Diagnostic Approach to Fever with Rash

1. Introduction

Fever associated with a rash (fever and exanthem) is a common and vexing clinical presentation in pediatric practice. The etiology ranges from self-limiting viral illnesses to life-threatening bacterial infections like meningococcemia and rickettsial diseases. A systematic approach is required to promptly identify children with serious treatable infections while avoiding unnecessary investigations in those with benign viral exanthems.

The most critical initial step is to determine if the child appears "toxic" or "ill," which necessitates rapid stabilization and empiric treatment for sepsis or meningitis.

2. Clinical Evaluation: History

A detailed history often provides the vital clues needed to narrow the differential diagnosis.

2.1. Characteristics of the Fever and Rash

• Prodrome: The relationship between the onset of fever and the appearance of the rash is diagnostically significant.
  • Measles: Fever increases with the rash.
  • Roseola Infantum: High fever lasts 3–4 days and disappears before the rash appears (defervescence rash).
  • Varicella: Rash appears 24–48 hours after prodromal symptoms.
• Nature of Rash: Is it itchy (varicella, drug rash) or painful (dermatomal zoster)?.
• Progression:
  • Centripetal: Spreading from trunk to face/extremities (e.g., Varicella).
  • Centrifugal: Spreading from face to body (e.g., Measles, Rubella).

2.2. Associated Symptoms

• Respiratory: Cough, coryza, and conjunctivitis are classic for measles. Sore throat is common in scarlet fever and infectious mononucleosis.
• Gastrointestinal: Vomiting and abdominal pain may suggest enteric fever, Kawasaki disease, or Henoch-Schönlein purpura (HSP).
• Musculoskeletal: Arthralgia or arthritis suggests Chikungunya, Dengue, Rubella, or Rheumatic fever.
• Neurological: Irritability or altered sensorium suggests meningitis or meningoencephalitis.

2.3. Epidemiological Risk Factors

• Age: Roseola is common in infants 6 months to 3 years; Scarlet fever is rare under 3 years.
• Immunization History: A fully immunized child is less likely to have measles, rubella, or varicella, though breakthrough varicella can occur (often atypical/maculopapular).
• Exposure and Travel:
  • History of sick contacts (varicella, measles).
  • Travel to endemic areas for Malaria, Dengue, or Rickettsial infections.
  • Animal or insect exposure: Ticks (Rickettsia, Lyme), fleas (Plague), or rodents (Rat-bite fever).
• Drug History: Recent antibiotic or anticonvulsant use points toward drug hypersensitivity (e.g., DRESS syndrome, Stevens-Johnson syndrome).

3. Physical Examination

A complete head-to-toe examination is essential.

3.1. General Assessment

Identify "red flag" signs of toxicity: tachycardia, hypotension, poor perfusion, altered mental status, or respiratory distress. These suggest conditions like meningococcemia, septic shock, or toxic shock syndrome (TSS).

3.2. Characterization of the Rash

Rashes are generally classified into specific morphologies which guide the differential diagnosis.

A. Macular / Maculopapular Rash

This is the most common presentation.

• Measles: Erythematous, blotchy rash beginning behind ears/hairline, spreading downward. Associated with Koplik spots (buccal mucosa).
• Rubella: Pink, discrete macules starting on the face, spreading rapidly. Fades in 3 days. Associated with postauricular/suboccipital lymphadenopathy and Forchheimer spots.
• Roseola Infantum (Exanthem Subitum): Pale pink, almond-shaped macules on trunk and neck appearing after fever lysis.
• Erythema Infectiosum (Fifth Disease): "Slapped cheek" appearance followed by a lacy, reticular rash on extremities.
• Dengue: Generalized flushing initially, followed by a maculopapular rash ("islands of white in a sea of red") during recovery.
• Kawasaki Disease: Polymorphous rash (never vesicular), associated with non-purulent conjunctivitis, strawberry tongue, and edema of hands/feet.
• Drug Rash: Morbilliform, often pruritic.

B. Vesicular / Bullous Rash

• Varicella (Chickenpox): Pleomorphic rash (papules, vesicles, crusts simultaneously). "Dewdrop on a rose petal." Centripetal distribution.
• Hand, Foot, and Mouth Disease (HFMD): Vesicles on palms, soles, buttocks, and oral ulcers. Caused by Coxsackievirus A16 or Enterovirus 71.
• Herpes Simplex (HSV): Grouped vesicles on an erythematous base. Can be disseminated in neonates or eczematous children (Eczema herpeticum).
• Rickettsialpox: Papulovesicular rash often with an eschar at the bite site.

C. Petechial / Purpuric Rash

This category represents a medical emergency until proven otherwise.

• Meningococcemia: Sudden onset, rapidly progressing from petechiae to purpura fulminans/ecchymoses. Associated with shock and meningitis.
• Dengue Hemorrhagic Fever: Petechiae, positive tourniquet test, gum bleeding, hepatomegaly.
• Rickettsial Diseases:
  • Rocky Mountain Spotted Fever (RMSF): Centripetal petechial rash involving palms and soles (starts on wrists/ankles).
• Vasculitis: Henoch-Schönlein Purpura (palpable purpura on buttocks/legs).

D. Diffuse Erythroderma

• Scarlet Fever: Diffuse erythematous, "sandpaper" texture rash, circumoral pallor, strawberry tongue, and Pastia’s lines in skin creases.
• Toxic Shock Syndrome (Staphylococcal/Streptococcal): Diffuse sunburn-like rash, hypotension, and multisystem involvement, followed by desquamation.

E. Eschar

Presence of a painless black eschar (tache noire) suggests rickettsial infections like Scrub Typhus (mite bite) or Mediterranean Spotted Fever.

3.3. Systemic Signs

• Lymphadenopathy: Generalized (Mononucleosis, Measles), Post-auricular (Rubella), Cervical (Kawasaki, Scarlet fever).
• Hepatosplenomegaly: Malaria, Enteric fever, EBV, Leukemia.
• Arthritis: Chikungunya, Rubella, Rheumatic fever.

4. Diagnostic Approach and Investigations

Investigations are guided by the clinical phenotype and severity.

4.1. The "Toxic" Child

For children with fever and petechiae/purpura or signs of shock, immediate extensive workup is mandatory:

• Complete Blood Count (CBC): Leukocytosis or leukopenia, thrombocytopenia.
• Blood Culture: For N. meningitidis, S. pneumoniae, S. aureus.
• Coagulation Profile: PT/APTT/Fibrinogen (to rule out DIC).
• CSF Analysis: If meningitis is suspected and patient is stable for LP.
• PCR: Meningococcal PCR from blood if available.

4.2. The Stable Child with Maculopapular Rash

Diagnosis is often clinical. Laboratory confirmation is reserved for atypical cases or public health surveillance (Measles/Rubella).

• Measles: IgM antibody (3 days after rash) or RT-PCR from throat/urine.
• Rubella: IgM antibody or PCR.
• Dengue/Chikungunya: In endemic areas, NS1 Antigen (Day 1–5) or IgM ELISA (after Day 5). RT-PCR is definitive in early phase.
• Kawasaki Disease: Diagnosis is clinical based on criteria (Fever >5 days + 4/5 distinct features). Supportive labs: Elevated CRP/ESR, sterile pyuria, thrombocytosis (week 2).

4.3. The Child with Vesicular Rash

• Varicella: Usually clinical. Tzanck smear shows multinucleated giant cells (low sensitivity). PCR of vesicular fluid is the gold standard.
• HFMD: Clinical diagnosis. PCR from throat/stool if confirmation needed for outbreaks.

4.4. Fever with Eschar or Tick Exposure

• Rickettsial Panels: IgM ELISA or Immunofluorescence assay (IFA) for Scrub Typhus or Spotted Fevers. Weil-Felix test is widely available but has low sensitivity/specificity.
• Platelet Count: Thrombocytopenia is a hallmark of rickettsial diseases.

4.5. Prolonged Fever with Rash (PUO/FUO context)

If fever persists >7 days with rash:

• Infectious: Enteric fever (Blood culture/Widal), Brucellosis, Tuberculosis, HIV.
• Autoimmune: JIA (Systemic onset), SLE (ANA, dsDNA).
• Malignancy: Leukemia/Lymphoma (Peripheral smear, Bone marrow).

5. Management Principles

5.1. Immediate Stabilization

Any child with fever and petechial/purpuric rash or shock requires:

• ABC stabilization: Airway, Breathing, Circulation.
• Fluid Resuscitation: For shock (Dengue shock, Septic shock).
• Empiric Antibiotics: Ceftriaxone (or appropriate broad-spectrum coverage) must be started immediately for suspected meningococcemia or RMSF (Doxycycline is the drug of choice for Rickettsia regardless of age).

5.2. Specific Therapy

• Bacterial: Antibiotics for Scarlet fever (Penicillin/Amoxicillin), Typhoid (Ceftriaxone/Azithromycin).
• Rickettsial: Doxycycline.
• Viral:
  • Measles: Vitamin A supplementation (reduces morbidity/mortality).
  • Varicella: Acyclovir for immunocompromised, neonates, or severe cases.
  • HSV: Acyclovir.
  • Influenza: Oseltamivir (if within 48 hours or high risk).
• Kawasaki Disease/MIS-C: IVIG and Aspirin (plus steroids for MIS-C).

5.3. Supportive Care and Isolation

• Antipyretics: Paracetamol. Avoid salicylates in viral fevers (Reye syndrome risk).
• Hydration: Critical in Dengue and HFMD.
• Isolation:
  • Airborne precautions: Measles, Varicella.
  • Droplet precautions: Meningococcal, Rubella, Mumps.