A homozygous loss-of-function C1S mutation is associated with Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limited inflammatory disease of unknown pathogenesis. Familial cases have been described and defects in classical complement components C1q and C4 have been identified in some patients. MATERIAL AND METHODS: We describe genetic and immune investigations of a 16 years old Omani male, a product of consanguineous marriage, who presented with typical clinical and histological features of KFD. RESULTS: We identified a novel homozygous single base deletion in C1S (c.330del; p. Phe110LeufsTer23) resulting in a defect in the classical complement pathway. The patient was negative for all serological markers of SLE. In contrast, two female siblings (also homozygous for the C1S mutation), one has autoimmune thyroid disease (Hashimoto thyroiditis) and a positive ANA and the other sibling has serology consistent with SLE. CONCLUSION: We report the first association between C1s deficiency and KFD.

Characterization of Kikuchi-Fujimoto Disease in Children and Risk Factors Associated with Its Course.

OBJECTIVE: To outline the characteristics of Kikuchi-Fujimoto disease (KFD) in children and analyze factors associated with severe and recurring courses. METHODS: Electronic medical records of children histopathologically diagnosed with KFD at Seoul National University Bundang Hospital from March 2015 to April 2021 were retrospectively reviewed. RESULTS: A total of 114 cases (62 males) were identified. The mean patient age was 12.0 ± 3.5 years. Most patients came to medical attention with cervical lymph node enlargement (97.4%) and fever (85%); 62% had a high-grade fever (≥39°C). Prolonged fever (≥14 days) was seen in 44.3% and was associated with a high-grade fever (P = .004). Splenomegaly, oral ulcer, or rash was present in 10.5%, 9.6%, and 15.8%, respectively. Laboratory findings showed leukopenia, anemia, and thrombocytopenia in 74.1%, 49%, and 24%, respectively. Sixty percent of cases had a self-limited course. Antibiotics were initially prescribed in 20%. A corticosteroid was prescribed in 40% of patients and was associated with oral ulcer (P = .045) and anemia (P = .025). Twelve patients (10.5%) had a recurrence with a median interval of 19 months. No risk factor for recurrence was identified in multivariable analysis. Clinical characteristics of KFD were similar between our current and previous studies. However, antibiotics use decreased (P < .001); nonsteroidal anti-inflammatory drugs use increased (P < .001), and, although statistically not significant, corticosteroid treatment also increased. CONCLUSIONS: Over a span of 18 years, the clinical characteristics of KFD did not change. Patients presenting with high-grade fever, oral ulcer, or anemia may benefit from corticosteroid intervention. All patients should be monitored for recurrence.

Hemophagocytic lymphohistiocytosis and histiocytic necrotizing lymphadenitis secondary to hemodialysis catheter-related bloodstream infection caused by Corynebacterium Striatum.

BACKGROUND: We herein described the coexistence of hemophagocytic lymphohistiocytosis (HLH) and histiocytic necrotizing lymphadenitis, alternatively known as the Kikuchi disease (KD), secondary to hemodialysis catheter-related bloodstream infection (BSI) caused by Corynebacterium striatum. CASE PRESENTATION: A patient on maintenance hemodialysis had developed persistent fever and Corynebacterium striatum was subsequently identified from the culture of both catheter tip and peripheral blood. During mitigation of the BSI, however, his fever was unabated and ensuing workup further found thrombocytopenia, hyperferritinemia, hypertriglyceridemia, low NK cell activity and a surge in serum CD25 levels. Moreover, biopsy of the bone marrow and lymph node detected histopathological evidence of hemophagocytosis and KD, respectively. Upon these abnormalities, the title-bound diagnosis was considered and the patient was eventually recovered from the treatment of dexamethasone instead of antibiotics. Consistently, aberrations in his serum CD25 levels and NK cell activity had subsided two months after discharge. CONCLUSIONS: Arguably, this encounter offered a unique chance to unravel the principal pathogenic cascade in immunobiology that made the three entities one disease continuum. As such, our work may add new understandings of HLH and/or KD secondary to severe infections in general and excessive release of cytokines in particular among patients with kidney diseases. The resultant early diagnosis is crucial to initiate appropriate treatment and improve the survival of patients with these challenging and potentially life-threatening disorders.

Kikuchi-Fujimoto Disease and COVID-19 vaccination: pharmacovigilance approach.

Summary: Background. Kikuchi-Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitys is a rare disorder characterized by subacute necrotizing regional lymphadenopathy. It is usually presented as painful cervical nodes and associated with fever, headache, night sweats, nausea, vomiting and sore throat. Etiology of KFD is still unclear, two theories have been proposed: infections and autoimmune origin. Due to recent reports of KFD related to COVID-19 vaccination, the novelty of the mechanism of these vaccines and the immunomodulated role of both matters, a literature and adverse event databases review was carried out in order to shed light on the relationship between these two matters. Methods. A search in the Spanish and the European adverse events databases (FEDRA and Eudravigilance) was performed. Search criteria were any drug and the diagnosis "Histiocytic necrotizing lymphadenitis" according to the Medical Dictionary for Medical Activities version 25.0. All adverse events registered as June 2, 2022, were included. Results. FEDRA encompassed two KFD reports, one related to a mRNA COVID-19 vaccine. Eudravigilance included a total of 62 KFD cases, 14 of them associated to COVID-19 vaccines and eight to other vaccines. Conclusions. Pharmacovigilance is of utter importance in detecting adverse events caused by new vaccines. More research is needed to establish a final connection between KFD and COVD-19 vaccines, but due to the physiopathology of the condition, how vaccines stimulate the immune system and the high number of reported KFD cases with vaccines given its rare incidence, it is plausible to think that both entities are related.

Kikuchi-Fujimoto disease as the initial manifestation of systemic lupus erythematosus complicated with macrophage activation syndrome: two case reports and a review of literature.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limiting and benign disease characterized by cervical lymphadenopathy and fever. Although KFD should be made differentially diagnosed from infectious, autoimmune, and malignant diseases, it sometimes occurs in patients with systemic lupus erythematosus (SLE) and can be complicated with macrophage activation syndrome (MAS). However, it is rare that KFD is the initial manifestation of SLE and to be complicated with MAS. CASE PRESENTATION: A 9.6-year-old girl presented with high-grade fever, double-side cervical lymphadenopathy with mild pain of one week, leukopenia, alopecia, and rash on the cheek. During hospitalization, laboratory investigations showed positive antinuclear antibody (ANA), low complement 3 (C3), and low complement 4 (C4). Imaging investigations showed pleural and pericardial effusion. A 10.3-year-old girl presented with intermittent high-grade fever, double-sided cervical lymphadenopathy with obvious pain of 1-month duration, and discoid lesion on the cheek. During hospitalization, laboratory investigations showed positive ANA, leukopenia, thrombocytopenia, anemia with positive Coombs' test, low C3, and positive Smith antibodies. Both cases were diagnosed with KFD using lymph node biopsy, simultaneously fulfilling the diagnostic criteria of SLE. Subsequently, the two girls became complicated with MAS, followed by interstitial lung disease and neuropsychiatric lupus, respectively. Both patients benefited from high-dose methylprednisolone pulse therapy combined with intravenous cyclophosphamide. CONCLUSIONS: More attention should be paid to differential diagnosis, especially SLE, in children diagnosed with KFD. In addition, children with SLE who presented with KFD as the initial manifestation seem to have a higher risk of developing MAS and experiencing organ involvement.

Hemophagocytic Lymphohistiocytosis Associated with Histiocytic Necrotizing Lymphadenitis: A Clinical Study of 13 Children and Literature Review.

OBJECTIVE: To analyze the clinical characteristics and prognosis of pediatric hemophagocytic lymphohistiocytosis (HLH) associated with histiocytic necrotizing lymphadenitis (HNL). STUDY DESIGN: We retrospectively collected the clinical data of all children with HNL-HLH enrolled in Beijing Children's Hospital from 2007 to 2019. The control patients with Epstein-Barr virus-associated HLH and simple HNL (not associated with HLH) were case matched (1:2). The clinical features and prognosis were analyzed by case-control study. Cases of HNL-HLH in the literature were reviewed. RESULTS: The male-to-female ratio of the 13 patients in our center was 9:4. The mean age of the patients at disease onset was 8.1 ± 1.2 years, younger than that of the 16 patients in the literature (P = .017). Clinical presentations, especially rash and splenomegaly, and laboratory examination of HNL-HLH group were statistically different from Epstein-Barr virus-HLH group, simple HNL group, and patients reported in the literature (P < .05). Three patients were treated with immunosuppressive drugs or chemotherapy owing to poor control of HLH. One patient died, and all 12 remaining patients survived, 2 of which developed autoimmune diseases. Kaplan-Meier survival curves showed no statistical difference among the 3 groups (P > .05). CONCLUSIONS: HNL-HLH is more common in school- and preschool-age children. Most patients have a favorable prognosis. Some patients suffer from relapses or develop autoimmune diseases. Prolonged follow-up should be carried out for patients with HNL-HLH.

Cutaneous Kikuchi disease-like inflammatory pattern without lymph node involvement is associated with systemic disease and severe features in lupus erythematous: A case-control study.

INTRODUCTION: Kikuchi-Fujimoto disease (KFD) is a self-limited histiocytic necrotizing lymphadenitis sometimes affecting the skin. "Kikuchi disease-like inflammatory pattern" (KLIP) has been described in cutaneous lesions as similar pathological features in patients without lymph node involvement and as a potential clue for the diagnosis of lupus. We aimed to describe KLIP-associated clinical and immunological features in lupus patients with a retrospective case-control study. METHODS: Thirteen cases of KLIP were included as well as thirty-nine age- and sex-matched control lupus patients without KLIP. At the time of KLIP diagnosis, 4/13 patients (31%) had isolated cutaneous lupus erythematosus (CLE) and 9/13 had (69%) systemic lupus erythematosus (SLE) including 6 (46%) with severe haematological, lung, cardiac or renal disease. KLIP features were observed in skin biopsies of different clinical presentations. RESULTS: Compared with our control group, KLIP patients more frequently had SLE 9/13 (69%) versus 8/39 (21%) (OR 12.9; IC95% [2.86-58.2]; p = 0.0004) and more frequently severe SLE. Two out of four CLE exhibiting KLIP lesions (50%) developed severe SLE with cardiac or renal involvement after 12 and 24 months, respectively.Treatment with thalidomide 100 mg/day allowed rapid and complete clearance of cutaneous lesions in 6/6 KLIP patients. The need to use thalidomide tended to be more frequent in KLIP patients than in controls. CONCLUSION: Our study suggests that KLIP features in lupus skin lesions are associated with SLE and severe systemic features. Despite a limited number of isolated CLE patients with KLIP features in the skin, this observation may warrant closer follow-up on patients with a higher risk of developing SLE.

Kikuchi-Fujimoto disease presenting in a patient with SARS-CoV-2: a case report.

BACKGROUND: We present a yet to be described association of SARS-CoV-2 infection with Kikuchi-Fujimoto disease. CASE PRESENTATION: A 32-year-old physician with history of SARS-CoV-2 infection presented to the emergency department with 2 weeks of fever, chills, and right sided cervical lymphadenopathy. He was treated empirically for presumed folliculitis with worsening of symptoms leading to repeat presentation to the emergency department. Extensive workup was unrevealing of an infectious cause and needle biopsy of the lesion was unrevealing. An excisional lymph node biopsy revealed follicular hyperplasia with necrotic foci showing abundance of histiocytes at the edge of necrosis with CD8 predominance of T-cells. Final diagnosis was deemed to be Kikuchi-Fujimoto disease. Antibiotic therapy was discontinued, and the patient's symptoms resolved with steroid therapy and expectant management. CONCLUSIONS: This is the first report of a patient developing Kikuchi-Fujimoto disease following SARS-CoV-2 infection. Clinicians should be aware of Kikuchi-Fujimoto disease as a possibility when approaching patients with hyper-inflammatory states who present with cervical lymphadenopathy.

Kikuchi disease as a possible cause of ischaemic stroke: a case report.

INTRODUCTION: Kikuchi disease (KFD) is a rare and self-limiting benign disease which usually occurs in young women. The difference between our case and the previous case is that the initial symptom of this case is transient ischemic attack (TIA). METHODS: A 46-year-old female patient presented at the clinic with a 2-week history of paroxysmal left limb weakness and fever. Imaging examinations showed the multiple lymph nodes in neck enlarged bilaterally. Finally, we arranged a lymph node biopsy for the patient. RESULTS: The resulted of lymph node biopsy showed the disorder of lymph node structures, widespread histiocytic infiltration and cell nucleus fragments, suggesting KFD. CONCLUSION: TIA as a complication of KFD has never been reported in the previous literature, which provided a new direction for diagnosis of TIA and suggested that KFD may be a rare cause of ischemic stroke.

[NEUROLOGIC COMPLICATIONS AROUND THE DIAGNOSIS OF KIKUCHI-FUJIMOTO DISEASE: A RARE PRESENTATION OF THE DISEASE OR A HINT OF AN ADDITIONAL DIAGNOSIS?]

INTRODUCTION: Neurologic symptoms are an extremely rare presentation of Kikuchi-Fujimoto disease. We report a case of a young female patient diagnosed with Kikuchi-Fujimoto disease, presenting with neurologic symptoms compatible with aseptic meningitis, along with radiographic findings which improved with steroidal treatment. Despite the rarity of these findings, they were reported as part of the disease manifestation, however, since Kikuchi-Fujimoto disease is associated with other diseases, such as systemic lupus erythematosus (SLE), other diagnoses cannot be ruled out.

Kikuchi-Fujimoto disease preceded by lupus erythematosus panniculitis: do these findings together herald the onset of systemic lupus erythematosus?

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare disorder that must be distinguished from systemic lupus erythematosus (SLE). Although a minority of patients with KFD develop SLE, most patients have a self-limited disease. Importantly, KFD can have skin manifestations resembling cutaneous lupus. Therefore, the diagnosis of SLE should be predicated on a complete rheumatologic workup and not on the constellation of skin disease and lymphadenitis. Nonetheless, as our exceedingly rare case illustrates, patients who do not initially meet diagnostic criteria for SLE require dermatologic follow-up. We present a young adult woman who had a remote history of KFD and later presented with combined features of discoid lupus and lupus erythematosus panniculitis (LEP). On subsequent rheumatologic workup, she fulfilled criteria for SLE. We discuss the differential diagnosis of both KFD and LEP and emphasize how strong communication among dermatologists and other healthcare providers is essential in the management of patients with KFD.

Kikuchi-Fujimoto disease: a case report and the evaluation of diagnostic procedures.

BACKGROUND: Kikuchi-Fujimoto disease, known as histiocytic necrotizing lymphadenitis, is a benign, self-limiting and systemic disorder involving lymph nodes with unknown aetiology. First reported in Japan, there has been an increase in its incidence globally. Because of its non-specific clinical features, the disease can be easily mistaken for other forms of lymphadenitis with a high rate of misdiagnosis and mistreatment, posing a considerable challenge. CASE PRESENTATION: A case of young Chinese woman with fever and cervical lymphadenopathy is presented. Physical examinations and imaging techniques were used to rule out common forms of lymphadenitis (e.g. cat-scratch disease and tuberculous lymphadenitis). Laboratory tests were then conducted to exclude others such as systemic lupus erythematosus and non-Hodgkin lymphoma. After Kikuchi-Fujimoto disease was identified, the patient was managed with symptomatic treatments. Our case was compared with relevant cases in the literature. A diagnostic flow chart was proposed to facilitate the diagnosis and treatment. CONCLUSIONS: With its shared clinical features, Kikuchi-Fujimoto disease can be mistaken for other forms of lymphadenitis. A combined use of medical imaging and laboratory tests is the effective way to avoid misdiagnosis.

Kikuchi-Fujimoto disease with multiple extra-nodal features - A clinical mimic.

Extranodal involvement in Kikuchi's disease is uncommon. A 31-year-old previously healthy Indian woman was admitted with high grade fever, multiple joint pain and skin rash for 3 weeks. She had negative anti-nuclear antibodies and had features of Kikuchi's disease on lymph node biopsy. She also had multiple extranodal manifestations including erythematous maculopapular rash, symmetric polyarthritis and hepatosplenomegaly. Kikuchi's disease with extranodal involvement can clinically mimic diseases like hematological malignancies, connective tissue disorders and certain infections. A lymph node biopsy plays a crucial role in making an accurate diagnosis by excluding other diseases. A discussion on the importance of differentiating Kikuchi's disease from systemic lupus erythematosus is included.

Macular capillary recovery in systemic lupus erythematosus complicated by Kikuchi-Fujimoto disease.

PURPOSE: Few case reports have described vaso-occlusive retinopathy in systemic lupus erythematosus (SLE) using optical coherence tomography (OCT) angiography. Here we report the clinical features of a patient with SLE, complicated by Kikuchi-Fujimoto disease, who developed vaso-occlusive retinopathy. We then describe the subsequent recovery of the macular capillaries as assessed by OCT angiography. CASE: A 16-year-old male was referred to us with fever, a 1-month history of violaceous red papules and erythematous plaques on his face and a painful nodule in his right neck. We diagnosed him with SLE complicated by Kikuchi-Fujimoto disease through physiological assessment and histology from his neck lymph node and chin skin. Systemic steroids were prescribed as treatment. After remission, his fever and cervical lymph node swelling with pain recurred and he developed blurred inferior vision in his left eye. His best-corrected visual acuities were 1.0 and 0.1 in the right and left eyes, respectively. Extensive cotton wool spots were observed in the right fundus, and retinal capillary occlusions were detected by OCT angiography of the left eye. We diagnosed this case as vaso-occlusive retinopathy with SLE and increased immunosuppressive treatment together with anticoagulation therapy. Macular capillaries, observed by OCT angiography, gradually recovered function following assessment at 7 and 16 months post-onset of the vaso-occlusive retinopathy. CONCLUSIONS: We reported a 1½-year course of vaso-occlusive retinopathy in a patient with SLE complicated by Kikuchi-Fujimoto disease. Occlusion of the retinal vasculature and the subsequent recovery of circulation are clearly observed by OCT angiography.

Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis) with atypical encephalitis and painful testitis: a case report.

BACKGROUND: Kikuchi-Fujimoto disease is a self-limited clinicopathologic entity that is increasingly recognized worldwide. Kikuchi-Fujimoto disease is characterized by cervical lymphadenopathy occurring in young adults. Neurologic involvement is rare, and testitis directly caused by Kikuchi-Fujimoto disease has not yet been reported. CASE PRESENTATION: A 19-year-old man was brought to our clinic with complaints of fever, headache, fatigue, and left lower quadrant pain that had persisted for 3 weeks. On physical examination, painful cervical lymphadenopathies were observed. Meningitis was suspected based on a cerebrospinal fluid examination, and left-sided orchitis was diagnosed based on findings from magnetic resonance imaging and ultrasonography. However, neither antibiotics nor antiviral drugs were effective in treating the patient's symptoms. On the 20th day of hospitalization, the patient experienced a loss of consciousness, and brain T2-weighted magnetic resonance imaging showed asymmetrical, high-signal intensities in both basal nuclei and the left temporal lobe. Encephalitis was suspected, and the patient was treated with intravenous prednisolone pulse therapy (1 g/day) for 3 days and intravenous immunoglobulin therapy for 5 days. A left cervical lymph node biopsy showed apoptotic necrosis in paracortical and cortical areas with an abundance of macrophages and large lymphoid cells, which had irregular nuclei suggestive of Kikuchi-Fujimoto disease; the pathological findings from a brain biopsy were the same as those of the cervical lymph node biopsy. The encephalitis and cervical lymphadenopathies followed a benign course, as did the testitis. CONCLUSIONS: This is the first report of Kikuchi-Fujimoto disease involving painful testitis and pathologically proven asymmetrical brain regions. Kikuchi-Fujimoto disease should be included in the differential diagnosis when a patient presents with encephalitis, testitis, and fever of unknown origin.