What are the causes of a maculopapular rash with fever?

Causes of Maculopapular Rash with Fever

Viral exanthems are the most common cause of maculopapular rash with fever, but you must immediately exclude life-threatening bacterial infections—particularly Rocky Mountain Spotted Fever (RMSF) and meningococcemia—before attributing symptoms to benign viral illness. 1, 2

Life-Threatening Causes Requiring Immediate Action

Rocky Mountain Spotted Fever (RMSF)

• Initiate doxycycline 100 mg twice daily immediately if ANY of the following are present: fever + rash + headache + tick exposure or endemic area exposure, without waiting for laboratory confirmation. 1
• Initial presentation includes small (1-5 mm), blanching, pink macules on ankles, wrists, or forearms appearing 2-4 days after fever onset 1
• Rash progresses to maculopapular with central petechiae by days 5-6, spreading to palms, soles, arms, legs, and trunk while sparing the face 3, 1
• Critical pitfall: Less than 50% of patients have rash in the first 3 days of illness, and up to 20% never develop a rash—absence of rash does NOT exclude RMSF 1, 4
• Up to 40% of patients report no tick bite history, so absence of tick exposure should not exclude diagnosis 2
• Case-fatality rate is 5-10% overall, but increases to 40-50% when treatment is delayed to days 8-9 of illness 3, 1
• Look for thrombocytopenia, leukopenia, hyponatremia, and elevated hepatic transaminases as critical red flags 3, 1

Meningococcemia (Neisseria meningitidis)

• Presents with rapid progression from maculopapular to petechial/purpuric rash with clinical deterioration 4, 2
• Associated with high fever, severe headache, altered mental status, elevated white blood cell count, and markedly elevated inflammatory markers 4, 2
• Can rapidly progress to purpura fulminans 4
• Administer intramuscular ceftriaxone immediately pending blood cultures if meningococcal disease cannot be excluded 2

Common Infectious Causes

Viral Exanthems (Most Common Overall)

• Enteroviral infections present with trunk and extremity involvement while sparing palms, soles, face, and scalp 1
• Human herpesvirus 6 (roseola) presents with macular rash following high fever resolution—timing of rash AFTER fever resolves is the key distinguishing feature 1, 2
• Epstein-Barr virus causes maculopapular rash, especially if patient received ampicillin or amoxicillin 1
• Parvovirus B19 presents with "slapped cheek" appearance on face with possible truncal involvement 1
• Measles is a leading cause of maculopapular rash with fever in adults 5

Other Tickborne Rickettsial Diseases

• Human Monocytic Ehrlichiosis (HME) causes rash in only approximately 30% of adults, varying from petechial or maculopapular to diffuse erythema 1
• HME rash appears later in disease course (median 5 days after onset) and rarely involves palms and soles 1
• Case-fatality rate is 3% 1
• Look for thrombocytopenia, leukopenia, and increased hepatic transaminase levels 3

Bacterial Causes

• Scarlet fever (Group A Streptococcus) presents with sandpaper-textured rash appearing during active fever, spreading from upper trunk, associated with pharyngitis and tonsillar exudates 2
• Secondary syphilis (Treponema pallidum) can cause maculopapular rash involving palms and soles 4
• Bacterial endocarditis may present with petechiae on palms and soles 4

Non-Infectious Causes

Drug Hypersensitivity Reactions

• Present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches 1
• Drug reactions are the second most common cause among noninfectious etiologies 5
• Can cause petechial rash on palms and soles 4

Autoimmune/Vasculitic Causes

• Adult-Onset Still's Disease (AOSD) is among the top 5 causes of fever with maculopapular rash in adults 5
• Can present with vasculitic purpuric rash 4

Immediate Diagnostic Workup Algorithm

When RMSF or ehrlichiosis is suspected, perform immediately: 1

• Complete blood count with differential (looking for leukopenia, thrombocytopenia)
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases)
• Acute serology for Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum

Key clinical features to assess: 2

• Timing of rash relative to fever (before, during, or after fever resolution)
• Distribution pattern (trunk vs. extremities, involvement of palms/soles/face)
• Rash evolution (blanching macules → maculopapular → petechial)
• Associated symptoms (headache, myalgia, gastrointestinal symptoms, altered mental status)
• Epidemiologic factors (tick exposure, travel history, medication history, season)

Critical Clinical Pitfalls to Avoid

• Never wait for the classic triad of fever, rash, and tick bite in RMSF—it is present in only a minority of patients at initial presentation 4
• Never dismiss a petechial rash without thorough evaluation, as meningococcemia requires urgent treatment 2
• Geography should not exclude RMSF, as cases occur nationwide 2
• Early serology for RMSF is typically negative, so negative early testing does not exclude diagnosis 2
• In darker-skinned patients, petechial rashes may be difficult to recognize, increasing risk of delayed diagnosis 4
• Rash on palms and soles is not pathognomonic for any single condition—consider RMSF, meningococcemia, secondary syphilis, endocarditis, and drug reactions 4

Expected Clinical Response

• Clinical improvement is expected within 24-48 hours of initiating doxycycline for RMSF 1
• Severe complications (meningoencephalitis, ARDS, multiorgan failure) can occur if treatment is delayed 1
• Mortality rate for all causes of fever with rash is approximately 5%, with toxic epidermal necrolysis, AOSD, staphylococcal toxic shock syndrome being leading causes of death 5