedes aegypti - day-biting, breeds in clean stagnant water
• "Breakbone fever" = severe myalgia/arthralgia; biphasic fever; rash on trunk spreading outward
• DHF diagnosis requires all 4 WHO criteria: fever + haemorrhage + thrombocytopenia + plasma leakage
• No antivirals; avoid NSAIDs/aspirin; fluid management is the cornerstone
• NS1 antigen = earliest lab marker (Days 1-6); IgM after Day 5
• Dengvaxia only for seropositive individuals; Qdenga (TAK-003) is the newer option

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Heart Attack (Myocardial Infarction) - Medication, Diagnosis & Procedures

What Is a Heart Attack?

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Pathophysiology

1. Plaque fissure with inflammation - T-cell driven adaptive immune dysregulation
2. Plaque fissure without inflammation
3. Plaque erosion - present in at least one-third of ACS cases

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Diagnosis

Symptoms ("MONA" mnemonic for initial management is taught, but here is the clinical picture)

• Chest pain/pressure: severe, at rest, >10 minutes, crushing or squeezing, radiating to left arm, jaw, back, or epigastrium
• Associated features: diaphoresis, dyspnea, nausea/vomiting, lightheadedness, sense of impending doom
• Atypical presentations: women, elderly, and diabetics may present with fatigue, dyspnea, or epigastric pain without classic chest pain

12-Lead ECG (First and Fastest Test - get within 10 minutes of arrival)

Biomarkers

• Most sensitive and specific biomarker available for myocardial necrosis
• High-sensitivity troponin (hsTn) assays allow earlier and more accurate detection
• Standard protocol: measure at presentation, 1 hour, and 3 hours if needed
• Troponin begins to rise 3-6 hours after symptom onset, peaks at 12-24 hours, remains elevated for 7-14 days (helpful for late presenters)
• Caveats: hsTn can be falsely elevated in AKI, myocarditis, PE, sepsis, and many other conditions

Other Investigations

• Chest X-ray: cardiomegaly, pulmonary edema (Killip class assessment)
• Echocardiogram: wall motion abnormalities, LV function, pericardial effusion, mechanical complications
• Coronary angiography: definitive anatomy - culprit artery identification; gold standard for STEMI
• CT coronary angiography (CTCA): for intermediate-risk patients in the ED, or to rule out obstructive CAD

Differential Diagnosis of Troponin Elevation (causes of myocardial injury that are NOT MI)

• Myocarditis, takotsubo cardiomyopathy, heart failure
• Pulmonary embolism, stroke/subarachnoid haemorrhage
• Sepsis, critical illness, renal failure
• Cardiac contusion, defibrillator shocks, ablation
• Chemotherapy agents (Fourth Universal Definition of MI, 2018)

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Treatment - Medications

1. Immediate ("Upstream") Therapy - ALL ACS

• High-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg): recommended for ALL ACS patients; reduce MACE (2025 ACC/AHA Guideline)
• Ezetimibe + statin: if LDL-C goal not achieved on statin alone (goal <70 mg/dL, or <55 mg/dL for very high risk)
• PCSK9 inhibitors (evolocumab, alirocumab): for recurrent ACS or LDL not at goal despite max statin + ezetimibe; LDL goal as low as <40 mg/dL in recurrent events within 2 years

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Procedures

1. Primary Percutaneous Coronary Intervention (Primary PCI) - Gold Standard for STEMI

1. Patient is taken to the cardiac catheterisation laboratory
2. Arterial access obtained - radial artery approach is now preferred over femoral (lower bleeding, possible mortality benefit)
3. A guiding catheter is inserted and advanced to the coronary ostium under fluoroscopy
4. A thin guidewire crosses the occlusion
5. A balloon catheter is inflated to open the artery (balloon angioplasty)
6. A coronary stent is deployed - drug-eluting stents (DES) are preferred over bare-metal stents (BMS); DES reduce restenosis
7. Post-procedure imaging confirms restored blood flow (TIMI 3 flow = normal)

• Door-to-balloon (D2B) time: ≤90 minutes from first medical contact
• If transfer required: first medical contact to balloon ≤120 minutes
• If neither target achievable, give fibrinolytics first

• Cardiogenic shock (Killip III/IV) or severe heart failure
• Contraindication to fibrinolytics exists
• Symptom onset >12 hours prior
• Prior CABG or recent PCI
• Diagnosis uncertain

2. Fibrinolytic (Thrombolytic) Therapy

• Any prior intracranial hemorrhage
• Ischemic stroke within 3 months
• Active internal bleeding
• Aortic dissection
• Severe head trauma/CNS surgery within 2 months
• Significant closed-head injury within 3 months

3. Coronary Artery Bypass Graft (CABG)

• Left main coronary artery disease
• Three-vessel disease, especially with diabetes or reduced LV function
• Anatomy unsuitable for PCI (heavily calcified, tortuous vessels)
• Failed PCI or mechanical complications of MI (VSD, papillary muscle rupture)

4. Invasive Strategy for NSTE-ACS

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Killip Classification (for risk stratification in STEMI)

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Complications of MI

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Summary: The "MONA + DAPT + Reperfuse" Approach

Acute MI → Aspirin + P2Y12 inhibitor (DAPT) + Anticoagulant
         → Nitroglycerin (if no contraindication)
         → Oxygen (if SpO2 <90%)
         → Beta-blocker (oral, within 24h if stable)
         → High-intensity statin (start immediately)
         → REPERFUSION:
              STEMI → Primary PCI (door-to-balloon ≤90 min)
                    → Fibrinolysis if PCI unavailable within 120 min
              NSTEMI → Risk-stratify → Invasive strategy within 24-72h
         → Long-term: ASA + ACEi/ARB + beta-blocker + statin ± eplerenone

• Ticagrelor/prasugrel preferred over clopidogrel for PCI patients
• Transition to ticagrelor monotherapy ≥1 month post-PCI reduces bleeding
• Complete revascularization recommended in stable STEMI with multivessel disease (within 45 days)
• Radial artery access recommended over femoral for coronary angiography
• High-intensity statin + ezetimibe ± PCSK9 inhibitor for aggressive LDL lowering post-MI
• In cardiogenic shock: culprit-lesion only PCI (not multivessel at same sitting)

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Heart Attack (Myocardial Infarction) - Definition, Clinical Features, Diagnosis & Medications

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1. DEFINITION

"The presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia."

What Happens Physiologically?

• Has zero or near-zero blood flow - unable to sustain function
• Within hours of no blood supply, cardiac muscle cells die
• The infarcted area becomes engorged with deoxygenated stagnant blood, taking on a bluish-brown hue
• Vessel walls become permeable, leaking fluid → local oedema
• Cellular metabolism shuts down → cell swelling and death

How Does the Occlusion Form? - The 4-Step Sequence

1. An atherosclerotic plaque is eroded or suddenly disrupted by endothelial injury, intraplaque haemorrhage, or mechanical forces - exposing subendothelial collagen and necrotic plaque contents to blood
2. Platelets adhere, aggregate, and activate - releasing thromboxane A2, ADP, and serotonin, causing further platelet aggregation and vasospasm
3. Coagulation is activated by exposed tissue factor - adding to the growing thrombus
4. Within minutes, the enlarging thrombus completely occludes the coronary artery lumen

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2. CLINICAL FEATURES (Symptoms and Signs)

ACS Spectrum - How Patients Present

A. Symptoms

B. "Atypical" or Silent Presentations

• Fatigue alone
• Dyspnea without chest pain
• Nausea/vomiting
• Jaw or arm discomfort without chest pain

C. Physical Examination Findings

D. Killip Classification (Severity Grading at Presentation)

E. Arrhythmias After MI

• First 30 minutes: re-entry arrhythmias (most dangerous - VF risk highest)
• 12 hours later: arrhythmias from increased automaticity
• 3 days to weeks: re-entry again (due to scarring)

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3. DIAGNOSIS

Step 1 - ECG (Electrocardiogram) - Get within 10 minutes of arrival

ECG Changes in MI - Three Stages

Why Does ST Elevation Occur? (Mechanism)

1. Rapid repolarization → current flows OUT of infarct → ST elevation
2. Decreased resting membrane potential → current flows INTO infarct during diastole → TQ depression (recorded as ST elevation)
3. Delayed depolarization → current flows OUT of infarct → ST elevation

Serial ECG Pattern in Anterior MI:

ECG Classification by Location

Pathological Q Wave Criteria

• Leads V2-V3: Q wave ≥0.02 seconds OR QS complex
• Other leads: Q wave ≥0.03 seconds AND ≥0.1 mV deep in ≥2 contiguous leads
• New LBBB (left bundle branch block) with symptoms = treat as STEMI

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Step 2 - Cardiac Biomarkers

Important: Initial biomarkers may be NORMAL if the patient arrives within the first few hours. A normal troponin on arrival never rules out STEMI - treat on ECG findings, not biomarkers, for STEMI.

• CK-MB: rises in 4-6 hours; useful for re-infarction detection (faster normalisation)
• Myoglobin: earliest to rise (1-3 hours) but very non-specific

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Step 3 - Other Investigations

STEMI vs NSTEMI vs Unstable Angina - Final Diagnosis Framework

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4. MEDICATIONS

A. Immediate Upstream Therapy (given to ALL ACS patients as soon as possible)

Antiplatelet Agents (Dual Antiplatelet Therapy - DAPT)

Anticoagulants

Anti-Ischaemic Agents

Statins - Start During Admission

• High-intensity statin: Atorvastatin 40-80 mg OR Rosuvastatin 20-40 mg
• Start immediately for ALL ACS patients regardless of baseline LDL
• 2025 ACC/AHA Guideline (Class I recommendation): high-intensity statins reduce major adverse cardiovascular events (MACE)
• If LDL not at goal: add ezetimibe; if still not at goal, add PCSK9 inhibitor (evolocumab or alirocumab)

B. Long-Term Post-MI Medications

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Quick Summary Reference

HEART ATTACK (MI)
│
├── DEFINITION: Ischaemic necrosis of myocardium from coronary
│   artery occlusion (>90% due to atherosclerotic plaque rupture
│   + thrombosis)
│
├── CLINICAL FEATURES:
│   ├── Chest pain (crushing, central, radiating to arm/jaw)
│   ├── Diaphoresis, nausea, vomiting, dyspnoea
│   ├── Atypical: fatigue, epigastric pain (women, elderly, DM)
│   └── Signs: tachycardia, S3/S4, rales, hypotension (if shock)
│
├── DIAGNOSIS:
│   ├── ECG (within 10 min): ST elevation → STEMI
│   │                         ST depression/normal → NSTEMI/UA
│   ├── Troponin: rises 3-6h, peaks 12-24h, measure at 0/1/3h
│   ├── CXR: pulmonary oedema, cardiomegaly
│   └── Echo: wall motion abnormalities, LV function
│
└── MEDICATIONS:
    ├── IMMEDIATE: Aspirin + Ticagrelor/Prasugrel + UFH/Enoxaparin
    ├── ANTI-ISCHAEMIC: GTN, Beta-blocker, Oxygen (if SpO2 <90%)
    ├── STATIN: High-intensity (atorvastatin 80 mg) - start now
    └── LONG-TERM: ASA + ACEi + Beta-blocker + Statin ± Eplerenone