Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis, is a rare disorder described primarily in adolescents and young adults. Clinically, it is characterized by lymphadenopathy, fever, and constitutional symptoms, and is often confused with infectious processes, lymphoma, or other autoimmune diseases due to its nonspecific clinical presentation.^1-3

A particularly relevant aspect is its association with systemic lupus erythematosus. Kikuchi-Fujimoto disease may precede, coexist, or develop during the course of systemic lupus erythematosus, and there is significant clinical and histopathological overlap with lupus lymphadenitis, which represents a significant diagnostic challenge.^1,19 Both disorders can share paracortical necrosis, absence of neutrophils, and an abundance of histiocytes and plasmacytoid dendritic cells; however, the presence of hematoxylin bodies and the Azzopardi phenomenon favors a diagnosis of systemic lupus erythematosus.⁴

Correct interpretation of the lymph node biopsy, together with clinical and immunological correlation, is decisive for differentiating between isolated Kikuchi-Fujimoto disease, lupus-associated lymphadenitis, and hematological malignancies, as the therapeutic implications differ substantially. The following is the case of an adolescent with fever, lymphadenopathy, and multisystem deterioration, initially interpreted as lymphoma, in whom an excisional biopsy confirmed Kikuchi-Fujimoto disease and systemic lupus erythematosus was subsequently documented, highlighting the diagnostic and therapeutic challenges of the overlap between Kikuchi-Fujimoto disease and systemic lupus erythematosus.

Case Report

A 15-year-old previously healthy female patient, with a complete vaccination schedule and appropriate weight and height for her age, began in March 2025 with recurrent upper respiratory tract infections treated on an outpatient basis. Concomitantly, she manifested morning arthralgia in bilateral metacarpophalangeal joints, initially treated with nonsteroidal anti-inflammatory drugs, as well as a photosensitive malar rash. In April, she manifested persistent intermittent fever, anorexia, joint limitation, and cervical and inguinal lymphadenopathy, associated with normocytic normochromic anemia. In June 2025, she was evaluated by staff from the Rheumatology service, who prescribed treatment with methotrexate, prednisolone, and hydroxychloroquine due to suspected autoimmune disease.

Subsequently, in the context of hospitalization for pneumonia and severe anemia, imaging studies showed bilateral ground-glass pulmonary infiltrates with areas of consolidation, as well as axillary and inguinal lymphadenomegaly. A complete blood count showed leukopenia and progressive anemia. Bone marrow biopsy showed increased cellularity with erythroid hypoplasia and reactive megaloblastic changes. The initial percutaneous lymph node biopsy suggested non-Hodgkin lymphoma; however, the immunohistochemical study concluded reactive polyclonal lymphoid hyperplasia. In July, a general urine examination reported proteinuria and an active urinary sediment (Table 1). Subsequently, an excisional biopsy of a right posterior cervical lymph node was obtained, the histopathological study of which revealed preserved architecture with foci of necrosis and cellular debris, without the presence of Reed-Sternberg cells or malignant atypia, compatible with necrotizing lymphadenitis (Kikuchi-Fujimoto disease). The histological microphotographs were evaluated by a certified pathologist. Figures 1 to 3

During her hospitalization, the patient presented with oral ulcers, jaundice, a skin rash, and significant elevation of transaminases and direct bilirubin (Figures 4 and 5). She progressed with bilateral pleural effusion, acute respiratory failure, and the need for mechanical ventilation. Positive antinuclear antibodies were documented at a titer of 1:640 (AC-20 pattern), thus meeting the immunological and clinical criteria for systemic lupus erythematosus. Treatment was initiated with high-dose corticosteroids, intravenous immunoglobulin, and subsequently cyclophosphamide for refractory lupus pneumonitis, with initial clinical improvement. The patient was sent to a tertiary care hospital; however, she reported progressive multisystem deterioration and died despite the established treatment.

The main contribution of this case lies in the clinical, evolutionary, and histopathological overlap between Kikuchi-Fujimoto disease and systemic lupus erythematosus. The excisional lymph node biopsy showed findings compatible with histiocytic necrotizing lymphadenitis, which initially allowed the diagnosis of Kikuchi-Fujimoto disease to be established and any hematological malignancy to be ruled out. However, the subsequent evolution, with multisystem involvement, positivity for antinuclear antibodies at high titers, and clinical progression, allowed the concomitant diagnosis of systemic lupus erythematosus to be confirmed. Although both diseases can share paracortical necrosis, absence of neutrophils, and an abundant concentration of histiocytes and plasmacytoid dendritic cells, in the patient in this study, no hematoxylin bodies or the Azzopardi phenomenon were documented—findings characteristic of lupus lymphadenitis—which initially supported the diagnosis of Kikuchi-Fujimoto disease over lupus-associated lymphadenitis.^1,4

Kikuchi-Fujimoto disease is an exceptional disorder, generally benign and self-limiting, with a worldwide distribution and higher prevalence in Asian populations. It usually affects adolescent and young adult patients, typically with acute onset of painful cervical lymphadenopathy, fever, and constitutional symptoms.^1-3 Its clinical spectrum is heterogeneous and is frequently confused with infectious processes, autoimmune diseases, or hematological malignancies, particularly lymphoma, which leads to delays in diagnosis and unnecessary interventions.^3,4 Since its initial description in Japan in 1972, it has been documented in various regions of the world, affecting both children and adults, with a clear predominance in women, although in the pediatric population this gender difference may be less marked.^5-8

The association between Kikuchi-Fujimoto disease and systemic lupus erythematosus has been widely described and represents one of the main diagnostic challenges of the disease. Lupus may precede, coexist, or develop subsequent to Kikuchi-Fujimoto disease, and some authors consider that certain cases represent manifestations of lupus lymphadenitis rather than isolated Kikuchi-Fujimoto disease.^1,4 This distinction is clinically relevant because, while isolated Kikuchi-Fujimoto disease usually resolves spontaneously and responds to supportive treatment or anti-inflammatory drugs, the coexistence with systemic lupus erythematosus implies a higher risk of severe organ involvement and the need for intensive systemic immunosuppression.⁴ In our case, the progression toward respiratory failure, acute kidney injury, and liver involvement reflected high lupus activity that conditioned a torpid clinical course.

From a histopathological point of view, excisional lymph node biopsy remains the gold standard for establishing the diagnosis. Characteristic findings of Kikuchi-Fujimoto disease include apoptotic debris phagocytized by crescent-shaped macrophages, loss of follicular architecture, and mixed infiltrate of lymphocytes, histiocytes, and immunoblasts, with an absence of neutrophils.^1,3 These findings allow it to be differentiated from lymphoma; however, the overlap with systemic lupus erythematosus requires careful interpretation and clinical-serological correlation. In patients with skin or other organ involvement, immunohistochemistry and the clinical context are fundamental to guide the diagnosis.^1,4

Regarding clinical manifestations, in addition to lymphadenopathy, up to one-third of patients with Kikuchi-Fujimoto disease suffer from skin alterations: malar rash, erythematous papules, or macules, which increases confusion with systemic lupus erythematosus.^1,10 Also, neurological manifestations (aseptic meningitis and encephalitis) and rare but serious complications have also been described, for example, hemophagocytic syndrome, pulmonary hemorrhage, and multiple organ failure.^9,11-14 These complications explain the occasional deaths described in the literature, particularly in cases associated with autoimmune diseases.

Recently, cases of Kikuchi-Fujimoto disease associated with SARS-CoV-2 infection or COVID-19 vaccination have been described, supporting the hypothesis of immune activation triggered by viral or vaccine stimuli.^15-19

In general, isolated Kikuchi-Fujimoto disease has a benign and self-limiting course (in weeks or months) and a low rate of recurrence. However, when associated with lupus, the prognosis depends on the degree of lupus activity and organ involvement; patients may even require aggressive immunosuppression and close long-term follow-up. Our case illustrates that the Kikuchi-Fujimoto disease–systemic lupus erythematosus overlap can be associated with severe outcomes, reinforcing the need for prolonged clinical surveillance, multidisciplinary care, and a high index of suspicion in patients with persistent fever, lymphadenopathy, and multisystem deterioration.

The limitations of this study are inherent to its nature as a case report, including its retrospective character and reliance on the electronic medical record, as well as the impossibility of performing genetic studies (HLA or exome), which could have provided additional information. However, it shows relevant clinical evidence by highlighting the diagnostic and therapeutic implications of the overlap between Kikuchi-Fujimoto disease and systemic lupus erythematosus in the pediatric population, particularly in public hospitals with limited resources.

The diagnosis and treatment of patients with Kikuchi-Fujimoto disease require a comprehensive approach and close multidisciplinary collaboration. Although it is considered a benign and self-limiting disease, the course can be complicated and life-threatening when associated with autoimmune diseases, such as systemic lupus erythematosus. In the case presented here, the overlap between Kikuchi-Fujimoto disease and systemic lupus erythematosus was accompanied by a torpid clinical course, with multisystem involvement and death, which underscores the importance of timely recognition of this association.

This report emphasizes the need to maintain a high index of suspicion in patients with persistent fever, lymphadenopathy, and progressive organ deterioration, as well as to perform an exhaustive histopathological and serological evaluation for proper differential diagnosis. Early recognition of the Kikuchi-Fujimoto disease–systemic lupus erythematosus overlap is essential to avoid treatment delays and guide the timely prescription of immunosuppression in severe cases. Prolonged clinical surveillance and close follow-up are decisive for the timely detection of complications and to optimize patient prognosis.