Fever with rash

Fever with rash is a temperature of 38.0 C or over with a new skin eruption. Most causes are self limiting viral exanthems.

Classification by morphology. Maculopapular or morbilliform, petechial or purpuric, vesicular, bullous or pustular, diffuse erythema with or without peeling, urticarial or targetoid, and nodular or ulcerated with eschar.

Timing. Measles gives 3 to 4 days of fever, cough, coryza and conjunctivitis before the rash. Roseola rash follows defervescence. Dengue rash appears on days 3 to 6 as fever falls. Rickettsial rash appears on days 3 to 5. Typhoid rose spots appear in week 2. Scarlet fever rash appears within 12 to 48 hours of fever.

Distribution. Centrifugal spread from face to limbs suggests measles. Centripetal spread from limbs suggests rickettsial disease. Palm and sole involvement points to secondary syphilis, rickettsial disease, Kawasaki disease, hand, foot and mouth disease, toxic shock syndrome, mpox, meningococcal disease and endocarditis.

Mechanisms. Direct skin infection, toxin mediated injury (scarlet fever, toxic shock, scalded skin syndrome), immune complex or hypersensitivity (drug eruption, serum sickness), vasculitis, and thrombosis with bleeding (disseminated intravascular coagulation, purpura fulminans).

Key distinctions. A nonblanching rash with an unwell patient is sepsis until proved otherwise. A blanching rash in a well patient is usually viral or drug related. Mucosal erosion or skin pain suggests severe drug reaction.

History

• Day of illness on which the rash appeared, site of onset, spread, itch, pain, and mucosal symptoms. Prodrome and fever pattern.
• Contacts with similar rash, school or household outbreaks, vaccination record (measles, rubella, varicella, meningococcal), and recent live vaccine (rash 7 to 12 days after measles vaccine).
• Travel with dates, tick bites, louse exposure, bushmeat, animal contact, freshwater exposure, sexual and injecting exposures, and funerals or healthcare contact during outbreaks.
• Drugs in the preceding 8 weeks: aminopenicillins (especially in infectious mononucleosis), sulphonamides, allopurinol, carbamazepine, lamotrigine, phenytoin, phenobarbital, nevirapine, abacavir, NSAIDs and vancomycin.
• HIV status, asplenia, immunosuppression, pregnancy, and malaria chemoprophylaxis.
• Joint pain, sore throat, diarrhoea, headache, photophobia, mouth ulcers and red eyes.

Examination

• Vital signs, perfusion, capillary refill, mental state and urine output before the skin.
• Lesion type, colour, confluence, palms, soles, scalp and flexures. Test blanching with a glass and mark the edge of spreading purpura.
• Oral enanthem (Koplik spots, strawberry tongue, ulcers, Forchheimer spots), conjunctivitis (measles, Kawasaki disease, leptospirosis), lip cracking, eschar (African tick bite fever, scrub typhus, anthrax), and inguinal and cervical nodes.
• Nikolsky sign, mucosal erosions, skin tenderness and percentage detached.
• Joints, hepatosplenomegaly, murmur, neck stiffness, and signs of plasma leakage.
• Genital and anal examination for chancre or ulcer.

Red flags

• Nonblanching rash with fever, hypotension, tachycardia, altered mental state, limb pain or cold peripheries.
• Rapidly spreading purpura or necrosis.
• Skin pain, mucosal erosions, blistering or positive Nikolsky sign.
• Facial oedema, eosinophilia, lymphadenopathy or organ dysfunction after a drug started 2 to 8 weeks earlier.
• Hypotension with diffuse erythema and palm or sole redness.
• Child with fever for 5 days or more, red eyes, lip changes, limb changes or cervical node.
• Bleeding from any site, or travel to or contact with an outbreak of viral haemorrhagic fever.
• Pregnancy, neonates, asplenia, neutropenia and advanced HIV.
• Respiratory distress, jaundice, encephalopathy or seizures.

Special groups

• Pregnancy: rubella, parvovirus B19, cytomegalovirus, varicella, Zika and syphilis carry foetal risk. Doxycycline and fluoroquinolones are avoided unless disease is severe.
• Children: measles, roseola, enterovirus, scarlet fever, parvovirus B19 and Kawasaki disease are common. Avoid aspirin for viral illness except as directed for Kawasaki disease.
• Immunocompromised: atypical presentation, disseminated fungal and mycobacterial disease, and hyperinfection with varicella zoster.
• Kidney and liver impairment: adjust doses of antibiotics and antivirals.
• Region specific: measles outbreaks, dengue, chikungunya, African tick bite fever, typhus group rickettsioses, louse borne relapsing fever, mpox, and viral haemorrhagic fevers.

Maculopapular and morbilliform

• Measles: confluent rash from the hairline, Koplik spots, conjunctivitis, cough.
• Rubella: mild fever, tender postauricular and occipital nodes, arthralgia.
• Parvovirus B19 infection: slapped cheeks then lacy rash, arthropathy in adults.
• Roseola infantum: 3 days of high fever then rash in infants.
• Enterovirus infection.
• Infectious mononucleosis (Epstein-Barr virus) and cytomegalovirus infection: pharyngitis, nodes, splenomegaly.
• Adenovirus infection.
• Acute HIV infection: mucocutaneous ulcers, nodes, pharyngitis.
• Dengue: rash at defervescence, thrombocytopenia, retro-orbital pain.
• Chikungunya and o'nyong nyong fever: severe polyarthralgia.
• Zika virus infection.
• COVID-19.
• Scarlet fever: sandpaper texture, Pastia lines, circumoral pallor.
• Secondary syphilis: palm and sole rash, condylomata lata, mucous patches.
• Typhoid fever: rose spots, relative bradycardia, abdominal pain.
• Leptospirosis: conjunctival suffusion, calf pain, jaundice.
• Rickettsial disease: African tick bite fever, other spotted fevers, murine and epidemic typhus, scrub typhus.
• Louse borne and tick borne relapsing fever.
• Lyme disease with erythema migrans.
• Acute schistosomiasis (Katayama syndrome) and East African trypanosomiasis.
• Morbilliform drug eruption and DRESS.
• Serum sickness like reaction.
• Kawasaki disease and multisystem inflammatory syndrome.
• Adult onset Still disease (salmon pink evanescent rash with fever spikes) and systemic lupus erythematosus.
• Acute graft versus host disease.

Petechial and purpuric

• Meningococcal disease.
• Disseminated gonococcal infection.
• Bacterial sepsis with disseminated intravascular coagulation (pneumococcus in asplenia, Staphylococcus aureus, Gram negative organisms).
• Infective endocarditis.
• Viral haemorrhagic fevers (Ebola, Marburg, Lassa, Crimean-Congo haemorrhagic fever, Rift Valley fever, yellow fever) and dengue.
• Severe malaria with coagulopathy.
• Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome.
• Acute leukaemia, including acute promyelocytic leukaemia.
• Haemophagocytic lymphohistiocytosis.
• Vasculitis (IgA vasculitis, ANCA associated vasculitis, polyarteritis nodosa, cryoglobulinaemia).

Vesicular, bullous and pustular

• Varicella and disseminated herpes zoster.
• Herpes simplex and eczema herpeticum.
• Hand, foot and mouth disease.
• Mpox.
• Staphylococcal scalded skin syndrome and bullous impetigo.
• Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Acute generalised exanthematous pustulosis.
• Vibrio vulnificus infection and necrotising fasciitis.

Diffuse erythema with or without peeling

• Toxic shock syndrome (staphylococcal and streptococcal).
• Scarlet fever and staphylococcal scalded skin syndrome.
• Kawasaki disease.
• Drug induced erythroderma.

Urticarial and targetoid

• Infection associated urticaria (hepatitis B prodrome, mycoplasma, parasitic infection).
• Erythema multiforme (herpes simplex, Mycoplasma pneumoniae).
• Urticarial vasculitis, Sweet syndrome and Schnitzler syndrome.

Nodular, ulcerated or eschar forming

• Erythema nodosum (streptococcal infection, tuberculosis, sarcoidosis).
• Disseminated histoplasmosis, cryptococcosis and penicilliosis.
• Miliary tuberculosis.
• Ecthyma gangrenosum.
• Bacillary angiomatosis.
• Cutaneous anthrax.
• Behcet disease.

Step 1. Triage. Check airway, breathing, circulation, mental state, glucose and lactate. Isolate suspected measles, varicella, mpox or viral haemorrhagic fever before further testing. Start antibiotics without waiting when meningococcal disease or sepsis is possible.

Step 2. Pattern recognition. Combine rash type, timing in relation to fever, distribution, mucosal findings, exposure and incubation period.

Step 3. First line tests

• Full blood count with differential: lymphopenia and atypical lymphocytes suggest viral illness, neutrophilia suggests bacterial infection, eosinophilia over 1.5 x 10^9/L suggests DRESS, and thrombocytopenia suggests dengue, rickettsial disease, sepsis, malaria or thrombotic microangiopathy.
• CRP, urea, creatinine, electrolytes, liver tests, creatine kinase, lactate and urinalysis.
• Blood cultures before antibiotics, two sets.
• Malaria rapid antigen test with thick and thin films.
• HIV fourth generation test, syphilis serology (treponemal and nontreponemal, with prozone dilution if suspicion is high and the test is negative), and pregnancy test.
• Coagulation screen, fibrinogen, D dimer and blood film when purpura or bleeding is present.

Step 4. Targeted tests

• Measles: nasopharyngeal swab and urine for RNA PCR (best in the first week), with 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 on 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. Flavivirus serology cross reacts.
• Vesicle swab for herpes simplex, varicella zoster and mpox PCR.
• Throat swab or rapid antigen test for group A streptococcus.
• Rickettsial disease: PCR of eschar swab or blood, with paired serology at 2 to 4 weeks. Treat before confirmation.
• Leptospirosis PCR in the first 10 days, then microscopic agglutination test or IgM.
• Meningococcal PCR of blood, and skin lesion aspirate for Gram stain.
• Lumbar puncture when meningitis is possible, after correction of coagulopathy, with no delay in antibiotics.
• Skin punch biopsy (4 mm, two samples, one for direct immunofluorescence) for persistent, atypical or severe drug or vasculitic eruptions.
• Echocardiography when endocarditis is possible.
• For viral haemorrhagic fever, contact public health and the reference laboratory before taking samples.

Limits. Early serology is falsely negative. Many viral exanthems are diagnosed clinically. Biopsy cannot always separate drug eruption from viral exanthem, so the drug and timing history decide.

Immediate

• Sepsis or nonblanching rash with illness: oxygen, intravenous access, blood cultures, crystalloid boluses of 250 to 500 mL with reassessment (up to 30 mL/kg in 3 hours when clearly hypovolaemic), and ceftriaxone 2 g intravenously without delay (2 g every 12 hours when meningitis cannot be excluded). Give benzylpenicillin 1.2 g intravenously or intramuscularly if ceftriaxone is not immediately available. Start noradrenaline to keep mean arterial pressure at 65 mmHg or over if hypotension persists after fluids.
• Isolate patients with suspected measles (airborne precautions until 4 days after rash onset), varicella (until all lesions are crusted), mpox and viral haemorrhagic fever. Notify public health for measles, rubella, meningococcal disease, dengue, syphilis, typhoid, mpox and viral haemorrhagic fever.
• Add doxycycline 100 mg orally or intravenously twice daily when rickettsial disease or leptospirosis is possible.

Supportive care. 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; 15 mg/kg for each dose under 50 kg, maximum 60 mg/kg daily). Avoid aspirin and NSAIDs in suspected dengue and viral haemorrhagic fever. Oral fluids and emollients for itch.

Cause directed

• Meningococcal disease: ceftriaxone 2 g intravenously every 12 hours for 5 to 7 days, with intensive care for shock. Contact prophylaxis: ciprofloxacin 500 mg orally as a single dose, or rifampicin 600 mg orally twice daily for 2 days, or ceftriaxone 250 mg intramuscularly once in pregnancy.
• Toxic shock syndrome: remove the source (tampon, packing, drain wound), give clindamycin 600 to 900 mg intravenously every 8 hours with flucloxacillin 2 g intravenously every 4 to 6 hours (vancomycin 15 to 20 mg/kg every 8 to 12 hours when MRSA is likely), and intravenous immunoglobulin 1 g/kg on day 1 then 0.5 g/kg on days 2 and 3 in severe streptococcal disease. Surgical review for necrotising infection.
• Scarlet fever: phenoxymethylpenicillin 500 mg orally four times daily for 10 days (clarithromycin 250 to 500 mg twice daily for 5 days if penicillin allergic).
• Secondary syphilis: benzathine benzylpenicillin 2.4 million units intramuscularly once. If penicillin allergic and not pregnant: doxycycline 100 mg orally twice daily for 14 days. Warn about the Jarisch-Herxheimer reaction. Trace contacts and test for HIV.
• Rickettsial disease: doxycycline 100 mg orally or intravenously twice daily for 5 to 7 days and for at least 3 days after fever settles. Children under 45 kg: 2.2 mg/kg twice daily, maximum 100 mg each dose.
• Typhoid fever: azithromycin 500 mg orally once daily for 7 days, or ceftriaxone 2 g intravenously once daily for 7 to 14 days.
• Leptospirosis: doxycycline 100 mg orally twice daily for 7 days in mild disease. Severe disease: benzylpenicillin 1.5 million units intravenously every 6 hours, or ceftriaxone 1 g intravenously once daily, for 7 days.
• Lyme disease with erythema migrans: doxycycline 100 mg orally twice daily for 10 days (amoxicillin 500 mg three times daily for 14 days in pregnancy and in children under 8 years).
• Disseminated gonococcal infection: ceftriaxone 1 g intravenously or intramuscularly once daily for 7 days with azithromycin 1 g orally once.
• Measles: supportive care and vitamin A 200,000 IU orally once daily for 2 days at age 12 months or over (100,000 IU at 6 to 11 months, 50,000 IU under 6 months). Susceptible contacts: measles vaccine within 72 hours, or immunoglobulin within 6 days.
• Varicella and disseminated zoster: aciclovir 800 mg orally five times daily for 7 days, started within 24 hours of rash in adults. Severe, pregnant after 20 weeks, or immunocompromised: aciclovir 10 mg/kg intravenously every 8 hours (adjust for creatinine clearance 25 to 50 mL/min every 12 hours, 10 to 25 mL/min every 24 hours, under 10 mL/min half dose every 24 hours, with hydration).
• Mpox: isolation, supportive care and analgesia. Evidence of benefit from antiviral therapy is limited; use only under specialist direction.
• 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) and give isotonic crystalloid 5 to 7 mL/kg/h for 1 to 2 hours, then 3 to 5 mL/kg/h adjusted to haematocrit and clinical response. For shock give 10 to 20 mL/kg over 15 to 30 minutes.
• Malaria: artemether with lumefantrine in uncomplicated falciparum malaria (4 tablets of 20 mg/120 mg at 0, 8, 24, 36, 48 and 60 hours for 35 kg or over, with fatty food), and artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then daily in severe malaria.
• Acute HIV infection: start antiretroviral therapy and test partners.
• Infective endocarditis: three sets of blood cultures, then flucloxacillin 2 g intravenously every 4 to 6 hours plus gentamicin 1 mg/kg intravenously every 12 hours (vancomycin 15 to 20 mg/kg every 8 to 12 hours when MRSA is likely, in penicillin allergy or with prosthetic valves).
• 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, and echocardiography.
• Morbilliform drug eruption: stop the suspected drug and nonessential drugs started in the last 2 months. Emollients and mometasone furoate 0.1% ointment once daily for 5 to 7 days.
• DRESS: stop the culprit, admit, prednisolone 0.5 to 1 mg/kg orally daily (maximum 80 mg), tapered over 6 to 12 weeks, with eosinophils, liver tests, creatinine, troponin and creatine kinase twice weekly at first.
• Stevens-Johnson syndrome and toxic epidermal necrolysis: stop the culprit, admit to intensive care or a burns unit, with fluid, eye and skin care.
• Viral haemorrhagic fever: single room isolation, full protective equipment for essential staff only, public health notification, supportive care and empirical antimalarial and antibiotic treatment.
• Rubella, parvovirus B19, cytomegalovirus, varicella or Zika in pregnancy: urgent obstetric and foetal medicine review.

Monitoring. Vital signs every 15 minutes in shock and every 1 to 4 hours in sepsis. Mark purpura edges and review hourly. Daily blood count, creatinine and liver tests in drug reactions and dengue. Urine output hourly in shock.

Referral and escalation. Intensive care for shock and respiratory failure. Infectious diseases for returned travellers, unexplained rash with fever and immunocompromise. Dermatology for severe cutaneous drug reactions and persistent rash. Paediatrics for Kawasaki disease. Rheumatology for lupus and Still disease. Public health for notifiable disease and contact tracing.

Admission criteria. Any red flag, nonblanching rash with illness, mucosal involvement, DRESS, dengue with warning signs, Kawasaki disease, suspected rickettsial disease with systemic features, pregnancy with fever and rash, immunocompromise and uncertain diagnosis in an unwell patient.

Discharge and follow up. Review within 24 to 48 hours for undiagnosed fever with rash. Record drug allergy with the culprit. Safety net advice: return for nonblanching spots, drowsiness, severe headache, neck stiffness, breathing difficulty, blistering, mouth or eye sores, bleeding, persistent vomiting, or reduced urine.