Dengue-Associated Myocarditis in the Intensive Care Unit: Recognition, Diagnosis, and Management

1. Dengue-Associated Myocarditis in the Intensive Care Unit: Recognition, Diagnosis, and Management Challenges

   Dr Neeraj manikath , claude.ai

   Abstract

   Dengue fever, caused by the dengue virus (DENV), affects over 390 million people annually worldwide. While most cases are self-limiting, severe complications including myocarditis can occur, particularly during the critical phase of illness. Dengue-associated myocarditis remains significantly underdiagnosed in intensive care units (ICUs), leading to suboptimal management and increased mortality. This review examines the pathophysiology, clinical presentation, diagnostic challenges, and evidence-based management strategies for dengue myocarditis in critically ill patients. We highlight key clinical pearls, diagnostic pitfalls, and practical management approaches that can improve outcomes in this challenging patient population.

   Keywords: Dengue, myocarditis, intensive care, troponin, arrhythmias, fluid management

   Introduction

   Dengue virus infection has emerged as one of the most important mosquito-borne viral diseases globally, with endemic transmission in over 100 countries. The World Health Organization estimates that dengue incidence has increased 8-fold over the past two decades, with climate change and urbanization contributing to expanding geographic distribution[1]. While the majority of dengue infections are asymptomatic or mild, approximately 5% progress to severe dengue, requiring intensive care management[2].

   Cardiac involvement in dengue fever, particularly myocarditis, has gained increasing recognition as a significant cause of morbidity and mortality in severe cases. However, dengue-associated myocarditis remains substantially underdiagnosed in clinical practice, with studies suggesting that subclinical cardiac involvement may occur in up to 62% of hospitalized dengue patients[3]. This underrecognition stems from overlapping clinical features with other dengue complications, lack of systematic cardiac evaluation, and the transient nature of many cardiac manifestations.

   The critical phase of dengue illness, typically occurring 3-7 days after fever onset, coincides with the period of highest risk for cardiac complications. During this phase, patients may develop plasma leakage, shock, and organ dysfunction, making the recognition of concurrent myocarditis particularly challenging yet crucial for optimal management.

   Epidemiology and Risk Factors

   Global Burden

   Dengue myocarditis has been reported across all endemic regions, with varying incidence rates depending on the population studied and diagnostic criteria employed. Prospective studies using systematic echocardiographic evaluation have documented cardiac dysfunction in 15-62% of hospitalized dengue patients[3,4]. The true incidence in ICU populations is likely higher, though precise epidemiological data remain limited due to underreporting and diagnostic challenges.

   Risk Factors for Cardiac Involvement

   Several factors have been identified as increasing the risk of cardiac complications in dengue fever:

   Host Factors:

   • Age extremes (pediatric patients and elderly)
   • Previous dengue infection (secondary dengue)
   • Underlying cardiovascular comorbidities
   • Diabetes mellitus
   • Hypertension

   Viral Factors:

   • DENV serotype (DENV-2 and DENV-3 associated with higher cardiac involvement)
   • High viral load during acute phase
   • Secondary infection with different serotype (antibody-dependent enhancement)

   Clinical Factors:

   • Severe dengue presentation
   • Prolonged shock
   • Fluid overload during management
   • Electrolyte imbalances[5,6]

   Pathophysiology

   Mechanisms of Cardiac Injury

   Dengue-associated myocarditis results from a complex interplay of direct viral effects, immune-mediated damage, and systemic inflammatory responses. Understanding these mechanisms is crucial for targeted therapeutic interventions.

   Direct Viral Effects

   Dengue virus has been demonstrated to directly infect cardiac myocytes through multiple mechanisms:

   • Binding to cellular receptors including DC-SIGN and mannose receptor
   • Direct cytopathic effects leading to myocyte death
   • Disruption of cardiac conduction system
   • Endothelial dysfunction affecting coronary microcirculation[7]

   Immune-Mediated Damage

   The host immune response plays a central role in cardiac injury:

   • Cytokine storm with elevated TNF-α, IL-1β, and IL-6
   • Complement activation and membrane attack complex formation
   • Molecular mimicry leading to autoimmune responses
   • T-cell mediated cytotoxicity against infected myocytes[8]

   Microvascular Dysfunction

   Capillary leak syndrome, a hallmark of severe dengue, affects cardiac function through:

   • Increased vascular permeability leading to myocardial edema
   • Coronary microvascular dysfunction
   • Impaired oxygen delivery and metabolic dysfunction
   • Activation of coagulation cascade with microthrombi formation[9]

   Clinical Presentation

   Spectrum of Cardiac Manifestations

   Dengue-associated cardiac involvement presents across a broad spectrum, from asymptomatic electrocardiographic changes to fulminant heart failure and cardiogenic shock.

   Asymptomatic Phase

   • Subclinical left ventricular dysfunction
   • Isolated troponin elevation without symptoms
   • Mild ECG abnormalities
   • Transient wall motion abnormalities on echocardiography

   Symptomatic Myocarditis

   • Chest pain (often atypical, may be overshadowed by dengue symptoms)
   • Dyspnea and exercise intolerance
   • Palpitations
   • Fatigue beyond that expected from dengue fever alone

   Severe Cardiac Dysfunction

   • Acute heart failure with pulmonary edema
   • Cardiogenic shock
   • Severe arrhythmias
   • Cardiac arrest[10]

   Temporal Relationship

   The timing of cardiac involvement in relation to dengue fever phases is critical for recognition:

   Febrile Phase (Days 1-3): Rare cardiac involvement, primarily subclinical Critical Phase (Days 4-6): Peak incidence of myocarditis, often coinciding with plasma leakage Recovery Phase (Days 7-10): Gradual improvement in most cases, though some patients may develop late complications[11]

   Diagnostic Challenges and Approaches

   Laboratory Investigations

   Cardiac Biomarkers

   Troponin Elevation - Clinical Pearls:

   • Troponin I/T elevation occurs in 15-35% of dengue patients
   • Levels are typically modest (0.1-2.0 ng/mL) compared to acute MI
   • Peak levels usually occur during critical phase (days 4-6)
   • Elevation may precede clinical symptoms by 24-48 hours
   • Pearl: Serial troponin monitoring in severe dengue can identify subclinical myocarditis before hemodynamic compromise
   • Oyster: Troponin elevation may be confused with acute coronary syndrome, leading to inappropriate anticoagulation in thrombocytopenic patients[12]

   Other Biomarkers:

   • CK-MB: Less specific, often elevated due to skeletal muscle involvement
   • NT-proBNP/BNP: Elevated in 40-60% of patients, correlates with severity
   • Hack: BNP/NT-proBNP ratio >1.5 may distinguish cardiac from non-cardiac causes of dyspnea in dengue[13]

   Inflammatory Markers

   • ESR and CRP: Often elevated but non-specific
   • Ferritin: May be markedly elevated, correlating with cytokine storm
   • D-dimer: Frequently elevated, must interpret carefully in context of bleeding risk

   Electrocardiographic Findings

   Common ECG Abnormalities

   Rhythm Disturbances:

   • Sinus bradycardia (most common, 30-50% of patients)
   • Sinus tachycardia (may indicate developing shock)
   • Atrial fibrillation/flutter (5-10% of patients)
   • Ventricular arrhythmias (rare but life-threatening)

   Conduction Abnormalities:

   • First-degree AV block
   • Bundle branch blocks
   • Complete heart block (rare but reported)

   Morphological Changes:

   • T-wave abnormalities (flattening, inversion)
   • ST-segment changes (depression more common than elevation)
   • QTc prolongation (may predispose to arrhythmias)
   • Low voltage complexes (suggests pericardial effusion)[14]

   Clinical Pearl: Serial ECG monitoring is essential as changes evolve rapidly during the critical phase.

   Echocardiographic Assessment

   Systematic Echocardiographic Evaluation

   Left Ventricular Function:

   • Global hypokinesis is most common pattern (60% of cases)
   • Regional wall motion abnormalities may mimic coronary artery disease
   • Ejection fraction typically ranges from 35-50% in symptomatic cases
   • Pearl: Perform echocardiography in all severe dengue patients, even if asymptomatic

   Right Heart Assessment:

   • Right ventricular dysfunction in 15-25% of cases
   • Elevated pulmonary artery pressures
   • May indicate concurrent pulmonary involvement

   Pericardial Assessment:

   • Pericardial effusion in 20-40% of patients
   • Usually small to moderate, rarely requires drainage
   • May contribute to hemodynamic compromise in volume-depleted patients[15]

   Advanced Echocardiographic Techniques

   Speckle Tracking Echocardiography:

   • Can detect subclinical dysfunction when LVEF appears normal
   • Global longitudinal strain typically reduced before EF decline
   • Hack: GLS <-18% may indicate myocarditis even with preserved EF[16]

   Cardiac MRI

   While not routinely available in many endemic regions, cardiac MRI provides valuable insights when accessible:

   • Lake Louise criteria can confirm myocarditis
   • T2-weighted imaging shows myocardial edema
   • Late gadolinium enhancement indicates fibrosis/scarring
   • Clinical Application: Reserve for cases with diagnostic uncertainty or suspected chronic sequelae[17]

   Management Strategies

   General Principles

   The management of dengue myocarditis requires a delicate balance between supporting cardiac function while managing the underlying dengue fever and its complications. The approach must be tailored to the phase of illness and severity of cardiac involvement.

   Supportive Care Framework

   Monitoring and Assessment:

   • Continuous cardiac monitoring for all suspected cases
   • Serial echocardiography every 24-48 hours during critical phase
   • Daily troponin and BNP monitoring
   • Strict fluid balance monitoring with hourly urine output
   • Pearl: Use central venous pressure monitoring judiciously - may guide fluid management but can be misleading during capillary leak phase

   Fluid Management - The Central Challenge

   Fluid management in dengue myocarditis represents one of the most challenging aspects of care, requiring navigation between cardiac dysfunction and capillary leak syndrome.

   Fluid Management Principles

   Phase-Based Approach:

   Critical Phase (Days 4-6):

   • Goal: Maintain perfusion while minimizing fluid overload
   • Strategy: Conservative fluid approach with frequent reassessment
   • Initial fluid bolus: 5-10 mL/kg over 30 minutes
   • Pearl: Use crystalloids over colloids to minimize oncotic load
   • Hack: If no response to first bolus, investigate cardiac function before additional fluids

   Recovery Phase (Days 7-10):

   • Goal: Facilitate reabsorption of extravasated fluid
   • Strategy: Cautious diuresis if volume overloaded
   • Monitor for rebound fluid accumulation[18]

   Fluid Management Algorithms

   When Myocarditis is Suspected:

   1. Immediate echocardiography if available
   2. If LVEF >45%: Standard dengue fluid protocol with close monitoring
   3. If LVEF 30-45%: Reduced fluid volumes, frequent reassessment
   4. If LVEF <30%: Minimal fluids, consider inotropic support

   Clinical Hack: Use the "fluid challenge test":

   • Give 250 mL crystalloid over 15 minutes
   • Measure CVP/echo before and after
   • If minimal hemodynamic improvement with significant venous pressure rise, suspect cardiac dysfunction

   Managing Fluid Overload Without Worsening Effusions

   Diuretic Strategy:

   • First-line: Furosemide 0.5-1 mg/kg IV
   • Monitoring: Hourly urine output, daily weight, chest X-ray
   • Goal: Negative fluid balance of 500-1000 mL/day during recovery phase
   • Caution: Avoid aggressive diuresis during critical phase due to ongoing capillary leak

   Advanced Techniques:

   • Ultrafiltration: Consider in severe fluid overload with refractory heart failure
   • Peritoneal drainage: For massive ascites contributing to respiratory compromise
   • Pearl: Small-volume, frequent drainage is preferred over large-volume drainage[19]

   Inotropic and Vasopressor Support

   Indications and Selection

   Inotropic Therapy:

   • Indication: LVEF <40% with signs of low cardiac output
   • First-line: Dobutamine 2.5-10 μg/kg/min
   • Alternative: Milrinone 0.25-0.75 μg/kg/min (phosphodiesterase inhibitor)
   • Pearl: Avoid high-dose dopamine due to increased arrhythmogenic potential

   Vasopressor Therapy:

   • Indication: Hypotension despite adequate filling pressures
   • First-line: Norepinephrine 0.05-0.5 μg/kg/min
   • Combination: Norepinephrine + dobutamine for cardiogenic shock
   • Avoid: High-dose epinephrine (increases myocardial oxygen consumption)[20]

   Arrhythmia Management

   Risk Stratification and Monitoring

   High-Risk Features:

   • QTc >500 ms
   • Frequent ventricular ectopy
   • Non-sustained ventricular tachycardia
   • Electrolyte abnormalities (hypokalemia, hypomagnesemia)

   Specific Arrhythmia Management

   Bradyarrhythmias:

   • Sinus bradycardia: Usually benign, no treatment needed if asymptomatic
   • AV block: Temporary pacing may be required for complete heart block
   • Pearl: Avoid atropine in dengue patients due to potential for inducing tachyarrhythmias

   Tachyarrhythmias:

   • Atrial fibrillation: Rate control preferred over rhythm control
     • Metoprolol 12.5-25 mg BID or diltiazem 30-60 mg QID
     • Avoid: Digoxin (narrow therapeutic window in acute illness)
   • Ventricular arrhythmias: Amiodarone 5-10 mg/kg loading dose
     • Hack: Consider magnesium supplementation (2-4 g IV) for VT/VF prevention[21]

   Specific Pharmacological Interventions

   ACE Inhibitors/ARBs

   Evidence and Considerations:

   • Rationale: Myocardial remodeling prevention, afterload reduction
   • Initiation: Start during recovery phase if hemodynamically stable
   • Dosing: Begin with low doses (enalapril 2.5 mg BID)
   • Monitoring: Renal function, potassium, blood pressure
   • Pearl: May help prevent late cardiac sequelae[22]

   Beta-Blockers

   Role in Dengue Myocarditis:

   • Indication: Heart rate control, anti-arrhythmic effects
   • Agent: Metoprolol succinate 25-50 mg daily
   • Caution: Avoid in acute phase if hypotensive or in high-degree AV block
   • Hack: Beta-blockers may mask tachycardic response to shock - use judiciously

   Mechanical Circulatory Support

   Indications and Options

   When to Consider:

   • Cardiogenic shock refractory to medical therapy
   • Bridge to recovery in young patients with reversible myocarditis
   • Mechanical complications (rare in dengue)

   Available Options:

   • IABP: Contraindicated due to thrombocytopenia and bleeding risk
   • ECMO: VA-ECMO for cardiogenic shock, consider bleeding risk
   • Impella: Limited experience, high bleeding risk
   • Pearl: Most dengue myocarditis is reversible - aggressive support may be warranted in young patients[23]

   Complications and Their Management

   Thrombotic Complications

   Risk Factors:

   • Severe myocardial dysfunction
   • Prolonged immobilization
   • Hemoconcentration during critical phase

   Management:

   • Prophylaxis: Mechanical prophylaxis preferred over anticoagulation
   • Treatment: Challenging due to concurrent thrombocytopenia
   • Pearl: Consider low-dose heparin (5000 units SC BID) if platelets >50,000/μL[24]

   Pulmonary Complications

   Pulmonary Edema:

   • Cardiogenic: Diuretics, afterload reduction, inotropes
   • Non-cardiogenic: Part of capillary leak syndrome
   • Mixed: Common scenario requiring careful assessment
   • Hack: BNP levels >400 pg/mL suggest cardiogenic component

   Pleural Effusion:

   • Usually bilateral and part of capillary leak syndrome
   • Drainage rarely required unless causing respiratory compromise
   • Pearl: Massive pleural effusion with normal BNP suggests primary capillary leak rather than heart failure

   Pediatric Considerations

   Unique Aspects in Children

   Clinical Presentation:

   • More likely to present with shock rather than heart failure
   • Tachycardia may be primary presenting sign
   • Feeding difficulties and irritability may be early signs

   Diagnostic Considerations:

   • Age-adjusted troponin reference ranges
   • Echocardiographic parameters vary with age and body surface area
   • Pearl: Fractional shortening <28% or EF <55% suggests dysfunction in children

   Management Modifications:

   • Fluid calculations based on body weight and surface area
   • Drug dosing adjustments for age and weight
   • Hack: Use inotrope infusion rates: dobutamine 5-20 μg/kg/min, milrinone 0.25-1.0 μg/kg/min[25]

   Clinical Pearls and Practical Tips

   Diagnostic Pearls

   1. The "Silent Myocarditis" Pearl: Up to 50% of dengue myocarditis cases are subclinical. Maintain high index of suspicion in severe dengue patients.

   2. The "Timing Pearl": Cardiac involvement peaks during the critical phase (days 4-6). Systematic evaluation during this period is crucial.

   3. The "Troponin Trend Pearl": Rising troponin levels during the critical phase, even if modest, warrant cardiac evaluation and monitoring.

   4. The "ECG Evolution Pearl": Serial ECGs are more informative than single tracings. T-wave changes often precede hemodynamic compromise.

   Management Pearls

   5. The "Conservative Fluid Pearl": When in doubt, give less fluid rather than more in suspected myocarditis. Reassess frequently.

   6. The "Echo-Guided Fluid Pearl": Use echocardiography to guide fluid management. IVC diameter and variation can be misleading during capillary leak.

   7. The "Gentle Diuresis Pearl": During recovery phase, aim for gradual fluid removal (500-1000 mL negative balance per day) to avoid hemodynamic instability.

   8. The "Electrolyte Pearl": Maintain potassium >4.0 mEq/L and magnesium >2.0 mg/dL to minimize arrhythmia risk.

   Monitoring Pearls

   9. The "Trend Over Absolute Pearl": Focus on trends in biomarkers and hemodynamic parameters rather than absolute values.

   10. The "Recovery Phase Pearl": Cardiac function typically improves during the recovery phase, but monitor for rebound fluid accumulation.

   Common Pitfalls and How to Avoid Them

   Diagnostic Pitfalls

   Oyster #1: Mistaking Dengue Myocarditis for ACS

   • Problem: Chest pain, troponin elevation, and ECG changes may mimic acute coronary syndrome
   • Solution: Consider age, dengue endemicity, absence of cardiovascular risk factors, and pattern of cardiac biomarkers
   • Hack: Coronary angiography rarely indicated unless typical ACS presentation in high-risk patient

   Oyster #2: Overlooking Cardiac Involvement in Dengue Shock Syndrome

   • Problem: Assuming all hypotension is due to capillary leak without considering cardiac contribution
   • Solution: Systematic cardiac evaluation in all shock cases, including echocardiography and troponin
   • Pearl: Mixed shock (distributive + cardiogenic) is common and requires tailored management

   Oyster #3: Misinterpreting Fluid Status

   • Problem: Clinical signs of fluid overload may be confused with capillary leak manifestations
   • Solution: Use multiple assessment tools: clinical examination, chest X-ray, echocardiography, and biomarkers
   • Hack: Lung ultrasound can differentiate cardiogenic (B-lines) from permeability pulmonary edema

   Management Pitfalls

   Oyster #4: Aggressive Fluid Resuscitation in Unrecognized Myocarditis

   • Problem: Standard dengue fluid protocols may worsen heart failure
   • Solution: Early cardiac assessment, modified fluid protocols for suspected myocarditis
   • Safety Net: Have diuretics readily available and monitor closely for signs of fluid overload

   Oyster #5: Inappropriate Anticoagulation

   • Problem: Treating elevated troponin as ACS with anticoagulation in thrombocytopenic patients
   • Solution: Careful risk-benefit analysis, consider non-ST elevation pattern and clinical context
   • Pearl: If antiplatelet therapy is essential, use single agent (aspirin 75 mg) with PPI coverage

   Oyster #6: Delayed Recognition of Arrhythmias

   • Problem: Focus on hemodynamic management while missing significant arrhythmias
   • Solution: Continuous cardiac monitoring, regular 12-lead ECGs, electrolyte optimization
   • Hack: Set monitor alarms appropriately for dengue patients (HR 50-120, wider QRS limits)

   Prognosis and Long-term Outcomes

   Short-term Outcomes

   The prognosis of dengue-associated myocarditis varies significantly based on severity of presentation and timing of recognition:

   Mild Cases (Subclinical):

   • Complete recovery in 95% of cases
   • Normal cardiac function within 2-4 weeks
   • No long-term sequelae

   Moderate Cases (Symptomatic):

   • Recovery in 85-90% of cases
   • May require 4-8 weeks for complete cardiac recovery
   • Risk of transient arrhythmias during recovery phase

   Severe Cases (Cardiogenic shock):

   • Mortality rate 15-25% if unrecognized
   • With appropriate management, mortality <5%
   • Higher risk of chronic complications[26]

   Long-term Follow-up

   Recommended Follow-up Protocol

   All Patients with Documented Myocarditis:

   • Clinical assessment at 2, 4, 8, and 12 weeks
   • ECG and echocardiography at 2 and 8 weeks
   • Exercise stress testing at 12 weeks if symptoms persist

   Patients with Severe Dysfunction (EF <40%):

   • Weekly assessment until EF >45%
   • Cardiac MRI at 3 months if incomplete recovery
   • Annual follow-up for 3 years

   Red Flags for Cardiology Referral:

   • Persistent symptoms beyond 8 weeks
   • Incomplete recovery of cardiac function
   • New arrhythmias during follow-up
   • Exercise intolerance[27]

   Chronic Sequelae

   While most patients recover completely, some may develop long-term complications:

   Dilated Cardiomyopathy:

   • Occurs in <5% of cases
   • Risk factors: severe acute dysfunction, delayed recognition, inadequate acute management
   • May require long-term heart failure therapy

   Chronic Arrhythmias:

   • Atrial fibrillation: 2-3% of patients
   • Ventricular arrhythmias: <1% of patients
   • Usually respond well to standard antiarrhythmic therapy

   Exercise Intolerance:

   • May persist for 3-6 months in some patients
   • Usually improves with cardiac rehabilitation
   • Rarely indicates underlying structural abnormality[28]

   Future Directions and Research

   Emerging Therapeutic Targets

   Immunomodulatory Approaches:

   • Corticosteroids: Limited evidence, potential for harm in dengue
   • IVIG: Case reports suggest benefit in severe cases
   • Tocilizumab: Anti-IL-6 therapy under investigation

   Antiviral Therapy:

   • No specific antiviral currently available for dengue
   • Several candidates in development (nucleoside analogs, protease inhibitors)
   • Potential to reduce cardiac complications if given early[29]

   Cardioprotective Strategies:

   • Statins: Potential anti-inflammatory effects
   • Colchicine: Anti-inflammatory properties, used in other myocarditis
   • Sodium-glucose co-transporter 2 inhibitors: Emerging role in heart failure

   Diagnostic Advances

   Point-of-Care Testing:

   • Rapid troponin assays for resource-limited settings
   • Portable echocardiography with AI-assisted interpretation
   • Biomarker panels for risk stratification

   Advanced Imaging:

   • Widespread availability of cardiac MRI in endemic regions
   • Strain echocardiography for subclinical dysfunction
   • 18F-FDG PET for inflammatory activity assessment[30]

   Prevention Strategies

   Vector Control:

   • Improved mosquito control measures
   • Community engagement programs
   • Environmental modification strategies

   Vaccination:

   • Dengvaxia: Limited efficacy, safety concerns in seronegative individuals
   • Second-generation vaccines in development
   • Potential for reducing severe complications including myocarditis[31]

   Conclusion

   Dengue-associated myocarditis represents a significant and underrecognized complication in critically ill patients with dengue fever. Early recognition through systematic cardiac evaluation, including troponin monitoring and echocardiography, is essential for optimal outcomes. The management requires a nuanced approach to fluid therapy, balancing the need to maintain perfusion while avoiding fluid overload in the setting of capillary leak syndrome and cardiac dysfunction.

   Key principles include: (1) maintaining high clinical suspicion during the critical phase of dengue illness, (2) using conservative fluid management strategies when myocarditis is suspected, (3) employing systematic monitoring with cardiac biomarkers and echocardiography, (4) managing arrhythmias promptly while considering the unique pathophysiology of dengue, and (5) providing appropriate follow-up to ensure complete recovery and identify rare chronic sequelae.

   The implementation of evidence-based protocols for cardiac assessment in severe dengue patients, combined with staff education about the recognition and management of myocarditis, can significantly improve outcomes in this challenging patient population. Future research should focus on developing specific therapeutic interventions, improving diagnostic tools for resource-limited settings, and preventing cardiac complications through vector control and vaccination strategies.

   As dengue continues to expand geographically due to climate change and urbanization, intensivists worldwide must be prepared to recognize and manage this important complication. The principles outlined in this review provide a framework for the optimal care of patients with dengue-associated myocarditis, ultimately leading to improved survival and reduced long-term cardiac sequelae.

   Funding

   [Funding sources to be specified]

   Conflict of Interest

   The authors declare no conflicts of interest.

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