Differential diagnosis: 17-year-old female with fever, sore throat and a neck/trunk rash

Rule out first (can deteriorate quickly)

Most likely

1. Scarlet fever (group A streptococcus). This is the leading diagnosis for sore throat, fever and rash together.
   • The rash is a diffuse, sandpaper-like erythema that blanches. It appears first on the neck, trunk and axillae, and it is accentuated in skin folds (Pastia lines).
   • Look for perioral pallor, strawberry tongue and palatal petechiae. The rash is caused by a phage-coded erythrogenic exotoxin (Quick Compendium of Clinical Pathology; Red Book 2021).
   • Confirm with a rapid antigen test and throat culture.
2. Infectious mononucleosis (EBV).
   • The classic triad is fever, sore throat and lymphadenopathy (Symptom to Diagnosis).
   • Suspect it if a rash appears after ampicillin or amoxicillin was given for the "sore throat" (Medical Microbiology 9e).
   • Look for posterior cervical nodes, splenomegaly and palatal petechiae. Atypical lymphocytes and a positive monospot or EBV VCA IgM support it.
3. Arcanobacterium haemolyticum pharyngitis. This is a classic cause in adolescents and young adults. The scarlatiniform rash is on the extensor surfaces of the arms and does not peel, unlike scarlet fever. It is seen in about half of patients (Textbook of Family Medicine 9e).

Other viral and bacterial causes

• Measles: cough, coryza, conjunctivitis, Koplik spots, and a rash spreading from the face downward. Consider it if the patient is unvaccinated.
• Rubella: postauricular and occipital nodes, mild fever.
• Adenovirus, enterovirus, parvovirus B19, and early HHV-6/CMV
• COVID-19 or other respiratory viruses with an exanthem
• Acute HIV seroconversion: mononucleosis-like illness with a truncal maculopapular rash and mucosal ulcers. Ask about sexual history.
• Secondary syphilis: sore throat, a rash that may involve the palms and soles, and lymphadenopathy.
• Mycoplasma pneumoniae, which can cause a rash and mucositis.
• Region-dependent: typhoid (rose spots), dengue, rickettsial disease, leptospirosis.

Non-infectious causes, especially if fever persists and cultures are negative

• Adult-onset Still disease: persistent spiking fever, sore throat, an evanescent salmon-pink rash on the trunk and neck, arthralgia, and very high ferritin. It is easily missed in teenagers.
• Kawasaki disease or MIS-C: less likely at 17, but possible. Look for conjunctival injection, cracked lips, extremity changes and cervical nodes.
• Drug reaction or DRESS: recent antibiotics, NSAIDs or anticonvulsants, with eosinophilia and transaminitis.
• SLE, with photosensitive rash, arthritis and cytopenias.
• Stevens-Johnson syndrome or toxic epidermal necrolysis if there is mucosal erosion or skin pain.

Suggested initial workup

• History: onset and spread of the rash, sick contacts, vaccination status, sexual history, menstrual and tampon use, new drugs (especially ampicillin), travel, joint pain.
• Examination: blanching or not, Pastia lines, tongue, tonsillar exudate, nodes, spleen, conjunctivae, oral lesions, palms and soles, joints, and signs of shock.
• Tests:
  • CBC with differential and smear (atypical lymphocytes), CRP, and ESR
  • Liver enzymes, renal function, and ferritin
  • Rapid strep test and throat culture
  • Monospot or EBV serology
  • HIV Ag/Ab and syphilis serology if indicated
  • Blood cultures if toxic-appearing
  • Urine or serum hCG
  • Measles IgM or PCR if suggestive
  • Consider ANA, ASO titre, and tests for dengue, typhoid, or malaria depending on region

Practical approach

Interpretation: fever, sore throat, rash, anemia, ferritin 8000, high ESR/CRP, WBC 19,000, normal triglycerides

Why AOSD fits

• Clinical picture: high spiking fever, sore throat, and an evanescent truncal or neck rash are the classic features. Also look for arthralgia or arthritis, lymphadenopathy, splenomegaly, and serositis.
• Ferritin: markedly elevated ferritin, disproportionate to the other acute-phase reactants, is a long-recognised feature of AOSD. It is not specific (Firestein & Kelley's Rheumatology).
• Glycosylated ferritin: a low fraction (under 20%) supports AOSD (Firestein & Kelley's Rheumatology; Dermatology 5e).
• Blood counts: neutrophilic leukocytosis (WBC 19,000), high ESR/CRP, and anemia of inflammation are typical. Platelets are often raised.
• Antibodies: ANA and RF are usually negative.

• Major:
  • Fever of 39°C or higher for at least 1 week
  • Arthralgia or arthritis for at least 2 weeks
  • Typical rash
  • WBC of 10,000 or more with at least 80% neutrophils
• Minor:
  • Sore throat
  • Lymphadenopathy or splenomegaly
  • Abnormal liver tests
  • Negative ANA and RF

Must exclude before labeling it AOSD

1. Hemophagocytic lymphohistiocytosis (HLH) or MAS. This is the dangerous complication.
   • Normal triglycerides and a high WBC argue against fully developed HLH/MAS, but do not exclude early MAS.
   • Ferritin above 10,000 is more than 90% sensitive and specific for HLH in children (Goldman-Cecil). Her level is approaching that range.
   • In active AOSD the WBC and platelets often fall as MAS develops. A falling platelet count, ESR, or fibrinogen with a rising ferritin, LFTs, and LDH is a warning sign.
   • About 40% of people with MAS meet AOSD criteria (Firestein & Kelley's).
   • The 2016 EULAR/ACR MAS classification in systemic JIA needs ferritin above 684 plus any 2 of: platelets 181 or below, AST above 48, triglycerides above 156, fibrinogen 360 or below (Rheumatology 2-volume set). A normal triglyceride level alone therefore does not exclude MAS.
   • Infection-triggered HLH is possible, especially with EBV. This matters because her initial presentation looked like mononucleosis.
2. Lymphoma or leukemia. Check the smear for blasts, and look for hepatosplenomegaly and nodes. Anemia with fever and a very high ferritin demands this.
3. Severe infection or sepsis: bacteremia, endocarditis, TB, EBV, CMV, HIV, parvovirus, dengue, typhoid, and salmonella, depending on region.
4. Other rheumatic disease: SLE, vasculitis (including Kawasaki or MIS-C), and catastrophic antiphospholipid syndrome.
5. Others to consider: liver disease, hemolysis, iron overload or transfusions, and drug reaction (DRESS).

Suggested next tests

• Blood and chemistry:
  • Peripheral smear, reticulocytes, Coombs test, and haptoglobin
  • LDH, AST/ALT, bilirubin
  • Coagulation profile, fibrinogen, D-dimer, and repeat triglycerides (fasting)
• Rheumatology:
  • ANA, RF, anti-dsDNA, complements, and antiphospholipid antibodies
  • Glycosylated ferritin, if available
• Infection:
  • Blood cultures
  • EBV, CMV, HIV, parvovirus B19, and hepatitis serology or PCR
  • Region-specific tests such as dengue or typhoid
• Imaging:
  • Chest X-ray, abdominal ultrasound, or CT chest, abdomen and pelvis for nodes, organomegaly, and occult focus
  • Echocardiography
• Bone marrow aspirate or biopsy: if cytopenias develop, the smear is abnormal, or MAS is suspected. This is the confirmatory test for hemophagocytosis.

Management principles

• Start AOSD treatment only after infection and malignancy are reasonably excluded. Giving steroids early can mask lymphoma and delay diagnosis.
• Mild disease: NSAIDs are a short trial.
• Active systemic disease: corticosteroids, then an IL-1 blocker (anakinra or canakinumab), an IL-6 blocker (tocilizumab), or methotrexate as a steroid-sparing drug.
• Suspected MAS: this is an emergency. Give pulse methylprednisolone, anakinra, and IVIG or cyclosporine, as for HLH (Rheumatology 2-volume set). Involve rheumatology and hematology.
• Monitor: ferritin, CBC, platelets, LFTs, and fibrinogen every day or two while she is inpatient.

Interpretation with the new findings

What each finding changes

Where this leaves the differential

1. AOSD / systemic JIA: most likely. She has fever, sore throat, a truncal rash, neutrophilic leukocytosis, thrombocytosis-range platelets, very high ferritin, and HSM. Ask about joint pain or morning stiffness, since arthralgia or arthritis for at least 2 weeks is a Yamaguchi major criterion.
2. Early or evolving MAS: currently unlikely, but it is the main risk during follow-up. Recheck ferritin, platelets, ESR, fibrinogen, LFTs, LDH, and triglycerides every 24 to 48 hours. A falling platelet count or ESR with a rising ferritin is the warning sign.
3. Lymphoma or leukemia: the main mimic to exclude. Anemia, HSM, fever, and a very high ferritin can all occur. Review the peripheral smear for blasts, and check LDH and uric acid. Do CT chest, abdomen, and pelvis, and consider a PET-CT if nodes or masses are found. Do a bone marrow aspirate and biopsy if the smear is abnormal or the diagnosis stays unclear.
4. Infection with HSM and fever: work through the following.
   • EBV (heterophile antibody and VCA IgM, EBV PCR) and CMV
   • Typhoid (blood culture)
   • Tuberculosis (chest imaging, Mantoux/IGRA, and cultures)
   • Brucellosis
   • Infective endocarditis (blood cultures times 3, echocardiogram)
   • Malaria (smear or antigen test)
   • Visceral leishmaniasis, if she lives in or has traveled to an endemic area (kala-azar usually has leukopenia and pancytopenia, so it is less likely with WBC 19,000)
   • HIV
5. SLE and other autoimmune disease: check ANA, anti-dsDNA, C3/C4, and RF. ANA and RF are typically negative in AOSD.
6. Vasculitis, Kawasaki-like illness, or MIS-C: less likely at this age, but consider them if there are other features.

Practical next steps

• Confirm the diagnosis of exclusion:
  • Blood cultures times 3, smear, LDH, and uric acid
  • ANA, RF, anti-dsDNA, and complements
  • EBV, CMV, and HIV tests
  • Typhoid and malaria testing as local epidemiology suggests
  • Imaging (CT or ultrasound for nodes and organomegaly) and an echocardiogram
• Support the diagnosis: glycosylated ferritin (under 20% favors AOSD) and a Yamaguchi criteria check.
• Marrow: do not skip it if anything remains unexplained. It also shows hemophagocytosis if MAS develops.
• Treatment: do not start steroids until lymphoma and infection are reasonably excluded. If AOSD is established, use steroids with or without an IL-1 or IL-6 blocker. If MAS develops, treat it as an emergency with pulse methylprednisolone plus anakinra, cyclosporine, or IVIG.

AOSD vs HLH/MAS vs lymphoma

How her results map onto this table

• Points to AOSD:
  • Fever, sore throat, a truncal and neck rash
  • WBC 19,000
  • Platelets 3 lakh
  • Normal LFTs
  • Normal triglycerides
  • Ferritin 8000 with high ESR and CRP
• Points against HLH/MAS: normal platelets, LFTs, and triglycerides. This could still change, so repeat the labs every 24 to 48 hours.
• What keeps lymphoma on the list: anemia and HSM. Her WBC and platelets are normal or high, which makes marrow failure less likely, but it does not exclude lymphoma. Do the smear, LDH, CT, and node or marrow biopsy before steroids.

Scoring against Yamaguchi and HLH-2004

Yamaguchi criteria (AOSD)

• Confirmed now: 2 minor criteria, plus the WBC count itself.
• Provisional (fever, rash, and WBC differential confirmed): 5 criteria with 3 major, which meets the cutoff.
• Result: probable AOSD that needs confirmation of the three major items, and exclusion of infection, lymphoma, and other rheumatic disease.

HLH-2004 criteria

Data that would settle this

1. Temperature chart with the pattern and peak (Yamaguchi, fever).
2. Joint history and examination (Yamaguchi, arthralgia).
3. Rash description and timing, ideally a photo taken during a fever spike.
4. WBC differential (neutrophil percentage).
5. LDH, fibrinogen, repeat fasting triglycerides, Hb value (HLH, MAS, and the lymphoma workup).
6. ANA, RF, and glycosylated ferritin (Yamaguchi, Fautrel).
7. Soluble CD25 and NK activity (HLH-2004), if available.
8. Marrow and imaging to exclude lymphoma, leukemia, and infection.

Updated scoring

Yamaguchi criteria

HLH-2004

Clinical points about this fever

• Pattern matters. AOSD classically gives a quotidian or double-quotidian fever of 39°C or more, with a return to normal (or near normal) between spikes. A fever that never falls is more worrying for infection, lymphoma, or HLH. Look at the chart over several days.
• Recheck for infection. Temperatures of 104 to 105°F in a febrile teen with HSM make bacterial sepsis, typhoid, malaria, endocarditis, TB, and EBV important to exclude. Do this before any steroids, and before labeling it as AOSD.
• Cooling. Use paracetamol and tepid sponging. NSAIDs also help in AOSD. Temperatures near or above 106°F (41.1°C) need urgent active cooling.
• Admit and monitor if she has not already been: vitals, hydration, urine output, and mental status.

Still needed to finish the scoring

• ANA (completes the negative ANA/RF minor criterion)
• WBC differential (neutrophil percentage)
• Rash description
• Joint history and examination
• Fever duration and daily pattern
• Fibrinogen, LDH, repeat triglycerides, Hb value
• Blood cultures, smear, and the infection and lymphoma tests listed earlier