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

Differential Diagnosis for Fever with Skin Rash

Immediate Life-Threatening Diagnoses to Exclude First

If a patient presents with fever and rash, immediately consider Rocky Mountain Spotted Fever (RMSF) and initiate doxycycline 100 mg twice daily without waiting for laboratory confirmation if any of these red flags are present: fever + rash + headache + tick exposure (or endemic area exposure), thrombocytopenia, or hyponatremia. 1

Critical Red Flags Requiring Immediate Doxycycline

• RMSF carries a 5-10% case-fatality rate, and delays in diagnosis significantly increase mortality. 1
• Less than 50% of patients have rash in the first 3 days of illness, and up to 20% never develop a rash. 1
• Up to 40% of RMSF patients report no tick bite history, so do not exclude this diagnosis based on absence of tick exposure. 1, 2
• RMSF initially presents as small (1-5 mm) blanching pink macules on ankles, wrists, or forearms appearing 2-4 days after fever onset, then progresses to maculopapular with central petechiae spreading to palms, soles, arms, legs, and trunk while sparing the face. 1

Other Tickborne Rickettsial Diseases

• Human Monocytic Ehrlichiosis (HME) causes rash in only approximately 30% of adults, appearing later in the disease course (median 5 days after onset), varying from petechial or maculopapular to diffuse erythema, and rarely involves palms and soles. 1
• HME carries a 3% case-fatality rate. 1
• Anaplasmosis typically presents with fever, headache, and myalgia, but rash is rare, making this less likely if prominent rash is present. 1

Categorization by Rash Morphology

Maculopapular Rashes (Most Common Pattern)

Viral Exanthems:

• Enteroviral infections are the most common cause of maculopapular rashes, presenting with trunk and extremity involvement while sparing palms, soles, face, and scalp. 1, 3
• Human herpesvirus 6 (roseola) presents with macular rash following high fever, though more common in children. 1, 3
• Epstein-Barr virus causes maculopapular rash, especially if the patient received ampicillin or amoxicillin. 1, 3
• Parvovirus B19 presents with "slapped cheek" appearance on face with possible truncal involvement. 1, 3
• Measles was identified as one of the five most common causes in a prospective study of 100 adult patients with fever and rash. 4
• Varicella (chickenpox) was among the top five causes in the same study. 4

Drug Reactions:

• Cutaneous drug reactions were the second most common cause overall and the leading noninfectious cause in a prospective study. 4
• Nonspecific drug eruptions present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches. 1, 3
• Query specifically about recent antibiotic use, NSAIDs, anticonvulsants, or any new medications within the past 2-3 weeks. 3

Rheumatologic Disease:

• Adult-onset Still's disease (ASD) was among the top five causes and accounted for one mortality case in a prospective study. 4

Petechial Rashes

• Meningococcemia is life-threatening and requires immediate recognition and treatment. 5
• Thrombotic thrombocytopenic purpura (TTP) presents with fever, altered mental status, thrombocytopenia, and acute renal failure. 6
• Rickettsial diseases can progress from maculopapular to petechial patterns. 1

Diffusely Erythematous with Desquamation

• Toxic shock syndrome presents with rash and multiple organ failure. 6
• Staphylococcal toxic shock syndrome accounted for one mortality case in a prospective study. 4
• Toxic epidermal necrolysis accounted for two mortality cases in the same study. 4

Vesiculobullous-Pustular Rashes

• Varicella and herpes simplex virus infections present with vesicular lesions. 5
• Disseminated gonococcal infection can present with pustular lesions. 5

Immediate Diagnostic Workup

Laboratory Testing Required Immediately if RMSF/Ehrlichiosis Suspected:

• Complete blood count with differential (looking for leukopenia, thrombocytopenia). 1, 3
• Comprehensive metabolic panel (looking for hyponatremia, elevated hepatic transaminases). 1, 3
• Acute serology for R. rickettsii, E. chaffeensis, and A. phagocytophilum. 1, 3
• Peripheral blood smear to look for morulae within granulocytes or schistocytes. 6

Additional Diagnostic Studies Based on Clinical Presentation:

• Blood cultures if sepsis or bacterial infection suspected. 6
• Lumbar puncture if meningitis or encephalitis suspected (though CSF may be unremarkable in encephalitis). 6
• Coagulation studies (PT/PTT) if disseminated intravascular coagulation (DIC) suspected. 6
• Skin biopsy or aspiration for histological and microbiological evaluation if diagnosis remains unclear, particularly in immunocompromised patients. 6

Critical Pitfalls to Avoid

• Do not wait for serologic confirmation before starting doxycycline if RMSF is suspected, as IgM/IgG are not detectable before the second week of illness. 2
• Do not exclude RMSF based on absence of rash, as up to 20% never develop a rash. 1
• Do not exclude RMSF based on absence of tick bite history, as 40% of patients do not report tick exposure. 1, 2
• Do not assume palmoplantar rash is benign, as multiple life-threatening infections present this way. 2
• In immunocompromised patients, the differential diagnosis is broader and includes bacterial, viral, fungal, and parasitic agents, and cutaneous lesions that appear localized may be manifestations of systemic or life-threatening infections. 6

Expected Clinical Response

• Clinical improvement is expected within 24-48 hours of initiating doxycycline for tickborne rickettsial diseases. 1, 2
• Severe complications (meningoencephalitis, ARDS, multiorgan failure) can occur if treatment is delayed, particularly in immunosuppressed patients. 1
• If clinical response to doxycycline is delayed, consider coinfection with Borrelia burgdorferi or Babesia microti in the appropriate epidemiologic setting. 1

Special Considerations in Specific Populations

Immunocompromised Patients:

• The differential diagnosis includes drug eruption, cutaneous infiltration with underlying malignancy, chemotherapy- or radiation-induced reactions, Sweet syndrome, erythema multiforme, leukocytoclastic vasculitis, and graft-vs-host disease among allogeneic transplant recipients. 6
• Biopsy or aspiration of the lesion should always be implemented as an early diagnostic step. 6
• Graft-versus-host disease accounted for one mortality case in a prospective study. 4

Pediatric Considerations:

• Kawasaki disease causes coronary artery aneurysms if left untreated and presents with 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 (typically truncal with accentuation in the groin region). 1
• If Kawasaki disease is suspected, obtain ESR, CRP, serum albumin, and urinalysis. 1

Historical and Epidemiologic Clues

• Recent travel history, contact with animals, medications, and exposure to forests and other natural environments are critical historical elements. 7
• Time of onset of symptoms and characteristics of the rash (morphology, location, distribution) are helpful in clinical diagnosis. 7
• Dogs can serve as sentinels for RMSF in human populations, and infections in canines have been associated with increased risk for infection in their owners. 6
• Summer months in endemic regions increase suspicion for tickborne diseases. 6, 3