Kikuchi-Fujimoto disease,simultaneously diagnosed with systemic lupus erythematosus in an Arabic female: an agonizing combination

Abstract

Kikuchi–Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare, benign condition affecting young Oriental-Asian females. It is characterized by fever and tender cervical lymphadenopathy with an unclear aetiology, and in most longitudinal reviews, KFD occurs before systemic lupus erythematosus (SLE). Herein, the case of a 28-year-old Kuwaiti female without any relevant past medical history, who was simultaneously diagnosed with KFD and SLE following an Ebstein–Barr virus infection, is reported. The patient was treated with oral prednisolone, hydroxychloroquine, cyclosporin, and belimumab and her response was clinically and biochemically favourable. Although KFD is prevalent in Asian populations, it may affect all races. Early diagnosis of KFD is difficult, particularly when simultaneously diagnosed with SLE, but crucial to preventing inappropriate therapy. Clinicians need to know about this rare disease, especially when patients present with fever and swollen lymph nodes, due to a risk of misdiagnosis with tuberculosis or lymphoma, as these are more often thought to be the cause of such symptoms.

Introduction

Kikuchi–Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare benign subacute disease. Fever and tender cervical lymphadenopathy are the most common clinical signs of KFD, ¹ and it usually affects young females of Asian origin. Although environmental variables, particularly viruses, have been postulated, the aetiology of KFD remains unclear. ² Patients with KFD might present with symptoms that resemble those of lymphoma, tuberculosis (TB), and other autoimmune disorders; hence, diagnosing KFD is crucial to prevent inappropriate therapy.^3,4 Here, the case of a 28-year-old Kuwaiti female who was simultaneously diagnosed with KFD and systemic lupus erythematosus (SLE) following an Ebstein–Barr virus (EBV) infection, is presented.

Case presentation

A 28-year-old Kuwaiti female, with unremarkable personal or family history, presented with 21 days of high-grade fever (39 °C) that responded poorly to antipyretics and was associated with easy fatiguability and tender enlargement of cervical lymph nodes. She also reported severe polyarthralgia of the shoulders and hands, along with a facial rash. There was no history of weight loss, nighttime sweets, oral ulcerations, hair loss, photosensitivity, or haematuria.

On physical examination, the patient appeared ill with otherwise normal vital signs. She had bilaterally enlarged cervical and axillary lymph nodes, the largest of which measured around 5 cm. The nodes were solid, tender, and nodular. All of the metacarpophalangeal joints, proximal interphalangeal joints, wrist, and shoulder joints also showed symmetrical tenderness and synovitis. Cutaneous lesions were noted over the forehead, nose, and external ears (Figure 1), which was not consistent with cutaneous lupus erythematosus. The precordium, abdomen, neurological system, and respiratory system were all examined and found to be normal.

Figure 1.

Images showing dermatological changes to the forehead, nose, and external ears in a 28-year-old Kuwaiti female patient who presented with high grade fever over the previous 21 days and tender enlarged cervical lymph nodes.

Laboratory tests showed leukopenia, mild normocytic normochromic anaemia, an increase in erythrocyte sedimentation rate (ESR), C-reactive protein, lactate dehydrogenase (LDH), and aspartate aminotransferase (AST), and markedly elevated D-dimer and ferritin (Table 1).

Table 1.

Laboratory data from a 28-year-old Kuwaiti female patient upon admission, and 8 weeks after discharge.

		Time-point
Parameter	Reference range	Admission	8 weeks after treatment
White blood cell count (×109/L)	4.5–11.0	2.50	10.25
Lymphocyte (×109/L)	1.0–4.0	0.49	2.24
Hemoglobin (g/L)	121–151	106	129
Hematocrit (L/L)	0.36–0.46	0.35	0.38
Platelets (×109/L)	150–400	161	358
Reticulocyte count (%)	0.5–1.5	1.1	0.8
Na (mmol/L)	138–145	139	138
K (mmol/L)	3.6–4.8	4.5	4.7
Creatinine (mg/dL)	0.46–0.79	0.51	71
ALT (U/L)	7–23	51	14
AST (U/L)	13–30	80.7	24
Triglyceride (mmol/L)	1.8–2.2	1.9	0.78
LDH (U/L)	124–222	535	208
CPK (µg/L)	10–120	45	43
Albumin (g/L)	35–55	30.8	40
D-dimer (µg/L)	<250	943	194
Ferritin (ng/mL)	6.2–138	2047	207
Fibrinogen (g/L)	2–4	3.4	3.89
CRP (mg/dL)	<10	123	9.7
ESR (mm/h)	22	114	34
C3 (g/L)	0.90–1.80	1.32	1.57
C4 (g/L)	0.10–0.40	0.29	0.40
Antinuclear antibody	<1: 40	1: 640 (Speckled)	1: 640 (Speckled)
Anti-RNP (U)	1–20	Negative	—
Anti-Jo-1 (AU/ml)	1–20	Negative	—
Anti-dsDNA antibody (IU/ml)	<20	44	8
Anti-Sm (U/mL)	<7	Negative	—
Anticardiolipin antibody (U/mL)	<10	Negative	—
Lupus anticoagulant	<1.3	Negative	—
Rheumatoid factor (IU/ml)	<20	18	—
Anti-CCP antibody (U/mL)	<20	7	—
24-h urine protein (g/day)	0.0–0.16	0.38	0.13
Urine R/M	—	Protein +	Normal
Direct Coombs test	—	Positive	—
Indirect Coombs test	—	Negative	—

ALT, alanine transaminase; AST, aspartate aminotransferase; CCP, cyclic citrullinated peptides; C3, complement C3; C4, complement C4; CPK, creatine phosphokinase; CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; RNP, ribonucleoprotein; Sm, Smith; R/M, routine/microscopy.

The variables included for differential diagnosis were SLE and other collagen disorders, viral infection, sepsis, hemophagocytic lymphohistiocytosis (HLH), TB, and lymphoma. However, in part because of their striking parallels, the diagnosis proved challenging. Further workup showed that the patient had antinuclear antibodies 1/640 (speckled pattern), and was also positive for anti-double-stranded (ds)-DNA antibodies, with a positive direct antiglobulin (Coombs) test. However, results for extractable nuclear antigens, complement C3, complement C4, rheumatoid factor, anti-cyclic citrullinated peptides, and antiphospholipid antibodies were all normal. A 24-h urine protein test revealed proteinuria in the subnephrotic range (0.38 g/24 h), while fibrinogen and triglyceride levels were normal. Positive immunoglobulin (Ig)G and IgM antibodies against EBV were found at moderate titres. EBV DNA by quantitative polymerase chain reaction, severe acute respiratory syndrome coronavirus 2, hepatitis B and C viruses, herpes simplex virus, coxsackievirus, cytomegalovirus, human immunodeficiency virus, parvovirus B19, toxoplasma, and Mantoux tuberculin skin test were all found to be negative in several blood and urine cultures and panels. The patient had an HScore of 129, suggesting only a 5–9% probability of having HLH. ⁵

The patient was diagnosed with SLE based on the presence of a European League Against Rheumatism/American College of Rheumatology criteria score of 18 and 5/17 Systemic Lupus International Collaborating Clinics criteria, ⁶ featuring leukopenia, a positive Coombs test, antinuclear antibodies and anti-dsDNA antibody positivity, arthritis, and fever, with mild to moderate activity of the disease (Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA]-Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score of 10 points). ⁷ Neck ultrasound revealed marked left cervical adenopathy, while abdominal ultrasonography, chest X-ray, and echocardiography were normal. Contrast-enhanced computed tomography (CECT) of the neck, thorax, and abdomen was suggestive of multiple heterogeneously enhanced necrotic bilateral cervical nodes, the largest measuring approximately 1.3 × 1.4 cm, and axillary lymph nodes, the largest measuring approximately 1.9 × 2.8 cm and showing inhomogeneous cortical thickening (Figure 2).

Figure 2.

Axial plane contrast-enhanced computed tomography (CECT) images from a 28-year-old Kuwaiti female patient showing: (a) neck CECT with numerous discrete cervical inflamed lymph nodes, mainly on the left side (small arrow); and (b) chest CECT with numerous discrete axillary inflamed lymph nodes, mainly on the left side (large arrow).

An excisional biopsy of the cervical lymph node showed extensive eosinophilic coagulative necrosis, which was surrounded by foamy macrophages (CD68+) and many karyorrhectic bodies. There was a predominance of CD8+ cells over CD4+ cells. In addition, rare plasma cells were noted, but there was no evidence of eosinophils or neutrophils (Figure 3), which is consistent with KFD. ² Additionally, the biopsy showed reactive lymphoid follicular tissue that extended beyond the lymph node capsule. Stains for fungal, bacterial, and mycobacterial organisms were negative, in addition to in situ hybridization for EBV and cytomegalovirus.

Figure 3.

Histopathological features in haematoxylin and eosin-stained cervical lymph node biopsy tissue sections from a 28-year-old Kuwaiti female patient, showing: (a) nodularity of the lymph node with zones of necrosis (low-power view); (b) areas of necrosis (at the right) surrounded by foamy macrophages (high power view); and (c) sheets of histiocytes and karyorrhectic bodies replacing the node, with no evidence of other inflammatory components.

Based on the above findings, the patient was diagnosed with KFD associated with SLE. Following patient counselling and acceptance, she was started on 0.5 mg/kg oral prednisolone, daily, along with 5 mg/kg oral hydroxychloroquine, daily, 200 mg/day oral cyclosporin, and 10 mg/kg belimumab, intravenously (i.v.), once every 2 weeks for 3 successive loading doses, followed by a maintenance dose of 10 mg/kg, i.v., once every 4 weeks. After 5 days of commencing treatment, the high-grade fever decreased to intermittent low-grade 37.4 °C, while the arthritis, fatigue, and white blood cell counts were completely resolved. The patient was discharged on a tapering dosage of prednisolone. An outpatient evaluation after 2 months showed that the patient’s inflammatory markers, anaemia, anti-ds-DNA levels, and 24-h urine protein had all returned to normal. The skin rash had also completely resolved, and the patient’s SLE activity had gone into remission (SELENA-SLEDAI score of 0). At 6 months following therapy, the patient remained symptom-free and displayed no probable side effects from taking the prescribed drugs, and the patient reported being satisfied.

The reporting of this study conforms to CARE guidelines. ⁸ Written informed consent was obtained from the patient to publish her anonymized data and the case report did not require ethics committee approval.

Discussion

Dr Seishi Kikuchi, a Japanese scientist, initially discovered KFD as an uncommon benign condition in 1972, ¹ with another independent report on KFD, by Fujimoto et al., published in the same year. ⁹ Numerous studies have demonstrated that in genetically predisposed people, KFD stimulates T cells to elicit an immunological response to many antigens. Patients with KFD have certain alleles of the human leukocyte antigen (HLA) class II, such as HLADPA1 and HLA-DPB1, and Asians are more likely than non-Asians to possess these alleles. ¹⁰ KFD may occasionally be linked to infections with Toxoplasma gondi and Yersinia enterocolitica.^11,12 Additionally, and particularly regarding the present case, EBV may be considered in the aetiology of KFD. ¹³ Patients with SLE have an abnormally elevated EBV load in their blood, which may contribute to enhanced antibody production. Poorly controlled latent EBV infection leads to a 40-fold increase in viral loads compared with controls, possibly due to altered T-cell responses to EBV. ¹⁴ The EBV nuclear antigen-1 (EBNA-1) protein has been shown to be involved in the production of IgG autoantibodies against Sm and ds-DNA. The production of specific autoantibodies against EBNA-1 leads to the production of SLE-specific autoantibodies and this causes a complicated autoimmune response and disease in the body. Thus, EBV is considered an environmental risk factor for SLE. ¹⁵

In a systematic review by Sopeña et al., ¹⁶ KFD was found to occur before SLE in 31% of cases, and in 18% of cases, KFD was found to follow SLE, even though it may coexist with SLE, as in the present case. The most common presentations are fever, cervical lymphadenopathy, night sweats, joint pain, weight loss, and hepatosplenomegaly. Leukopenia, transaminitis, and raised LDH and ESR are common laboratory abnormalities. ¹⁰

Skin involvement is the most common extranodal organ affected in patients with KFD, accounting for 40% of cases. Usually, a nonspecific rash is discovered, which is consistent with the present case. According to small observational studies, more severe cases have been linked to a higher degree of skin involvement. ¹⁷

Fine needle aspiration cytology, which was used to test for KFD, has been associated with 50% of false-negative results, and a lymph node excisional biopsy is the only way to accurately diagnose this disease. ¹¹ KFD typically resolves in 1–4 months with a recurrence rate of 3–4%, ¹² however, coexistence with SLE may result in a more aggressive fatal course, and lead to sudden heart failure, severe sepsis, and HLH, leading to coagulopathy and multiorgan failure. ¹³ KFD has no known effective therapy. If lymph node pain and fever are present together, symptomatic treatments with analgesics, antipyretics, and nonsteroidal anti-inflammatory drugs may be utilized. Glucocorticoids combined with i.v. immunoglobulins may be used to treat patients with more severe or chronic symptoms. ³

Conclusion

Although KFD is most prevalent in Asian populations, it may occur in all races. The present case is the first report of a simultaneous KFD and SLE diagnosis in Kuwait. We hypothesize that KFD and SLE may be two autoimmune diseases that are interrelated, the former being a milder symptom of the latter, or that they may be two separate autoimmune entities connected by the same pathogenetic component, namely EBV infection. KFD and SLE, when diagnosed simultaneously, make an early diagnosis difficult. Clinicians must be extremely knowledgeable about this rare illness in order to properly identify and treat patients, particularly when they present with fever and lymphadenopathy. This is because such patients may be misdiagnosed with TB or lymphoma. The provision of appropriate patient reassurance, education, and long-term follow-up is an evident necessity.