Fever, tender neck nodes and a low white count in a young woman, with antibiotics failing. An interactive case built on the differential and one biopsy.
November 14, 2026 · 18 min
1. The Presentation
A 19-year-old woman has had three weeks of painful swelling on both sides of her neck, worse on the left, with pain referred to the left ear. In primary care she is afebrile with normal vital signs. Both posterior cervical chains hold tender, mobile nodes, the largest about 2 × 1 cm on the left. Ears, throat and tonsils look normal. Rapid streptococcal, influenza and SARS-CoV-2 tests are negative. White-cell count 2900/µL (4000–11,000); haemoglobin and platelets are normal. EBV serology shows past infection, and CMV is nonreactive.
What does the white-cell count add to the picture?
✗ Not quite — the correct answer is highlighted above
Not yet. The EBV result reflects past infection and CMV is nonreactive, so there is no serological evidence of an acute viral cause. A viral trigger is possible, but a low count does not establish one, and this illness turns out to be protracted.
✓ Correct
Bacterial lymphadenitis from staphylococci or streptococci typically comes with local redness and warmth. Leukopenia does not fit that pattern, and it widens the list to viral infection, mycobacterial disease, lymphoproliferative disorders and inflammatory conditions.
✗ Not quite — the correct answer is highlighted above
She has a mildly low white count with a normal haemoglobin and platelet count, and nothing so far points to marrow involvement. The nodes are the obvious place to look for a cause.
✗ Not quite — the correct answer is highlighted above
A normal haemoglobin and platelet count are reassuring about marrow failure, but they do not make a low white count irrelevant. Together with the nodes it is the first hint that this is not routine lymphadenitis.
2. Ultrasound and a First Treatment
Neck ultrasound shows mildly enlarged oval nodes with preserved fatty hila and increased vascularity. In the left lower jugular chain (level IV) they are clustered, with indistinct margins and swollen fat around them. There is no drainable collection. She is given amoxicillin–clavulanate, ibuprofen and paracetamol, but the pain persists. Four days before admission she develops fever up to 39.5°C, drenching night sweats and exhausting fatigue, and attends the paediatric emergency department.
How should the lack of response to antibiotics be read?
✗ Not quite — the correct answer is highlighted above
Escalating the same strategy without a new reason is the trap here. The ultrasound shows no collection to drain, and persistence on broad-spectrum therapy is itself information.
✗ Not quite — the correct answer is highlighted above
Drainage needs a collection, and the ultrasound found none. The clustered nodes and perinodal swelling describe an inflamed nodal group, not an abscess.
✓ Correct
Staphylococcal and streptococcal lymphadenitis typically shows local redness and warmth, and a fever that persists through broad-spectrum antibiotics makes it unlikely. With no pus to drain, attention shifts to other causes.
✗ Not quite — the correct answer is highlighted above
Reassurance is premature. She now has fever with drenching sweats and debilitating fatigue after weeks of node swelling, which is not the course of a simple reactive node.
3. The Emergency Department
Temperature 38.3°C, pulse 71 a minute, other vital signs normal. She has shaking chills under several blankets. The neck nodes are tender and neck movement is normal. White-cell count 2710/µL, haemoglobin 11.5 g/dL (12.0–16.0), platelets normal. The chest radiograph shows no lung disease and no hilar or mediastinal widening. Blood cultures are drawn, vancomycin, ampicillin–sulbactam and fluids are started, and she is admitted to paediatrics.
On the ward, which step is likely to give the most information with the least risk?
✗ Not quite — the correct answer is highlighted above
Glucocorticoids are kept for later, once infection and cancer have been ruled out. Starting them now would treat one hypothesis before the others are excluded.
✗ Not quite — the correct answer is highlighted above
She has a mildly low white count and a mild anaemia, with no blasts and no other significant cytopenias. Marrow involvement is unlikely, and simpler steps come first.
✓ Correct
The cheapest information is still unrecorded. A full systematic enquiry can help separate infection, malignancy and rheumatic disease, and in this case it does.
✗ Not quite — the correct answer is highlighted above
A plain film already showed no hilar or mediastinal widening. Daily films add radiation without answering the question.
4. The Fuller History
She reports persistent fever and fatigue, aching in both wrists and proximal interphalangeal joints without swelling, and tenderness over the left Achilles tendon. She has no cough, rash, mouth or genital ulcers, dry eyes or mouth, Raynaud phenomenon, hair loss, diarrhoea or abdominal pain. She has anxiety, treated with sertraline. She was raised in Canada and now lives in Massachusetts with her mother and two dogs. She has not travelled outside New England except to Canada, has no tuberculosis contacts, is not sexually active and uses no alcohol, tobacco or drugs. Her mother has Graves disease, and a cousin has juvenile rheumatoid arthritis.
Which part of this history points most firmly away from a purely infectious illness?
✗ Not quite — the correct answer is highlighted above
Cat scratch disease comes from kittens and cats, and she has no such exposure. Dogs are a low-yield thread here.
✗ Not quite — the correct answer is highlighted above
The only travel outside New England was to Canada, which does not add an unusual exposure. It is not the discriminating feature.
✓ Correct
Wrist and PIP joint pain with an irritable Achilles insertion suggests an inflammatory process, and a family history of Graves disease and juvenile arthritis nudges in the same direction. None of this is specific, but it turns a fever-and-nodes problem into a rheumatic one worth pursuing.
✗ Not quite — the correct answer is highlighted above
This lowers the likelihood of gonococcal and other sexually transmitted causes, which is useful, but it does not point towards any other diagnosis. It narrows the infectious list without opening a rheumatic one.
5. The Examination
Oral temperature 38.4°C, blood pressure 110/56, pulse 95, respiratory rate 20, oxygen saturation 100% on air; weight 48.3 kg (BMI 20.5). She looks tired but is not in distress. The throat is clear with no mouth ulcers and the neck is supple. Nodes are palpable on both sides in the cervical chains, with new submandibular and supraclavicular nodes, none fluctuant. There are no axillary, epitrochlear or inguinal nodes. Heart, lungs and abdomen are unremarkable. The wrists, PIP joints and left Achilles tendon are tender without synovitis. No rash.
How is the musculoskeletal examination best described?
✗ Not quite — the correct answer is highlighted above
No synovitis was found. The joints are tender, but there is no swelling, so a diagnosis of inflammatory arthritis is not supported by the examination.
✗ Not quite — the correct answer is highlighted above
The tenderness sits over the Achilles tendon, with no joint swelling, and there are multiple sites. A single septic joint would look very different.
✓ Correct
Pain without synovitis is arthralgia. Tenderness over the left Achilles tendon suggests inflammation at the enthesis, which raises the possibility of a seronegative spondyloarthropathy.
✗ Not quite — the correct answer is highlighted above
Her review of systems was negative for myalgia, and the tenderness is localised to joints and a tendon. Attributing it to a viral-type ache ignores that.
6. First Laboratory Results
CRP 25.5 mg/L (under 8) and ESR 38 mm/h (0–19). Neutrophils 1450/µL, lymphocytes 1030/µL, haemoglobin 11.5 g/dL, platelets 221,000/µL. AST 62 and ALT 57 U/L are both raised, and LDH is 732 U/L (110–210). Creatinine, uric acid, C3 and C4 are normal, and so is the ferritin (172 µg/L). Urinalysis is bland. ANA, ANCA, anti-CCP and rheumatoid factor are negative. Blood cultures show no growth; HIV antigen/antibody, syphilis, hepatitis B and C, and an interferon-γ release assay are negative.
Which result is most useful for setting aside two specific inflammatory mimics?
✗ Not quite — the correct answer is highlighted above
LDH is a non-specific marker. It can rise in lymphoproliferative disease, but EBV and CMV infection also raise LDH, AST and ALT. It cannot carry a diagnosis by itself.
✗ Not quite — the correct answer is highlighted above
Negative cultures do not prove that nothing infectious is going on. The team went on to test for tularaemia, Lyme disease, bartonellosis and toxoplasmosis as well.
✓ Correct
A raised ferritin is typical of systemic juvenile idiopathic arthritis (Still’s disease) and of macrophage activation syndrome. A normal level has a high negative predictive value, so both become much less likely, and secondary haemophagocytic disease would also usually come with a high ferritin.
✗ Not quite — the correct answer is highlighted above
They show that inflammation is present, but they do not point to a cause.
7. Computed Tomography
Contrast CT of the neck and chest shows diffuse enlargement of left cervical and supraclavicular nodes with fat stranding around them. One lower jugular node is heterogeneous inside, suggesting evolving necrosis. There are no axillary or mediastinal nodes and the lungs are clear. Fever persists on broad-spectrum antibiotics.
What is the most appropriate next step?
✗ Not quite — the correct answer is highlighted above
She has already failed antimicrobial therapy and the infectious tests are negative, so more antibiotics and repeat imaging will not move the diagnosis.
✗ Not quite — the correct answer is highlighted above
She has no tuberculosis risk factors, a negative interferon-γ release assay and a normal chest CT. Treating without tissue would also leave the diagnosis unproven.
✗ Not quite — the correct answer is highlighted above
Glucocorticoids are kept for later, once infection and cancer have been ruled out. At this point it is not yet known which of those she has.
✓ Correct
Persistent fever, necrotic-looking nodes and an unrevealing non-invasive workup call for tissue. A single specimen can address infection, lymphoproliferative disease and specific inflammatory patterns together.
8. The Differential: Infection
While tissue is arranged, the team works through the differential. Infection comes first: bacterial lymphadenitis, cat scratch disease (Bartonella), gonococcal pharyngitis, EBV, CMV, acute HIV, and tuberculosis or non-tuberculous mycobacteria. Cultures, serologies and the antibiotic trial have each been unrewarding.
Which combination of findings argues most against tuberculous lymphadenitis (scrofula)?
✗ Not quite — the correct answer is highlighted above
These occur in tuberculosis, so they do not argue against it. The case against rests on other features.
✓ Correct
Scrofula tends to enlarge slowly, here the nodes swelled over weeks. With no epidemiological risk, a negative interferon-γ release assay and a clear chest CT, tuberculosis becomes unlikely. Non-tuberculous mycobacterial nodes are also commoner in children and in immunocompromised people than in healthy young adults.
✗ Not quite — the correct answer is highlighted above
A negative HIV antigen–antibody test makes acute HIV unlikely, but it says nothing about whether a mycobacterium is present.
✗ Not quite — the correct answer is highlighted above
Leukopenia broadens the differential and does not discriminate tuberculosis from the other possibilities. The case against it rests on the tempo of nodal growth, risk factors and test results.
9. The Differential: Cancer
Malignancy stays on the list because of fever, persistent nodes and a high LDH. Hodgkin lymphoma peaks between ages 15 and 29. Non-Hodgkin lymphomas and acute leukaemias are less common or less likely in this age group and with this blood picture.
Which findings most weigh against Hodgkin lymphoma in her case?
✗ Not quite — the correct answer is highlighted above
Her age fits the peak incidence for Hodgkin lymphoma. If anything it raises the pre-test probability.
✗ Not quite — the correct answer is highlighted above
These are classic “B symptoms”, so they fit lymphoma and do not argue against it.
✓ Correct
Most patients with Hodgkin lymphoma have thoracic or mediastinal nodal disease, and she has none, and her uric acid is normal. Both make the diagnosis unlikely, but neither excludes lymphoma, which is why tissue is still needed.
✗ Not quite — the correct answer is highlighted above
ANA is an autoimmune test and says nothing useful about lymphoma.
10. The Differential: Rheumatic Disease
Inflammatory conditions are next. Kawasaki disease is a disease of young children. Felty syndrome needs long-standing seropositive rheumatoid arthritis and splenomegaly. Sarcoidosis nearly always shows chest imaging abnormalities. Still’s disease is unlikely with a normal ferritin, and reactive arthritis has no preceding infection. Systemic lupus matches the picture best: fever, nodes, arthralgia, leukopenia and raised transaminases.
Why is SLE set aside at this stage?
✗ Not quite — the correct answer is highlighted above
It can. Lymphadenopathy is part of the lupus constellation the team lists for this patient, so the reasoning cannot rest on that.
✗ Not quite — the correct answer is highlighted above
Age is not the reason given. Her fever, nodes, arthralgia, leukopenia and raised transaminases all fit SLE, and the negative ANA is what counts against it.
✓ Correct
A negative ANA makes SLE unlikely. Rare biopsy-proven ANA-negative cutaneous lupus exists, but with a systemic illness the negative result should be accepted at face value. The team is left with an SLE-like picture and no lupus, and that is worth pausing on.
✗ Not quite — the correct answer is highlighted above
It is not. ANA-negative cases have been reported, especially in cutaneous disease, so the reasoning is about probability in this patient, not an absolute rule.
11. The Leading Diagnosis
Fever, cervical lymphadenopathy and leukopenia in a young adult is the classic triad of Kikuchi–Fujimoto disease, also called histiocytic necrotizing lymphadenitis. It is rare, usually self-limited and of unknown cause, thought to follow an exaggerated immune response to a viral trigger such as human herpesvirus 6 or 8, EBV or parvovirus B19. The nodes may or may not be painful, are usually unilateral, and can look necrotic on imaging, which can be mistaken for cancer.
How is Kikuchi–Fujimoto disease confirmed?
✗ Not quite — the correct answer is highlighted above
These point to lupus, which is a mimic, and a negative ANA here argues against it. They do not confirm this disease.
✗ Not quite — the correct answer is highlighted above
Several viruses have been proposed as triggers, but no virological test confirms the diagnosis. Testing mainly serves to exclude active infection.
✗ Not quite — the correct answer is highlighted above
Necrosis on imaging is the very feature that can be mistaken for cancer. It raises suspicion without proving anything.
✓ Correct
The diagnosis is histological. Ultrasound-guided aspiration is sometimes enough, but excisional biopsy is generally preferred because it preserves nodal architecture, shows the histology, and lets lymphoproliferative disease be ruled out in the same specimen.
12. The Biopsy
Fine-needle aspiration and core biopsy of a left neck node yield little: the core shows only clot and the aspirate is paucicellular. A few macrophages are odd, with crescent-shaped, sharply angulated nuclei pushed aside by nuclear debris, unlike ordinary tingible-body macrophages. A cell block shows a focus of necrosis. Because the material is limited, an excisional biopsy is done a few days later.
Which histological pattern in the excised node best fits the diagnosis?
✗ Not quite — the correct answer is highlighted above
That points to infections such as plague, tularaemia, cat scratch disease, lymphogranuloma venereum and some mycobacterial and fungal infections. The absence of neutrophils is one of the features that separates this disease from them.
✗ Not quite — the correct answer is highlighted above
Granulomas suggest sarcoidosis, certain infections, a foreign-body reaction or some tumours. None were seen.
✓ Correct
This is the histological signature of Kikuchi–Fujimoto disease. Stains for CMV, EBV and HSV, acid-fast and silver stains, cultures, flow cytometry and immunohistochemistry were all negative, so infection and lymphoproliferative disease were excluded as well.
✗ Not quite — the correct answer is highlighted above
That would indicate a lymphoproliferative process. Flow cytometry and immunostaining in this case showed none.
13. Treatment
Kikuchi–Fujimoto disease is most often benign and self-limited, lasting one to four months. She still has fever, fatigue and joint pain, and treatment should control symptoms without compromising investigation of other diseases not yet fully excluded.
What is the usual treatment approach?
✗ Not quite — the correct answer is highlighted above
Lupus has been set aside, so treating it would give her drugs she does not need. Hydroxychloroquine is used as a glucocorticoid-sparing option for patients with multiple recurrences.
✓ Correct
NSAIDs treat pain and fever. Glucocorticoids are for severe symptoms or when control is insufficient, and only after infection and malignancy are ruled out. The best duration is not established, with a mean of about three to five weeks.
✗ Not quite — the correct answer is highlighted above
Antimicrobials are not treatment for this disease, and she already failed them. Biopsy, cultures and stains excluded the common infections.
✗ Not quite — the correct answer is highlighted above
Necrosis looked ominous on CT, but biopsy showed no malignancy, so there is nothing for chemotherapy to treat.
14. Looking Ahead
After the biopsy she takes naproxen for two weeks. Three days after discharge her fever has gone, and it does not return. The nodes do not come back.
What should her follow-up take into account?
✗ Not quite — the correct answer is highlighted above
Recurrence is reported in somewhere between 3% and over 40% of patients, depending on how it is defined. Risk factors include childhood onset, autoimmune disease and symptoms lasting more than two weeks, and she had symptoms for about three weeks.
✗ Not quite — the correct answer is highlighted above
A single negative ANA at presentation is not a lifetime guarantee. Her negative test only addresses the present, and later SLE can still appear.
✓ Correct
Around 3% of patients have SLE, the commonest associated autoimmune disease. In about a third of people with both, SLE develops after the nodal illness, often years later, which supports a shared predisposition. Still’s disease and mixed connective-tissue disease are also associated.
✗ Not quite — the correct answer is highlighted above
Recurrence and later autoimmune disease are real possibilities, so planned follow-up with autoantibody checks is reasonable even when the acute illness has resolved.
15. Outcome and Take-Aways
Outcome. At five months she was well and her repeat ANA was negative. A rheumatology visit was booked for a year later (17 months after symptom onset), with autoantibody monitoring for early signs of SLE.
Take-aways
Fever, tender cervical nodes and leukopenia in a young adult is the classic triad for Kikuchi–Fujimoto disease, but it must be diagnosed after infection and malignancy are excluded.
Failure of antibiotics, necrotic-looking nodes and an unrevealing non-invasive workup mean the next step is tissue, and an excisional biopsy is preferred over aspiration.
A normal ferritin argues against Still’s disease and macrophage activation syndrome, and a negative ANA in a systemically ill patient argues against lupus.
The histology is characteristic: paracortical necrosis with karyorrhectic debris, crescentic histiocytes, and no neutrophils or granulomas.
Treatment is symptomatic: NSAIDs first, with glucocorticoids reserved for severe or uncontrolled disease once infection and cancer are excluded.
It can recur, and it can precede SLE. About 3% of patients have SLE, and in about a third of those the lupus appears after the nodal illness, so rheumatology follow-up with autoantibody checks is worthwhile.