Dengue - Clinical Manifestations

WHO 2009 Classification of Dengue Severity

1. Dengue Without Warning Signs

• Nausea/vomiting
• Rash
• Aches and pains (myalgias, arthralgias, headache, retro-orbital pain)
• Leukopenia
• Positive tourniquet test

2. Dengue With Warning Signs

• Abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation (ascites, pleural effusion)
• Mucosal bleeding
• Lethargy or restlessness
• Liver enlargement >2 cm
• Rapid decline in platelet count with rising hematocrit

3. Severe Dengue

• Severe plasma leakage leading to shock or respiratory distress
• Severe bleeding (as evaluated clinically)
• Severe organ involvement: AST or ALT ≥1000 IU/L, impaired consciousness, heart or other organ failure

Clinical Phases

Febrile Phase (Days 1-3)

• Abrupt onset of high fever (39-40°C)
• Severe myalgias, arthralgias, and bone pain - classic "breakbone fever"
• Headache and retro-orbital pain (pain on eye movement)
• Facial erythema and injected oropharynx
• Leukopenia is characteristic
• Minor bleeding: petechiae, positive tourniquet test, easy bruising

Critical Phase (Days 3-7, around defervescence)

• Hemoconcentration (rising hematocrit)
• Pleural effusion, ascites
• Hypovolemic shock (dengue shock syndrome)
• Rapid platelet drop
• Patients with mild disease improve here; those with severe disease deteriorate

Convalescent Phase

• Gradual hemodynamic stabilization
• Bradycardia is common
• Reabsorption of extravasated fluid - watch for fluid overload (hematocrit falls due to dilutional effect)
• Characteristic confluent rash with "islands of white in a sea of red" often appears as fever breaks

Skin Manifestations

• Appears between days 3-5 (in 90% of cases), often as fever defervesces
• Usually generalized maculopapular/morbilliform, confluent
• Spares small islands of normal skin - the classic "islands of white in a sea of red" pattern
• Distribution: generalized (50%), extremities only (30%), trunk only (20%)
• Usually asymptomatic or only mildly pruritic

Dengue Hemorrhagic Fever (DHF)

1. Fever lasting 2-7 days
2. Hemorrhagic tendency - positive tourniquet test, petechiae, ecchymosis, purpura, epistaxis, gingival bleeding, hematemesis, melena
3. Thrombocytopenia (platelet count <100,000/mm³)
4. Increased vascular permeability - hematocrit rise ≥20%, pleural effusion, ascites, hypoalbuminemia

Laboratory Findings

Uncommon/Atypical Manifestations

• Myocarditis
• Pancreatitis
• Hepatitis (can be severe with fulminant liver failure)
• Hemophagocytic lymphohistiocytosis (HLH)
• Neurological: acute meningoencephalitis, post-dengue ADEM (acute disseminated encephalomyelitis), Guillain-Barre syndrome
• Renal involvement: acute kidney injury (more severe in secondary infections)

Pathophysiology of Severe Dengue

• Infection with one serotype produces lifelong immunity against that serotype only
• Cross-reactive antibodies from a first infection cannot neutralize a different serotype
• These non-neutralizing antibodies enhance uptake of the new serotype into macrophages via Fc receptors - amplifying viral replication and cytokine storm
• Severe dengue predominantly occurs with secondary infection, especially with serotype DENV-2
• Same mechanism explains why dengue is more severe in infants born to dengue-immune mothers (maternal antibodies act similarly)

Key Clinical Pearls

• Helpful bedside predictors: petechiae, skin rash, myalgia, retro-orbital pain, positive tourniquet test, gingival bleeding (validated in a Honduras study)
• Severity risk with secondary infection (especially DENV-2)
• Aspirin and NSAIDs are contraindicated (increase bleeding risk)
• Early aggressive fluid therapy reduces case fatality of severe dengue from 5-10% to <1%
• The critical phase lasts only 24-48 hours - identifying it early is the key to survival

Leptospirosis - Manifestations and Management

Overview

Incubation Period

Clinical Spectrum

Biphasic Course (Classic Pattern)

Phase 1: Leptospiremic / Septicemic Phase (Days 1-7)

• Abrupt-onset high fever with chills and rigors (75-100% of patients)
• Severe myalgias - especially calf and lumbar muscles (40-97%); "myalgia out of proportion to fever" is a hallmark
• Intense headache
• Nausea, vomiting
• Conjunctival suffusion without purulent discharge (28-99%) - a very characteristic finding; non-purulent conjunctival redness
• Pharyngitis, hepatomegaly, splenomegaly, lymphadenopathy

• Pretibial (Fort Bragg) fever: 1-5 cm erythematous patches/plaques most marked on the shins
• Petechiae and purpura on skin and mucous membranes (in severe/icteric form)
• Facial flushing

Phase 2: Immune Phase (Days 7-14+)

• Return of fever (often lower-grade)
• Aseptic meningitis - the hallmark of the immune phase (CSF: lymphocytosis)
• Intense headache, photophobia
• Ocular manifestations: conjunctival hemorrhage, uveitis (may appear 4-8 months after illness)
• This phase is less responsive to antibiotics

Severity Categories

1. Mild Anicteric Leptospirosis (~90%)

• Influenza-like illness: fever, headache, myalgias
• Self-limited; resolves in 5-7 days
• Frequently misdiagnosed as dengue, malaria, influenza

2. Weil Syndrome (Severe Icteric Leptospirosis, ~5-10%)

• Jaundice - marked hyperbilirubinemia (often >30 mg/dL / 512 µmol/L), with only moderately elevated aminotransferases (unlike viral hepatitis where transaminases are proportionally higher)
• Acute Kidney Injury (AKI) - present in 44-67% of hospitalized patients
• Hemorrhage - pulmonary, gastrointestinal, cutaneous, adrenal

3. Pulmonary Hemorrhage Syndrome (ARDS-like, "ARDS leptospirosis")

• Most lethal form
• Diffuse alveolar hemorrhage, respiratory failure
• Can occur even without jaundice
• Mortality >50%
• Requires mechanical ventilation with low tidal volumes

4. Meningitis / Meningoencephalitis

• Aseptic meningitis with lymphocytic CSF pleocytosis
• Can mimic bacterial meningitis early on

Organ System Manifestations in Detail

Renal

• Most common severe manifestation; seen in 44-67% of patients
• Mechanism: acute tubulointerstitial nephritis (not glomerulonephritis); leptospires invade tubular cells
• Proximal tubular dysfunction: bicarbonaturia, glycosuria, phosphaturia, magnesuria, uricosuria
• Electrolyte abnormalities: hypokalemia or hyperkalemia, hypomagnesemia (require aggressive correction)
• May be nonoliguric AKI (an important and favorable feature vs. typical ATN)
• Oliguria = poor prognostic sign
• Rhabdomyolysis can further worsen AKI

Hepatic

• Jaundice with markedly elevated bilirubin but only mild-moderate transaminase elevation (unlike viral hepatitis)
• Hyperbilirubinemia >30 mg/dL is characteristic of Weil disease

Pulmonary

• Spectrum: mild cough → pulmonary hemorrhage → ARDS
• Reduced pulmonary compliance; treat with low tidal volume ventilation

Cardiac

• Myocarditis with arrhythmias
• Circulatory collapse / refractory shock

Neurological

• Aseptic meningitis
• Uveitis (late finding, 4-8 months after acute illness)
• Meningoencephalitis

Hematologic

• Thrombocytopenia
• Hemorrhagic tendency (petechiae, ecchymoses, hemoptysis, GI bleeding)
• Leukocytosis (15,000-30,000/mm³) in severe disease

Diagnosis

Management

Antibiotic Therapy

• Doxycycline is contraindicated in pregnant women and children
• In areas where rickettsial diseases are co-endemic, prefer doxycycline or azithromycin
• Azithromycin (3-day course) is an alternative, especially when doxycycline is contraindicated
• No antibiotic resistance reported in clinical isolates to date
• Jarisch-Herxheimer reaction can occur within hours of starting antibiotics (rare)

⚠️ Recent Evidence Note: A 2024 Cochrane systematic review (PMID: 38483092) found that the evidence for antibiotics in leptospirosis remains of very low certainty due to small trial numbers and methodological limitations. The review could not confirm a statistically significant mortality benefit for penicillin vs. placebo. Despite this uncertainty, antibiotics are still recommended given the plausibility of benefit and the severity of the disease. A 2025 Cochrane review (PMID: 40704556) found insufficient evidence to recommend corticosteroids in leptospirosis.

Supportive Care (Essential - Can Be Life-Saving)

• Aggressive fluid and electrolyte resuscitation for nonoliguric AKI (prevent progression to oliguria)
• Correct hypokalemia, hypomagnesemia aggressively
• Hemodialysis or peritoneal dialysis for oliguric renal failure - rapid initiation reduces mortality; usually needed only for short periods
• Monitor for fluid overload during recovery

• Mechanical ventilation with low tidal volumes (lung-protective strategy, as in ARDS) for pulmonary hemorrhage
• Evidence for glucocorticoids and desmopressin as adjunct therapy is contradictory - not routinely recommended

• Blood product transfusions as needed for severe bleeding

• Watch for early signs of shock, occult bleeding, plasma leak
• Monitor hematocrit, renal function, electrolytes closely

Chemoprophylaxis

Key Clinical Pearls

• Conjunctival suffusion (non-purulent) + severe calf myalgias + fever in a flood-exposed or occupationally at-risk patient = leptospirosis until proven otherwise
• AKI in leptospirosis is often nonoliguric and reversible with adequate fluid resuscitation - do not mistake it for a late/terminal finding
• Leptospirosis is frequently misdiagnosed as dengue, malaria, or influenza - a high index of suspicion is needed
• The immune phase is less antibiotic-responsive; supportive care is paramount then
• Uveitis can appear months after apparent recovery - patients should be warned