Maculopapular rash

A maculopapular rash is a mixture of flat (macules) and raised (papules) lesions under 1 cm, often confluent. The first clinical point is to identify the small group of dangerous causes that need immediate action.

Patterns. Morbilliform (measles like, confluent pink macules and papules), scarlatiniform (diffuse erythema with fine sandpaper texture), roseola like (discrete pink macules), reticulate, papulosquamous and targetoid.

Setting. Infectious (viral, bacterial, rickettsial, spirochaetal, parasitic), drug related, immune mediated and inflammatory, and others.

Distribution. Centrifugal spread (face to trunk to limbs) is typical of measles. Truncal predominance suggests viral exanthems or drug eruption. Palm and sole involvement narrows the differential considerably.

Timing. Morbilliform drug eruption starts 4 to 14 days after the drug begins (earlier on re-exposure). DRESS starts 2 to 8 weeks after. Viral rashes appear after a prodrome of 1 to 4 days.

Key distinction. Blanching rash with fever is usually viral or drug related, while nonblanching rash with fever and illness suggests sepsis.

History

• Day of rash relative to fever, site of onset, progression, itch, pain, mucosal symptoms.
• Prodrome: measles gives 2 to 4 days of fever, cough, coryza and conjunctivitis. Rubella gives mild fever with tender posterior cervical nodes and arthralgia. Parvovirus B19 gives slapped cheeks then a lacy rash. Roseola gives 3 days of high fever then rash on defervescence. Dengue gives fever for 3 to 5 days then rash around defervescence. Chikungunya gives severe polyarthralgia.
• Vaccination history (a rash 7 to 12 days after measles vaccination can occur).
• Drugs in the preceding 8 weeks, including antibiotics, allopurinol, antiepileptics (carbamazepine, lamotrigine, phenytoin, phenobarbital), sulphonamides, nevirapine, abacavir, NSAIDs and vancomycin. Amoxicillin in infectious mononucleosis causes a rash.
• Sexual history, HIV risk, syphilis exposure.
• Travel, insect and tick bites, animal exposure, freshwater exposure, sick contacts, outbreaks.
• Pregnancy and exposures: rubella, parvovirus B19, cytomegalovirus, Zika, syphilis.
• Immune status.

Examination

• Vital signs and perfusion first.
• Distribution and confluence, including palms, soles, scalp and flexures.
• Blanching on pressure with a glass.
• Oral enanthem (Koplik spots in measles, strawberry tongue in scarlet fever), conjunctivitis, lip changes.
• Eschar (African tick bite fever, scrub typhus), lymph nodes, hepatosplenomegaly, joint swelling, facial oedema, skin tenderness, Nikolsky sign, target lesions.
• Neck stiffness and neurological state.

Red flags

• Nonblanching rash with fever and hypotension or altered mental state.
• Skin pain, mucosal erosions, blistering or positive Nikolsky sign (Stevens-Johnson syndrome or toxic epidermal necrolysis).
• Facial oedema, fever, lymphadenopathy and eosinophilia (DRESS).
• Rash with hypotension and palms or soles erythema (toxic shock syndrome).
• Child with fever for 5 days or more, conjunctivitis, lip and mouth changes and limb changes (Kawasaki disease).
• Rash with bleeding and fever (viral haemorrhagic fever, severe dengue).
• Pregnancy with fever and rash.
• Immunocompromise.
• Rash with respiratory distress, encephalopathy or jaundice.

Special groups

• Children: measles, roseola, enterovirus, scarlet fever, Kawasaki disease and parvovirus B19 are common.
• Pregnancy: rubella, parvovirus B19, cytomegalovirus, Zika and syphilis carry foetal risk.
• HIV: acute seroconversion rash, drug eruptions are more frequent.
• Region specific: measles outbreaks, dengue, chikungunya, African tick bite fever and typhus group rickettsioses.

Viral

• Measles.
• Rubella.
• Parvovirus B19 infection (erythema infectiosum).
• Roseola infantum (human herpesvirus 6).
• Enterovirus and echovirus infection.
• Infectious mononucleosis (Epstein-Barr virus) and cytomegalovirus infection.
• Dengue.
• Chikungunya and o'nyong nyong fever.
• Zika virus infection.
• Acute HIV seroconversion illness.
• Adenovirus infection.
• Mpox in the early macular phase.
• Viral haemorrhagic fevers (early).

Bacterial, rickettsial and spirochaetal

• Scarlet fever (group A streptococcus).
• Secondary syphilis.
• Typhoid fever (rose spots).
• Meningococcaemia (early blanching phase).
• Toxic shock syndrome (staphylococcal or streptococcal).
• African tick bite fever and other spotted fever rickettsioses.
• Murine typhus and epidemic typhus.
• Scrub typhus.
• Leptospirosis.
• Brucellosis.
• Relapsing fever.

Drug related

• Morbilliform (exanthematous) drug eruption.
• DRESS.
• Early Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Serum sickness like reaction.

Immune mediated and inflammatory

• Systemic lupus erythematosus.
• Dermatomyositis.
• Adult onset Still disease.
• Kawasaki disease.
• Acute graft versus host disease.
• Pityriasis rosea.
• Guttate psoriasis.
• Lichen planus.
• Erythema multiforme.
• Gianotti Crosti syndrome (children).
• Urticarial vasculitis.

Parasitic and other

• Acute schistosomiasis (Katayama syndrome).
• Trypanosomiasis.
• Early cutaneous leishmaniasis.
• Cutaneous T cell lymphoma, patch stage.

Step 1. Triage. Check vital signs, perfusion and mental state. Identify patients who need isolation (suspected measles, varicella, viral haemorrhagic fever) and urgent treatment (sepsis, toxic shock, severe cutaneous drug reaction, rickettsial disease).

Step 2. Pattern and timing. Combine morphology, distribution, prodrome, drug timing and exposure.

Step 3. First line tests

• Full blood count with differential: leucopenia and lymphopenia suggest viral illness; atypical lymphocytes suggest Epstein-Barr virus; eosinophilia over 1.5 x 10^9/L suggests DRESS; platelets under 100 x 10^9/L with a rising haematocrit (over 20% rise) suggest dengue plasma leakage.
• CRP, urea and creatinine, liver tests (ALT over 2 times the upper limit in DRESS; AST higher than ALT in dengue), urinalysis.
• Blood cultures when febrile; malaria rapid test and film in all febrile patients from endemic areas.
• HIV fourth generation antigen and antibody test, with HIV RNA if acute infection is suspected.
• Syphilis serology (treponemal and nontreponemal; request prozone dilution if clinical suspicion is high and the test is negative).
• Pregnancy test in women of reproductive age.

Step 4. Targeted tests

• Measles: throat or nasopharyngeal swab and urine for RNA PCR (best in the first week), and IgM (may be negative in the first 72 hours of rash).
• Rubella and parvovirus B19 IgM; cytomegalovirus and Epstein-Barr virus serology.
• Dengue: NS1 antigen or RT PCR in days 1 to 5, IgM from day 5. Chikungunya: RT PCR in the first 5 to 7 days, then IgM. Zika: RT PCR of blood and urine. Serological cross reactivity between flaviviruses limits specificity.
• Group A streptococcus: throat swab or rapid antigen test; ASO titre in later illness.
• Rickettsial disease: PCR of eschar swab or blood; paired serology at 2 to 4 weeks. Treat before confirmation.
• Leptospirosis PCR or microscopic agglutination test.
• Systemic lupus erythematosus: antinuclear antibodies, anti dsDNA, complement, extractable nuclear antigens. Dermatomyositis: creatine kinase and myositis antibodies.
• Skin punch biopsy (two samples, one for histology and one for direct immunofluorescence) when the rash persists, is atypical or severe cutaneous reaction or vasculitis is suspected.
• DRESS diagnosis: fever over 38.5 C, rash over 50% of the body surface, lymphadenopathy, eosinophilia, atypical lymphocytes, organ involvement (liver, kidney, lung, heart), onset 2 to 8 weeks after the drug, and exclusion of other causes.

Limits. Early serology is falsely negative. Viral rashes are often diagnosed clinically. Biopsy cannot always separate drug eruption from viral exanthem.

Immediate. Sepsis, toxic shock, severe cutaneous drug reaction, Kawasaki disease and haemorrhagic fever need resuscitation and urgent admission. Isolate suspected measles or varicella using airborne precautions. Notify public health for measles, rubella, dengue, suspected viral haemorrhagic fever and syphilis.

Supportive care. Oral fluids, rest. Paracetamol 1 g orally every 4 to 6 hours, maximum 4 g daily (3 g daily in hepatic impairment, chronic alcohol use or weight under 50 kg; for under 50 kg use 15 mg/kg each dose, maximum 60 mg/kg daily). Avoid aspirin and NSAIDs in suspected dengue (bleeding) and in children with viral illness.

Cause directed

• Morbilliform drug eruption: stop the suspected drug and all nonessential drugs started in the last 2 months. Emollients, mometasone furoate 0.1% ointment once daily for 5 to 7 days, and cetirizine 10 mg orally once daily for itch (5 mg if creatinine clearance is under 50 mL/min). Systemic corticosteroids are usually not needed.
• DRESS: stop the culprit, admit, prednisolone 0.5 to 1 mg/kg orally daily (equivalent intravenously if unwell), tapered over 6 to 12 weeks. Monitor eosinophils, liver tests, creatinine, troponin and creatine kinase twice weekly at first. Flares on tapering are common. Specialist review.
• Stevens-Johnson syndrome and toxic epidermal necrolysis: stop the culprit, admit to intensive care or a burns unit, with specialist skin and eye care.
• Scarlet fever and streptococcal pharyngitis: phenoxymethylpenicillin 500 mg orally four times daily for 10 days. If penicillin allergic: clarithromycin 250 to 500 mg orally twice daily for 5 days.
• Secondary syphilis: benzathine benzylpenicillin 2.4 million units intramuscularly as a single dose. If penicillin allergic and not pregnant: doxycycline 100 mg orally twice daily for 14 days. Warn about the Jarisch-Herxheimer reaction (fever within 24 hours; give paracetamol). Repeat nontreponemal titres at 3, 6 and 12 months; a fourfold fall is the response target. Test for HIV and other sexually transmitted infections; trace contacts.
• Rickettsial disease: doxycycline 100 mg orally or intravenously twice daily for 5 to 7 days (at least 3 days after fever settles), started on clinical suspicion. Children under 45 kg: 2.2 mg/kg twice daily, maximum 100 mg each dose. Use in pregnancy only when disease is severe.
• Measles: supportive care and isolation. Vitamin A 200,000 IU orally once daily for 2 days for age 12 months or over (100,000 IU at 6 to 11 months; 50,000 IU under 6 months), with a third dose 2 to 4 weeks later if signs of deficiency. Post exposure measles vaccination within 72 hours and immunoglobulin within 6 days for susceptible high risk contacts.
• Dengue: oral fluids and paracetamol. Admit for warning signs (abdominal pain, persistent vomiting, mucosal bleeding, lethargy, liver enlargement over 2 cm, rising haematocrit with falling platelets), giving isotonic crystalloid 5 to 7 mL/kg/h for 1 to 2 hours, then reducing to 3 to 5 mL/kg/h adjusted to haematocrit and clinical response.
• Infectious mononucleosis: supportive care; avoid amoxicillin; avoid contact sport for 4 weeks.
• Kawasaki disease: urgent paediatric admission for intravenous immunoglobulin 2 g/kg as a single infusion over 10 to 12 hours, with aspirin as directed by the paediatric specialist.
• Parvovirus B19, rubella, Zika or cytomegalovirus in pregnancy: urgent obstetric and foetal medicine review.

Monitoring. Vital signs, urine output, skin progression (blistering, mucosal involvement), blood counts and liver tests where drug reaction or dengue is suspected.

Referral and escalation. Infectious diseases for diagnostic uncertainty, immunocompromise or return from travel with fever. Dermatology for severe cutaneous drug reactions and persistent rash. Rheumatology for suspected lupus or dermatomyositis. Public health for notifiable disease.

Admission criteria. Haemodynamic instability, mucosal involvement, skin detachment, DRESS, dengue with warning signs, Kawasaki disease, suspected meningococcal disease, pregnancy with fever and rash, severe immunocompromise.

Discharge and follow up. Review at 48 to 72 hours for undiagnosed fever and rash. Allergy referral for drug eruptions to record culprit and alternatives. Safety net advice: return for blistering, mouth or eye sores, nonblanching spots, breathing difficulty, severe headache, confusion, persistent vomiting or bleeding.