Laboratory Workup for Skin Pain and Flu-like Symptoms Without Fever or Rash
For a patient presenting with skin pain and flu-like symptoms without fever or rash, obtain a complete blood count with differential, inflammatory markers (ESR and CRP), comprehensive metabolic panel, and consider dermatology consultation for skin biopsy if symptoms persist or worsen.
Initial Laboratory Assessment
Essential First-Line Tests
Complete blood count (CBC) with manual differential to assess for leukocytosis (WBC >14,000 cells/mm³), left shift (band neutrophils ≥6% or >1,500 cells/mm³), or other hematologic abnormalities that suggest bacterial infection or systemic inflammation 1
Inflammatory markers (ESR and CRP) to evaluate for occult inflammatory or infectious processes, as these can be elevated even in the absence of fever 2, 3. CRP is particularly useful for acute conditions while ESR is better for chronic inflammatory states 2
Comprehensive metabolic panel including liver and kidney function tests to rule out systemic disease and assess for organ involvement, particularly important when considering drug reactions or DRESS syndrome 1
Clinical Context Matters
The combination of skin pain (described as "sunburn-like") with flu-like symptoms (malaise, myalgias, arthralgias) without visible rash raises concern for several conditions 1:
- Prodromal phase of severe cutaneous adverse reactions (SCAR) including Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome 1
- Early autoinflammatory syndrome particularly if symptoms are recurrent 1
- Occult infection that may not yet manifest with fever or typical signs 1
Additional Workup Based on Clinical Suspicion
If Autoinflammatory Disease Suspected
When flu-like symptoms are recurrent or associated with joint pain and malaise without clear infectious etiology 1:
- Elevated inflammatory markers (CRP and ESR) to document systemic inflammation 1
- Consider genetic testing for periodic fever syndromes (FMF, TRAPS, HIDS) if febrile attacks occur with joint or abdominal pain 1
- Rule out malignancy and autoimmune disease before pursuing autoinflammatory workup 1
If Drug Reaction or Immune-Related Adverse Event Suspected
Particularly relevant if patient is on immune checkpoint inhibitors or other high-risk medications 1:
- Dermatology consultation for consideration of skin biopsy with direct immunofluorescence, even without visible rash 1
- Further serologic workup including ELISA testing or indirect immunofluorescence may be pursued based on dermatology recommendations 1
- Monitor closely with serial examinations as skin pain can precede visible manifestations of serious drug reactions 1
Interpretation Pearls
Understanding Inflammatory Markers
- ESR >50 mm/hr significantly increases likelihood of serious underlying disease (likelihood ratio 6-8 depending on presentation) 4
- ESR <20 mm/hr is generally reassuring except in abdominal presentations 4
- Normal WBC with elevated CRP (>100 mg/L) can occur in bacterial infections and does not exclude serious pathology 5
- ESR:CRP ratio may help distinguish inflammatory flares from infection in certain contexts 6
Critical Pitfalls to Avoid
- Do not dismiss symptoms based on absence of fever alone, as serious conditions including severe drug reactions can present without fever initially 1
- Do not wait for rash to develop before pursuing workup, as skin pain may be the earliest manifestation of conditions like DRESS or TEN 1
- Inflammatory markers between 20-50 mm/hr provide limited diagnostic information (likelihood ratio 1.2-1.5) and should not be over-interpreted 4
Monitoring Strategy
- Reassess within 24-48 hours if initial workup is unrevealing but symptoms persist 1
- Perform full skin examination at each visit, specifically evaluating all mucous membranes (eyes, nares, oropharynx, genitals, perianal area) 1
- Assess for lymphadenopathy and facial/extremity swelling which may indicate DRESS syndrome 1
- Consider serial photography if any skin changes develop to document progression 1