What is the differential diagnosis for an adult patient presenting with fever and skin rash?

Differential Diagnosis of Fever with Rash in Adults

The differential diagnosis for an adult presenting with fever and rash must prioritize life-threatening tickborne rickettsial diseases (particularly Rocky Mountain Spotted Fever), meningococcemia, and bacterial endocarditis, as these conditions require immediate empiric antibiotic therapy to prevent mortality.

Immediate Life-Threatening Diagnoses Requiring Urgent Action

Rocky Mountain Spotted Fever (RMSF)

• Initiate doxycycline 100 mg twice daily immediately without waiting for laboratory confirmation if fever, rash, and headache are present, regardless of tick exposure history 1
• The classic presentation includes small blanching pink macules (1-5 mm) appearing 2-4 days after fever onset on ankles, wrists, or forearms, progressing to maculopapular lesions with central petechiae that spread to palms, soles, arms, legs, and trunk while sparing the face 2, 3
• Critical pitfall: Less than 50% of patients have rash in the first 3 days, and up to 20% never develop a rash 2, 3
• Approximately 40% of patients report no tick bite history 3
• Case-fatality rate is 5-10%, with 50% of deaths occurring within 9 days of illness onset 2, 1
• Lack of rash or late-onset rash is associated with delays in diagnosis and increased mortality 2
• Associated laboratory findings include thrombocytopenia, increased immature neutrophils, elevated hepatic transaminases, and hyponatremia 2

Meningococcemia (Neisseria meningitidis)

• Presents with petechial or purpuric rash that can rapidly progress to purpura fulminans alongside high fever, severe headache, and altered mental status 1
• Add ceftriaxone immediately if meningococcemia cannot be excluded based on clinical presentation 1
• Clinical features include fever, lethargy, vomiting, and petechiae or purpura with shock in 20% of cases 1
• Up to 50% of early meningococcal cases lack rash 1

Bacterial Endocarditis

• Consider in patients with cardiac risk factors presenting with fever and petechiae 1
• Can cause rash involving palms and soles 3

Tickborne Rickettsial Diseases (Beyond RMSF)

Human Monocytic Ehrlichiosis (Ehrlichia chaffeensis)

• Rash occurs in approximately 30% of adults and 60% of children, appearing a median of 5 days after illness onset 2, 3
• Rash patterns vary from petechial or maculopapular to diffuse erythema, and can involve palms and soles 2, 3
• Rash appears later in disease course compared to RMSF and is less common 3
• Common symptoms include fever (96%), headache (72%), malaise (77%), myalgia (68%), and prominent gastrointestinal manifestations including nausea (57%), vomiting (47%), and diarrhea (25%) 2
• Case-fatality rate is 3% 2, 3
• Laboratory findings include leukopenia, thrombocytopenia, increased hepatic transaminases, and hyponatremia 2

Rickettsia parkeri Rickettsiosis

• Typically milder than RMSF 2
• Nearly all patients present with an inoculation eschar as the first manifestation 2
• Sparse maculopapular or vesiculopapular rash that might involve palms and soles 2

Rickettsia species 364D Rickettsiosis

• Relatively mild illness characterized by eschar and regional lymphadenopathy 2

Human Anaplasmosis

• Rash is rare, occurring in less than 10% of patients 2
• Case-fatality rate is less than 1% 2
• Less likely diagnosis when prominent rash is present 3

Other Infectious Causes

Secondary Syphilis (Treponema pallidum)

• Can cause rash involving palms and soles 3
• Consider in appropriate epidemiologic context

Rat-Bite Fever

• Rash can involve palms and soles, similar to RMSF and secondary syphilis 4
• Critical diagnostic clue is history of rodent exposure 4
• Rash typically appears 2-10 days after rat bite or exposure 4

Viral Exanthems

• Enteroviral infections present with trunk and extremity involvement while sparing palms, soles, face, and scalp 3
• Human herpesvirus 6 (roseola) presents with macular rash following high fever 3
• Epstein-Barr virus causes maculopapular rash, especially if patient received ampicillin or amoxicillin 3
• Parvovirus B19 presents with "slapped cheek" appearance on face with possible truncal involvement 3
• Viral causes typically progress more slowly than bacterial infections 1

Hemorrhagic Fevers

• Ebola or Marburg have incubation period of 5-10 days with abrupt fever, myalgia, headache, nausea, vomiting, abdominal pain, and diarrhea 1
• Maculopapular rash on trunk develops approximately 5 days after illness onset 1
• Travel to endemic areas is critical part of clinical history 1

Non-Infectious Causes

Immune Thrombocytopenic Purpura

• Autoimmune cause of petechial rash 1

Henoch-Schönlein Purpura

• Autoimmune/vasculitic cause of petechial rash 1

Drug Eruptions

• Present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches 3

Kawasaki Disease

• Causes coronary artery aneurysms if left untreated 3
• Rash is typically truncal with accentuation in groin region 3
• Diagnostic criteria include fever for ≥5 days plus 4 of 5 features: bilateral conjunctival injection, oral mucosal changes, cervical lymphadenopathy ≥1.5 cm, extremity changes, and polymorphous rash 3

Diagnostic Workup Algorithm

Immediate Laboratory Studies

• Complete blood count with differential (looking for leukopenia, thrombocytopenia, bandemia) 1, 3
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases) 1, 3
• Peripheral blood smear examination 1
• Blood cultures before antibiotics if possible, but do not delay treatment 1

Specific Testing

• Acute serology for Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum 3
• Urinalysis (microscopic hematuria suggests systemic vasculitis) 3
• If Kawasaki disease suspected: ESR, CRP, serum albumin 3

Critical Red Flags Requiring Immediate Doxycycline

• Fever + rash + headache + tick exposure or endemic area exposure 3
• Thrombocytopenia and/or hyponatremia 3
• Systemic toxicity (tachycardia, confusion, hypotension, altered mental status) 1

Management Approach

Empiric Antibiotic Therapy

• Start doxycycline 100 mg twice daily immediately if RMSF or ehrlichiosis cannot be excluded, even in children <8 years old 3
• Add ceftriaxone if meningococcemia cannot be excluded 1
• Clinical improvement expected within 24-48 hours of initiating doxycycline 3

Hospitalization Criteria

• Systemic toxicity 1
• Rapidly progressive rash 1
• Diagnostic uncertainty between serious causes 1
• Generalized petechiae or purpuric rash 1

Key Clinical Pitfalls to Avoid

• Do not wait for the classic triad of fever, rash, and tick bite in RMSF, as it is present in only a minority of patients at initial presentation 1, 5
• Do not exclude serious disease based on absence of rash, as up to 20% of RMSF cases and 50% of early meningococcal cases lack rash 1
• Do not exclude RMSF based on lack of tick exposure history, as approximately 40-50% of patients do not recall tick exposure 3, 6
• Severe complications (meningoencephalitis, ARDS, multiorgan failure, cutaneous necrosis, shock) occur if treatment is delayed 2, 3
• Immunosuppressed patients, elderly (≥60 years), and children <10 years have higher case-fatality rates 2