Kikuchi-Fujimoto disease (KFD) also known as histiocytic necrotizing lymphadenitis, was first described in Japan in 1972, by Japanese Pathologists Kikuchi and Fujimoto. Kikuchi-Fujimoto disease is an extremely rare, benign, and self-limiting disease that mainly affects young women of Asian origin with the female-to-male ratio of occurrence of 4:1. Kikuchi-Fujimoto disease largely affects young adults (young than 30 years) and is most frequently found in East Asian and Japanese populations but rare in the United States and Europe. This geographic association can be related to certain HLA alleles such as HLA class II alleles, HLA-DPA1, and HLA-DPB1, which are more prevalent in Asian Kikuchi-Fujimoto disease patients and rare in Caucasians.
Kikuchi-Fujimoto disease is a disease of unknown etiology. Several infectious agents have been suggested as possible causative agents, for example, herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus (EBV), human herpesvirus (HHV 6, 7, 8), parvovirus B19, human papillomavirus, hepatitis B virus, human T-lymphotropic virus 1, Brucella, toxoplasma, and Yersinia. However, none of them have been proven to have any significant role in the causation of Kikuchi-Fujimoto disease. Epstein-Barr virus has been studied extensively in Kikuchi-Fujimoto disease, but no causative link has been demonstrated. On the other hand, some authors have hypothesized that Kikuchi-Fujimoto disease has an autoimmune etiology induced by virus-infected transformed lymphocytes and is also associated with systemic lupus erythematosus. This is because histopathological findings in the lymphocytes and the endothelial cells in patients with systemic lupus erythematosus are similar to those found in patients with Kikuchi-Fujimoto disease. Kikuchi-Fujimoto disease can mimic systemic lupus erythematosus. However, the association of Kikuchi-Fujimoto disease with systemic lupus erythematosus remains unclear. There have been some patients with Kikuchi-Fujimoto disease that have developed systemic lupus erythematosus. So it is important that the patients with Kikuchi-Fujimoto disease should have a regular follow up with rheumatology for a detailed autoimmune work up.
Kikuchi-Fujimoto disease can affect both males and females. The ratio of affected males to females in three series was 1:4, 1:1.6, and 1:1.26, respectively. In a Korean report of 20 individuals with Kikuchi-Fujimoto disease that were younger than 18 years, the gender distribution was equal. Most patients are younger than 40 years of age, but this condition has been reported in patients ranging in age from six to 80 years, most of whom were previously well. The mean age at presentation in a United States series was 30 years. Although initially described in two separate cases from Japan, Kikuchi-Fujimoto disease has since been found in all racial and ethnic groups and many countries, including the United States. In a study of 88 patients with Kikuchi-Fujimoto disease in the United States, 75 percent were Caucasian. The frequency of this condition varies widely in different groups, but it has been most frequently reported from Asia.
While the pathogenesis of Kikuchi-Fujimoto disease is unknown, the clinical presentation, course, and histologic changes suggest an immune response of T cells and histiocytes to an infectious agent. An observation that is consistent with a viral etiology is increased levels of interferon-alpha and some other proteins stimulated by interferon-alpha including 2',5'-oligoadenylate synthetase and tubuloreticular structures in the cytoplasm of stimulated lymphocytes, histiocytes, and vascular endothelium.
A possible role for interferon-gamma and interleukin (IL)-6 in the pathogenesis of this syndrome is suggested by one study of four men with biopsy-proven Kikuchi-Fujimoto disease. During the acute phase of illness, these patients had elevated serum levels of interferon-gamma and IL-6 but not interferon-alpha, tumor necrosis factor, or IL-2. The interferon-gamma and IL-6 levels returned to normal during convalescence.
Kikuchi-Fujimoto disease presents classically as cervical lymphadenopathy (predominantly unilateral and posterior cervical lymph nodes) with or without fever in young women. Cervical lymph nodes are most commonly involved (70% to 98%) followed by axillary (14%) and supraclavicular lymph nodes (12%). Fever is the first symptom in 30% to 50% of the cases. Some patients have non-specific presentation including weight loss, nausea, vomiting, night sweats, generalized lymphadenopathy, and hepatosplenomegaly. Cutaneous involvement involves maculopapular, morbilliform, urticarial rashes, or a disseminated erythema. Also, there has been one case report of a patient presenting with eyelid edema revealing Kikuchi-Fujimoto disease. Clinically, Kikuchi-Fujimoto disease resembles a lot of other diseases, and the differential is broad including reactive lymphadenitis, viral infections (HIV, Epstein-Barr, herpes simplex, cytomegalovirus), tuberculosis, systemic lupus erythematosus, lymphoma, and metastasis. Kikuchi-Fujimoto disease is also underdiagnosed in a lot of cases that get labeled with a presumptive diagnosis of viral infection or reactive lymphadenitis.
Routine laboratory investigations do not help much in making a diagnosis of Kikuchi-Fujimoto disease. The only significant lab abnormalities are leukopenia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Around 30% of the patients also have atypical lymphocytosis. Some patients with Kikuchi-Fujimoto disease have elevated aminotransferases and lactate dehydrogenase (LDH) levels. Antibodies against nuclear antigens (ANA), double-stranded DNA (dsDNA), Rheumatoid factor (RF) and ANCA are also negative even though systemic lupus erythematosus and several other autoimmune diseases have been described in patients with Kikuchi-Fujimoto disease. CT and MRI scans are not diagnostic for Kikuchi-Fujimoto disease as there are no characteristic radiological features. In fact, imaging is not able to differentiate Kikuchi-Fujimoto disease from other nodal diseases including lymphoma, metastasis or Tuberculosis. Kwon et al. did a retrospective analysis of CT scans of 96 patients with confirmed Kikuchi-Fujimoto disease and found out that 94% of the enlarged lymph nodes had a size of less than 2.5 cm. This can somehow help in differentiating Kikuchi-Fujimoto disease from lymphoma that typically produces larger lymphadenopathy.
The gold standard diagnostic test for Kikuchi-Fujimoto disease is the histopathological analysis of excised lymph node biopsy specimen. The histopathological features can be classified into three stages: (1) proliferative stage expressing various histiocytes, plasmacytoid monocytes, lymphoid cells containing karyorrhectic nuclear fragments, and eosinophilic apoptotic debris; (2) necrotizing stage showing a degree of coagulative necrosis; and (3) xanthomatous stage predominantly containing foamy histiocytes. The absence of granulocytes is also an important feature. Histologically it can mimic lymphoma. However, the absence of monoclonal lymphocyte receptors on the histologic analysis rules out a lymphoma. Other histological differential diagnoses of Kikuchi-Fujimoto disease include reactive lymphadenitis associated with systemic lupus erythematosus, infectious mononucleosis, tuberculosis, and metastatic cancer.
There is no specific treatment available for Kikuchi-Fujimoto disease. It is typically a self-limited disease, and spontaneous resolution occurs in one to four months. However, the possible recurrence rate of 3% to 4% has been reported that can occur even eight to nine years later. Management is symptomatic including analgesic (e.g., NSAIDs) and antipyretic. Some authors have seen a positive clinical response to glucocorticoids in Kikuchi-Fujimoto disease patients with a severe or relapsing clinical course. Takada et al. reported a case of Kikuchi-Fujimoto disease that dramatically resolved with oral minocycline suggesting that the causative agent of Kikuchi-Fujimoto disease might be especially sensitive to this antibiotic. There have been some case reports demonstrating hydroxychloroquine and intravenous immunoglobulins as successful alternative treatment options for Kikuchi-Fujimoto disease.
Because kikuchi-fujimoto disease is rare and seen in Japanese individuals, it is best managed by a multidisciplinary team that includes an infectious disease expert, internist, pathologist, and a pharmacist. The diagnosis is only made after a biopsy. There is no specific treatment available for Kikuchi-Fujimoto disease. It is typically a self-limited disease, and spontaneous resolution occurs in one to four months. However, the possible recurrence rate of 3% to 4% has been reported that can occur even eight to nine years later. Management is symptomatic including analgesic (e.g., NSAIDs), steroids and antipyretic. Some patients may require intravenous immunoglobulin or hydroxychloroquine. The lifespan is not altered and the outcomes are good. (Level V)
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