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

Differential Diagnosis for Fever, Rash, and Lymphadenopathy

The differential diagnosis for fever, rash, and lymphadenopathy requires immediate consideration of life-threatening infectious causes first—particularly tickborne rickettsial diseases and viral syndromes—followed by immune dysregulation disorders, drug reactions, and malignancies.

Immediate Life-Threatening Considerations

Tickborne Rickettsial Diseases (Highest Mortality Risk)

If the patient has fever + rash + lymphadenopathy with any history of tick exposure or residence in an endemic area, initiate doxycycline 100 mg twice daily immediately without waiting for laboratory confirmation. 1

• Rocky Mountain Spotted Fever (RMSF) presents with small blanching pink macules on ankles, wrists, or forearms appearing 2-4 days after fever onset, progressing to maculopapular rash with central petechiae that spreads to palms, soles, and trunk while sparing the face 1
• RMSF carries a 5-10% case-fatality rate, with mortality risk increased by delayed diagnosis when rash is absent or appears late 1
• Less than 50% of patients have rash in the first 3 days, and up to 20% never develop a rash 1
• Human Monocytic Ehrlichiosis (HME) causes rash in only 30% of adults, appearing later (median 5 days after onset) as petechial, maculopapular, or diffuse erythema, rarely involving palms and soles 1
• HME carries a 3% case-fatality rate 1

Critical red flags requiring immediate doxycycline: thrombocytopenia and/or hyponatremia on initial labs 1

Expected clinical response: improvement within 24-48 hours of starting doxycycline; lack of response suggests alternative diagnosis or coinfection 1

Immediate Diagnostic Workup Required

• Complete blood count with differential (evaluate for leukopenia, thrombocytopenia) 1
• Comprehensive metabolic panel (evaluate for hyponatremia, elevated hepatic transaminases) 1
• Acute serology for Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum 1

Viral Syndromes (Most Common Overall)

Common Viral Exanthems

• Enteroviral infections are the most common cause of maculopapular rashes, characteristically involving trunk and extremities while sparing palms, soles, face, and scalp 1
• Epstein-Barr virus (EBV) causes maculopapular rash, particularly if the patient received ampicillin or amoxicillin 1
• Human herpesvirus 6 (roseola) presents with macular rash following high fever resolution 1
• Parvovirus B19 presents with "slapped cheek" facial appearance with possible truncal involvement 1

Multisystem Inflammatory Syndrome in Children (MIS-C)

In pediatric patients with SARS-CoV-2 exposure within the past 4 weeks, MIS-C must be considered when fever, rash, and lymphadenopathy are present. 2

• MIS-C presents with polymorphic, maculopapular, or petechial rash (not vesicular), bilateral conjunctivitis without exudate, oral mucosal changes (red/cracked lips, strawberry tongue), and cervical lymphadenopathy 2
• MIS-C occurs in approximately 2 of 200,000 individuals <21 years old, typically emerging 2-6 weeks after peak COVID-19 incidence in the geographic area 2
• Diagnostic evaluation requires SARS-CoV-2 PCR and/or serologies, CBC, CMP, ESR, CRP, procalcitonin, and cytokine panel if available 2

Immune Dysregulation Syndromes

Acute/Fulminant Presentations

When fever, lymphadenopathy, and hepatosplenomegaly present with toxic appearance, consider hemophagocytic lymphohistiocytosis (HLH) and related syndromes. 2

• Familial hemophagocytic lymphohistiocytosis (FHL) or accelerated phase of Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), or Hermansky-Pudlak syndrome (HPS) present with acute fulminant fever, toxic appearance, and lymphoproliferation 2
• Autoimmune lymphoproliferative syndrome (ALPS) and X-linked lymphoproliferative syndrome (XLP) present when lymphoproliferation and autoimmune disease are prominent features 2

Adult-Onset Still's Disease (AOSD)

AOSD presents with high spiking fever (>39-40°C), salmon-colored evanescent rash, and lymphadenopathy in adults >18 years old. 2

• The rash is typically transient, appearing with fever spikes and resolving between episodes 2
• AOSD was identified as one of the five most common causes of fever and rash in adults in a prospective study 3
• Diagnosis requires exclusion of infectious (viral syndromes lasting >3 months), neoplastic (leukemia, lymphoma), and other autoimmune disorders 2
• Laboratory findings show neutrophilia and markedly elevated ferritin levels 2

Kawasaki Disease (Pediatric Population)

In children with ≥5 days of fever plus ≥4 of the following principal features, diagnose Kawasaki disease: 2

1. Erythema and cracking of lips, strawberry tongue, and/or erythema of oral/pharyngeal mucosa 2
2. Bilateral bulbar conjunctival injection without exudate 2
3. Maculopapular, diffuse erythroderma, or erythema multiforme-like rash 2
4. Erythema and edema of hands/feet in acute phase and/or periungual desquamation in subacute phase 2
5. Cervical lymphadenopathy (≥1.5 cm diameter), usually unilateral 2

Critical pitfall: Cervical lymphadenopathy may be the most prominent initial finding, mimicking bacterial lymphadenitis and significantly delaying diagnosis 2

Drug Reactions

• Nonspecific drug eruptions present as fine reticular maculopapular rashes or broad, flat erythematous macules and patches 1
• Query about new medications within the past 2-3 weeks, particularly antibiotics, NSAIDs, or anticonvulsants 4
• Up to 40% of patients may not recall or report new medications 4

Malignancies and Atypical Lymphoproliferative Disorders

Warning Signs for Malignancy

• Lymph nodes >2 cm in size, supraclavicular location, and generalized lymphadenopathy with hepatosplenomegaly or systemic symptoms suggest malignant etiology 5
• Leukemia, lymphoma, and angioblastic lymphadenopathy can present with fever, rash, and lymphadenopathy 2, 6

Benign Lymphoproliferative Disorders

• Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) presents with fever, diffuse lymphadenopathy, and erythematous scaly rash, most commonly in Japanese populations but reported in all ethnic groups 7
• Laboratory findings include leukopenia with bandemia, anemia, and thrombocytopenia 7
• Diagnosis requires lymph node biopsy showing histiocytic necrotizing lymphadenitis 7
• Angioimmunoblastic lymphadenopathy presents with high spiking fever, lymphadenopathy, intermittent maculopapular rash, positive Coombs test, elevated gamma globulin levels, polyclonal gammopathy, and hepatosplenomegaly 6

Algorithmic Approach to Diagnosis

Step 1: Assess for Immediate Life-Threatening Conditions

• If fever + rash + headache + tick exposure OR thrombocytopenia/hyponatremia present: Start doxycycline 100 mg twice daily immediately 1
• If toxic appearance with high fever, lymphadenopathy, hepatosplenomegaly: Consider HLH and related syndromes 2

Step 2: Characterize the Rash Morphology

• Maculopapular rash sparing palms/soles/face/scalp: Viral exanthem most likely 1
• Maculopapular rash progressing to petechiae involving palms/soles: RMSF 1
• Salmon-colored evanescent rash with fever spikes: AOSD 2
• Polymorphic rash with conjunctivitis and oral changes: MIS-C (pediatric) or Kawasaki disease 2

Step 3: Evaluate Epidemiologic and Temporal Factors

• Recent tick exposure or endemic area residence: Tickborne rickettsial disease 1
• SARS-CoV-2 exposure within 4 weeks (pediatric): MIS-C 2
• New medication within 2-3 weeks: Drug reaction 4
• Age <16 years with ≥5 days fever: Kawasaki disease 2
• Age >18 years with high spiking fever: AOSD 2

Step 4: Laboratory Evaluation Guides Further Workup

• Thrombocytopenia + hyponatremia: Strongly suggests tickborne rickettsial disease 1
• Leukopenia with bandemia: Consider Kikuchi-Fujimoto disease 7
• Neutrophilia with markedly elevated ferritin: AOSD 2
• Lymph nodes >2 cm with hepatosplenomegaly: Lymph node biopsy to exclude malignancy 5

Common Pitfalls to Avoid

• Do not wait for rash to appear before treating suspected RMSF: up to 20% never develop rash, and delayed treatment increases mortality 1
• Do not dismiss viral exanthem diagnosis in afebrile patients: fever may have resolved or been mild 4
• Do not overlook drug history: up to 40% of patients fail to report new medications 4
• Do not assume bacterial lymphadenitis in children with prominent cervical lymphadenopathy: this may be the initial presentation of Kawasaki disease 2
• In darker-skinned patients, petechial rashes may be difficult to recognize, increasing risk of delayed diagnosis 4