Kikuchi–Fujimoto disease associated with systemic lupus erythematosus complicated with hemophagocytic lymphohistiocytosis: a case report

Kikuchi–Fujimoto disease (KFD) is a rare benign disease characterized by fever and cervical lymphadenopathy. It was initially described by Japanese pathologists Kikuchi and Fujimoto in 1972. Its etiology remains unknown even though various environmental and infectious factors have been suspected [1]. Females are affected more often than males, and the disease is more prevalent in Asia. It can be associated with other autoimmune disorders especially systemic lupus erythematosus (SLE) [1]. Three types of associations between KFD and SLE have been reported: KFD before the occurrence of SLE, the simultaneous occurrence of KFD and SLE, and KFD after the occurrence of SLE [2]. Both KFD and SLE are rarely associated with the life-threatening complication, hemophagocytic lymphohistiocytosis (HLH) [3]. Only a limited number of cases are found in the literature showing an association between KFD and SLE in male patients. Here, we report a rare case of KFD in a Sri Lankan boy, which was complicated with HLH and subsequently met the diagnostic criteria for SLE.

A 17-year-old previously healthy Sinhalese schoolboy presented with high-grade fever associated with chills, rigors, and right-sided cervical lymphadenopathy of 2 weeks’ duration. He also had a loss of appetite following fever onset but there was no significant loss of weight. There was no cough, hemoptysis, night sweats, or contact history of tuberculosis (TB). He denied any arthralgia, rashes, skin eruptions, or alopecia. His bladder and bowel habits were normal. There was no significant travel history or high-risk sexual behavior and he did not have any significant past medical history or significant family history of illnesses. He was initially admitted to the local hospital with fever and lymphadenopathy and he underwent a right-sided cervical lymph node biopsy even though the biopsy report was received later. On day 20 of the fever, he was started on empirical anti-TB treatment, which was stopped after 5 days due to several episodes of loose watery stools. He was admitted to our institution on day 40 of the illness, by which time he had bilateral cervical lumps. On examination he had bilateral firm discrete tender cervical lymphadenopathy and a firm hepatomegaly and mild splenomegaly. The rest of the examination including funduscopy was normal.

The initial laboratory findings are summarized in Table 1.

Urine analysis was normal and repeated blood cultures, urine cultures, and sputum cultures remained sterile. A Mantoux test was negative. A sputum stain for acid-fast bacilli, TB culture, and GeneXpert TB test were negative. The serology for Epstein–Barr virus (EBV), cytomegalovirus (CMV), Toxoplasma, and human immunodeficiency virus (HIV) were negative. Tests for hepatitis B surface antigen and hepatitis C antibody were negative as were antibody tests for Rickettsiae and Brucella.

A transthoracic echocardiogram and transesophageal echocardiogram did not reveal any vegetation. He had a normal chest X-ray (Fig. 1) and high resolution computed tomography (CT) scan of his chest. An ultrasound scan (USS) of his abdomen revealed a fatty liver with hepatomegaly and a prominent spleen. There was no lymphadenopathy.

A blood picture showed normochromic normocytic red cells with a minor population of hypochromic microcytic red cells and mild leukopenia and thrombocytopenia. Lactate dehydrogenase was 608 U/L. The initial antinuclear antibody (ANA) and anti-double-stranded deoxyribonucleic acid (anti-dsDNA) tests were negative and C3 and C4 levels were normal.

The excision biopsy of the cervical lymph node that was done at the local hospital was available at this point and revealed a partially effaced, normal nodal architecture with scattered lymphoid follicles with germinal centers. There were foci comprising necrosis, nuclear debris (Fig. 2), epithelioid histiocytes (Fig. 3), and lymphocytes; these features were compatible with necrotizing lymphadenitis. Immunohistochemistry showed CD20 to be positive in lymphoid follicles, CD3 to be positive in lymphoid cells in the parafollicular region, and myeloperoxidase (MPO) to be positive in histiocyte-like cells. The presence of MPO positivity, necrotic nuclear debris, and absent neutrophil infiltrate strongly favored KFD. Based on the blood picture and lymph node biopsy result, a bone marrow biopsy (Fig. 4) was performed to rule out lymphoproliferative or hematological malignancies. It revealed cellular marrow with mild granulocytic hyperplasia. There was no evidence of hematological malignancies.

His initial treatment with indomethacin and prednisolone 40 mg daily dose led to fever resolution. However, after 8 days, he developed high fever spikes again. A further laboratory evaluation showed elevated serum ferritin, hypertriglyceridemia, and pancytopenia and there was mild hepatosplenomegaly in a repeat USS of his abdomen. The laboratory findings at this point are shown in Table 2.

A repeat bone marrow biopsy was performed to look for evidence of HLH and it revealed hemophagocytosis. The diagnosis of HLH was made at this point according to the HLH 2004 clinical trial diagnostic guidelines [4]. HLH was presumed secondary to KFD.

He was treated with intravenously administered methylprednisolone pulse therapy 1 g daily for 3 days followed by orally administered prednisolone 60 mg/day. He significantly improved with immunosuppression with steroids. Six weeks from the diagnosis of KFD, he complained of blurring of vision. An ophthalmological evaluation revealed bilateral cotton wool spots, retinal bleeds, and choroidal ischemic changes, which were suggestive of SLE. During this period he also developed acute kidney injury, which required hemodialysis. Antiphospholipid screening, which was done to assess his elevated activated partial thromboplastin time (APTT) and thrombocytopenia to rule out catastrophic antiphospholipid syndrome, was negative. His urine protein creatinine ratio revealed subnephrotic range proteinuria. A repeat ANA titer was positive with a titer of 1:160 in the speckled pattern and the C3/C4 levels were low. A renal biopsy was inconclusive, and he declined a repeat renal biopsy. He also developed a maculopapular rash involving his face, ear lobes, and upper limbs. A skin biopsy showed leukocytoclastic vasculitis. The diagnosis of SLE was made according to the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) diagnostic criteria. He was started on hydroxychloroquine in addition to orally administered prednisolone. The orally administered prednisolone dose was gradually tapered to a minimum and he showed remarkable improvement in terms of settling of the fever, reduction in the inflammatory marker erythrocyte sedimentation rate (ESR) of 15 mm/first hour), and improvement of pancytopenia.

For timeline of our patient’s clinical course see Table 3.

KFD is an uncommon benign condition of necrotizing histiocytic lymphadenitis commonly seen in East Asian and Japanese populations, and it was first described by Kikuchi and Fujimoto in 1972 [2]. Males are affected rarely with a male to female ratio of 1:4 [5]. KFD can be associated with other autoimmune disorders especially SLE [2]. A possible viral etiology was proposed particularly due to its self-limiting nature and nonspecific symptoms. Due to its association with SLE, it is important to look for SLE in patients with KFD as the outcomes may differ when it is associated with SLE. It is sometimes recommended to screen for ANA at the diagnosis of KFD and during follow-up, especially in patients with cutaneous lesions, for the early detection of an autoimmune disease [6].

On day 40 from illness onset, our patient was admitted to our institute with fever of unknown origin and with associated lymphadenopathy for further evaluation and treatment. He had an extensive workup as an out-patient to rule out infectious etiologies. Fever and tender cervical lymphadenopathy are the classic presentations of KFD. However, there are many other possible differential diagnoses such as TB, cat scratch disease, leukemia, and lymphoma; they were excluded by history, examination, and investigations including a bone marrow biopsy. An acid-fast bacilli stain of the lymph node was negative as were the CD30 and anaplastic lymphoma kinase (ALK) stains. His initial ANA done as an out-patient was negative. After the exclusion of other possible differential diagnoses for a similar presentation, the diagnosis of KFD was made based on the lymph node biopsy, histology, and immunohistochemistry. KFD is characterized by focal necrosis in the cortical and paracortical areas associated with marked karyorrhexis and proliferation of the distinctive crescentic histiocytes and plasmacytoid monocytes. The absence of granulocytes, plasma cells, and hematoxylin bodies within the lesions may help to differentiate KFD from lupus lymphadenitis [7]. The lymph node biopsy of our patient revealed a normal nodal architecture with focal necrosis and immunohistochemistry features compatible with KFD.

Our patient developed a fever again despite being on prednisolone 40 mg and indomethacin after the initial response to treatment. He also developed pancytopenia with hepatosplenomegaly on day 55. By that time, all the potential infective causes that could precipitate syndromic manifestation were excluded and other rare possibilities such as HLH and macrophage activation syndrome were suspected. Further laboratory testing revealed hypertriglyceridemia and elevated ferritin. A repeat bone marrow biopsy was performed and it showed evidence of hemophagocytosis. Our patient fulfilled the clinical, laboratory, and histopathology (bone marrow) criteria for HLH (Table 4; our patient’s positive findings are highlighted in yellow) and he was started on high-dose steroids.

HLH is a life-threatening disorder characterized by fever, hepatosplenomegaly, cytopenia, and increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system [8]. There are few cases reported with concurrent HLH and KFD and very few reports in which KFD was associated with HLH and SLE simultaneously [7]. There were no case reports on SLE after the onset KFD in a male patient especially with associated HLH to the best of our knowledge. The recognition of this association is of significance for the management of affected patients as they require early intensive immunosuppressive therapy for a favorable outcome [7].

While on high-dose steroids, our patient developed acute kidney injury with proteinuria and leukocytoclastic vasculitis, in addition to the persistent cytopenia and fever. On day 70 SLE was suspected and ANA and complements were tested. SLE was diagnosed on day 70 based on the SLICC criteria [9] for diagnosis of SLE (Table 5). Our patient fulfilled the clinical criteria (thrombocytopenia, leukopenia, and renal failure with proteinuria) and immunological criteria (positive ANA and low complements) with a total of 5 out of 11 criteria.

Several reports have emphasized the importance of the association between KFD and SLE as KFD can precede or coexist with SLE. Because of the clinical and pathological correlation between KFD and SLE, some authors have postulated that KFD may be a clinical feature or an incomplete phase of lupus lymphadenitis. However, there are several case reports of KFD without SLE, which may favor them to be two independent entities that commonly coexist, as happens with most autoimmune diseases in susceptible individuals [2].

One could argue how our patient developed SLE while on immunosuppressive therapy and the answer is not entirely clear. However we could postulate a few things:

Although KFD is uncommon in male patients, it should be considered in patients with lymphadenopathy and fever. The disease can be complicated with HLH and patients need continuous monitoring for the possible development of SLE later in the course.