Kikuchi–Fujimoto Disease Presenting with Prolonged Fever and Severe Anaemia: A Diagnostic Challenge

Summary

Kikuchi–Fujimoto disease (KFD) is a rare, benign, self-limiting necrotizing lymphadenitis that predominantly affects young adults and commonly presents with fever and cervical lymphadenopathy^1–3. Severe anaemia is unusual and may lead to diagnostic confusion with lymphoma, tuberculosis, or systemic inflammatory disorders ^3,4

Case Presentation: A 19-year-old male presented with a month of high-grade fever, progressive fatigue, and right cervical lymphadenopathy. Investigations revealed severe anaemia, markedly elevated inflammatory markers, lymphopenia, and hepatosplenomegaly. Excisional lymph node biopsy demonstrated necrotizing lymphadenitis consistent with Kikuchi–Fujimoto disease, with immunohistochemistry excluding lymphoma and EBV-associated disease. The patient was found to have moderate glucose-6-phosphate dehydrogenase (G6PD) deficiency, which likely contributed to haemolysis during the prolonged inflammatory state. Intravenous methylprednisolone resulted in rapid defervescence and clinical improvement.

This case highlights Kikuchi–Fujimoto disease as an important differential diagnosis in young patients with prolonged fever and lymphadenopathy, even when complicated by severe anaemia. Coexisting G6PD deficiency may exacerbate anaemia during inflammatory stress and should be considered in endemic regions.

Case Report

A 19-year-old previously healthy male presented with a one-month history of high-grade intermittent fever associated with progressive weakness and painful right cervical lymphadenopathy. There was no history of weight loss, night sweats, tuberculosis exposure, recent drug intake, or autoimmune disease. Physical examination revealed marked pallor, tender enlarged right cervical lymph nodes, and hepatosplenomegaly. Initial laboratory investigations showed severe anaemia with hemoglobin levels ranging from 5.9 to 7.0 g/dL, mild lymphopenia, and normal to elevated platelet counts. Erythrocyte sedimentation rate and C-reactive protein were markedly elevated, indicating significant systemic inflammation. Lactate dehydrogenase was raised. Peripheral blood film revealed microcytosis, target cells, and fragmented red blood cells. Reticulocyte count was increased, suggesting an appropriate marrow response. IGRA and antinuclear antibody testing were negative, and infectious workup including dengue and viral hepatitis (HBV, HCV) serology, retro antibody were also unremarkable. Ultrasonography of the abdomen demonstrated hepatosplenomegaly, while neck imaging showed multiple enlarged cervical lymph nodes. Chest radiography was normal. Given the persistent fever and lymphadenopathy, an excisional lymph node biopsy was performed. Histopathological examination revealed patchy areas of necrosis with abundant karyorrhectic debris, numerous histiocytes, plasmacytoid dendritic cells, and scattered immunoblast-like cells, with an absence of neutrophils and granuloma formation—features characteristic of Kikuchi–Fujimoto disease^4,5. Immunohistochemistry showed CD3-positive reactive T-cell predominance, with negative staining for CD20, CD30, CD56, and EBV latent membrane protein-1, effectively excluding lymphoma and EBV-associated lymphoproliferative disorders ^5,7. Further evaluation identified moderate glucose-6-phosphate dehydrogenase deficiency. Given the prolonged fever, systemic inflammatory response, and severe anaemia, intravenous methylprednisolone was initiated. The patient exhibited dramatic defervescence within 24 hours, with subsequent improvement in clinical condition and laboratory parameters. He was transitioned to oral corticosteroids with a gradual taper and remained stable on follow-up.

Fig 1. Histopathology and IHC stain of cervical lymph node biopsy of patient.

Table (1) Investigation parameters of patient

Table (2) Investigation parameters of patient

Discussion

Kikuchi–Fujimoto disease is an uncommon inflammatory condition first described in Japan in 1972 and is characterized by necrotizing lymphadenitis with a predilection for young adults ^1,2. Although its aetiology remains unclear, current evidence supports an immune-mediated process driven by cytotoxic T lymphocytes, possibly triggered by viral infections such as Epstein–Barr virus, human herpesvirus-6, or other viral agents ^4–6. The clinical presentation of KFD often overlaps with lymphoma, tuberculosis, and systemic autoimmune diseases, making histopathological confirmation essential ^3,4. The absence of neutrophils and granulomas, along with the presence of histiocytic necrosis and karyorrhectic debris, are key diagnostic features that help distinguish KFD from other causes of necrotizing lymphadenitis. The major differential diagnoses of necrotizing lymphadenitis include lymphoma, tuberculous lymphadenitis, and systemic lupus erythematosus. Kikuchi–Fujimoto disease is distinguished histologically by patchy necrosis with abundant karyorrhectic debris, crescentic histiocytes, and a conspicuous absence of neutrophils. Immunohistochemistry demonstrates a reactive polyclonal T-cell predominance, effectively excluding lymphoma. The absence of granulomas and acid-fast bacilli rules out tuberculosis, while negative autoimmune serology and lack of plasma cell predominance help exclude lupus lymphadenitis.^5,7Anaemia in Kikuchi disease is typically mild; however, severe anaemia has been reported in a small number of cases, often associated with prolonged inflammation or hemophagocytic activity ⁸. In this patient, anaemia was multifactorial. Chronic inflammation likely caused anaemia of inflammation through cytokine-mediated hepcidin upregulation, iron sequestration, and suppression of erythropoiesis ^9,10. Additionally, the presence of moderate G6PD deficiency likely exacerbated haemolysis during the prolonged febrile and inflammatory state, contributing to the severity of anaemia observed^11. Hepatosplenomegaly may have further worsened anaemia through splenic sequestration. Corticosteroids are not routinely required in Kikuchi disease but are recommended in severe or refractory cases with prolonged fever, extensive lymphadenopathy, or significant systemic involvement ^4,13. The rapid defervescence observed after intravenous methylprednisolone in this patient supports the cytokine-driven pathogenesis of the disease and is consistent with previous reports ^13,14.

Table (3). Key histological differences in necrotizing lymphadenitis ¹⁵

Table (4) Difference Immunohistochemistry patterns in necrotizing lymphadenitis ¹⁶

Conclusion

Kikuchi–Fujimoto disease should be considered in young patients presenting with prolonged fever and cervical lymphadenopathy, even in the presence of severe anaemia. Coexisting conditions such as G6PD deficiency may exacerbate haemolysis during inflammatory stress and complicate the clinical picture. Early lymph node biopsy with immunohistochemistry is crucial to exclude malignancy and guide appropriate management. Prompt recognition of this benign condition can prevent unnecessary invasive investigations and ensure favorable outcomes.

References

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Author Information

Aye-Mya-Theingi-Win¹, Khin-Rupar-Ko², Aye-Aye-Win³, May-Zabe⁴, Nyunt Thein⁵

1. Senior Consultant physician, Tropical and Infectious Diseases Department, Yangon General Hospital
2. Professor, Tropical and Infectious Diseases Department, Yangon General Hospital
3. Associate Professor, Tropical and Infectious Diseases Department, University of Medicine (1), Yangon
4. Senior Consultant Physician, Tropical and Infectious Diseases Department, Yangon General Hospital
5. Senior Consultant Physician, Former Head of Department of Medicine, Emeritus Professor of Medicine, University of Medicine (1), Yangon