Kikuchi-Fujimoto Disease (Histiocytic Necrotizing Lymphadenitis)

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GENERAL DESCRIPTION

Kikuchi-Fujimoto disease, also known as Kikuchi’s disease or histiocytic necrotizing lymphadenitis, is a benign, self-limiting cause of lymphadenopathy, variably associated with systemic symptoms. First described independently by Kikuchi (27) and Fujimoto (19) in 1972, Kikuchi-Fujimoto disease is increasingly recognized in the literature, but its true incidence is unknown.

Microbiology

The role of infectious agents in the pathogenesis and evolution of Kikuchi-Fujimoto disease is a matter of debate.

Epidemiology

Kikuchi-Fujimoto disease is an extremely rare disease known to have a worldwide distribution with a higher prevalence among Asiatic individual (4). Kikuchi-Fujimoto disease affects individuals of all ages, preferentially adult females under 30 years of age, but it has rarely been reported in children.(17, 31, 33, 47, 51, 61) This gender difference, with female predominance, has not been confirmed in more recent reports from Eastern countries and in pediatric studies.(4, 31, 33, 34, 35, 64).

Clinical Manifestations

The onset of Kikuchi-Fujimoto disease is acute or subacute, evolving over a period of two to four weeks. Clinically, the most common presentation is unilaterally lymphadenopathy with tenderness: cervical lymph nodes are the principle site of disease in 70-90% of patients; other lymph nodes, such as the axillary and abdominal ones, may be less frequently involved. Generalized adenopathy is uncommon.(11, 16, 17, 34, 47, 61). The size of affected lymph nodes is usually less than 4 cm and rarely larger than 6 cm. In addition to lymphadenopathy, 30-50% of patients have fever; (17, 31, 35) occasionally, Kikuchi-Fujimoto disease has been reported as a cause of prolonged fever of unknown origin (33). Parotidomegaly, with intragland lymphadenitis and hepatosplenomegalia may be present (4, 26, 32, 51). Less frequent symptoms include fatigue, arthralgia, night sweats, headache, myalgia, weight loss and gastroenteric complaints. Cutaneous involvement, like facial rash, exudative erythema and erythematous papules, is observed in 30-40 % of cases (31, 64, 65).

The outcome of the disease is usually favorable, with spontaneous resolution within a period of one to 6 months after diagnosis. There are occasional reports of unusual features of Kikuchi-Fujimoto disease (46), including severe extranodal involvement -such as myocarditis(48) and pulmonary hemorrhage(63)- and disseminated disease with fatal outcome (7, 29, 38).

A low recurrence rate has been described in 3% to 4% of cases (3, 16, 31, 34, 50, 61). Kikuchi-Fujimoto disease has been linked to systemic lupus erythematosus (SLE), as well as to other autoimmune diseases.(4, 8, 14, 18, 31, 34, 35). In particular, KLD and SLE may coexist with one preceding the other; this association is significantly high in cases from Eastern countries compared to cases from Europe (29). Other autoimmune connective tissue disorders, such as Still’s disease and primary Sjogren’s syndrome, have been described in association with SLE (13, 43, 53, 64). Post-transplantation development of Kikuchi-Fujimoto disease is a further interesting issue (60). Patients require a regular follow-up for several years to rule out the development of SLE.

Laboratory Diagnosis

No specific laboratory test is available for the diagnosis.

Leukopenia occurs in 30 to 70% of cases. Other nonspecific laboratory findings include anemia, atypical peripheral blood lymphocytes and increased erythrocyte sedimentation rate with low C-reactive protein values in most patients (30-50% of cases); serum hepatic transaminase activities and lactate dehydrogenase levels are also frequently increased (4, 34, 61, 64).

Diagnosis of Kikuchi-Fujimoto Disease

The diagnosis of Kikuchi-Fujimoto disease is based on the histological findings of affected lymph nodes. Due to partial lymph node involvement an excisional biopsy is mostly preferred, although fine needle aspiration biopsy sometimes may prove helpful (59, 62).

Typical histopathological features (Figure 1) include extensive fibrinoid necrosis, loss of lymph node architecture, absence of granulomatous reaction with foamy histiocytes at the margin of the necrotic areas. The karyorrhectic foci are formed by different cellular types, predominantly histiocytes and plasmacytoid monocytes, but also immunoblasts, some of which may be atypical, and small or large lymphocytes (4). Neutrophils are characteristically absent and plasma cells are either absent or scarce. Immunohistochemistry is an important tool for distinguishing Kikuchi-Fujimoto disease from lymphoma. The immunophenotype of Kikuchi-Fujimoto disease typically consists of a predominance of T cells, with prevalence of CD8+ expression over CD4+ cells. Relatively few B cells and NK cells are present. The histiocytes express histiocyte-associated antigens such as lysozyme, myeloperoxidase and CD68. Striking plasmacytoid monocytes are also positive for CD68 but not for myeloperoxidase (4, 31, 52).

Pathogenesis

Although the etiology of Kikuchi-Fujimoto disease remains unclear, infectious causes and autoimmune mechanisms have been alternatively suggested. Both the benign course and complete recovery of Kikuchi-Fujimoto disease seem to correlate with a self-limited infectious process. An autoimmune contribution to the pathogenesis is based on observations showing an association of Kikuchi-Fujimoto disease with systemic lupus erythematosus and other connective tissue disorders (16, 17, 34, 40).

Currently, the most favored theory proposes that Kikuchi-Fujimoto disease might represent an exuberant T-cell mediated immune response to a variety of non-specific stimuli in genetically susceptible individuals.(4, 17) To further suggest a genetic predisposition, some HLA class II genes have been more frequently observed in patients with Kikuchi-Fujimoto disease (58).

Due to histopathologic and clinical features of Kikuchi-Fujimoto disease, several lymphocyte-infecting viruses have been postulated to have a causative role. These include Epstein-Barr virus (EBV),(9, 11, 23, 54) cytomegalovirus (CMV),(23) parvovirus B19,(9, 42) human herpesvirus 6 (HHV-6),(10, 15, 21, 36, 39, 55) varicella-zoster virus, parainfluenza virus, human herpesvirus 7 (HHV-7),(10) human herpesvirus 8 (HHV-8) (10, 20, 24) and human T-cell lymphotrophic virus-1.(1, 9) So far, such investigations have produced conflicting results; most of the immunohistochemical and molecular studies failed to link Kikuchi-Fujimoto disease to specific pathogens or demonstrated that these viruses are no more common than in control patients.(9, 10, 20, 21, 39, 55) Therefore the role of virus in the pathogenesis and evolution of Kikuchi-Fujimoto disease remains controversial and not yet convincingly demonstrated.

Among bacteria and parasites, Yersinia enterocolitica, Brucella melitensis,(6) Toxoplasma gondii, Giardia lamblia (5) and Entamoeba histolytica (2) have been occasionally identified by serologic and cultural methods and have all been implicated in the pathogenesis, without any convincing corroborating evidence. Interestingly, gene products of Bartonella henselae have been recently detected in lymph nodes of children with Kikuchi-Fujimoto disease (12).

Although the mechanism of cell death involved in Kikuchi-Fujimoto disease has not been extensively studied, Ohshima et al (45) have shown that apoptotic cell death may play a role in the pathogenesis of the disease. According to these Authors, proliferating CD8 positive T-cells may act as “killers” and victims” in the apoptotic process via Fas- end perforine- pathways (45). Perforine, a killer cell-specific cytolytic protein essential for provoking apoptosis in target cells, has been reported to be expressed abundantly by infiltrating cytotoxic T lymphocytes. Therefore, the necrosis associated with Kikuchi-Fujimoto disease might be attributable to trans apoptotic death of the killer cell target in the affected nodes (57). Serum concentration of some inflammation mediators, such as interferon- and interleukin-6, have been reported to be increased during the acute phase of Kikuchi-Fujimoto disease, raising the possibility that these cytokines could have a role in the pathogenesis of this condition (28).

Differential Diagnosis

In terms of clinical and laboratory presentation, Kikuchi-Fujimoto disease could easily be confused with other infectious, reactive and lymphoproliferative diseases, such as tuberculosis, toxoplasmosis, mononucleosis, sarcoidosis, Kawasaki’s disease, SLE and non-Hodgkin's lymphoma (46).

Owing to the variable degree of microscopic necrosis found within the lymph nodes as well as the atypia in the reactive immunoblastic component, the histopathological appearances of Kikuchi-Fujimoto disease may be very similar to those found in other diseases, especially SLE and lymphoma (4). That confusion has led some patients to extensive and aggressive diagnostic evaluations and even unnecessary treatment (17, 41).

The presence of numerous plasma cells and hematoxylin bodies favors SLE-associated lymphadenitis over Kikuchi-Fujimoto disease(4, 17, 65). Immunohistochemistry is an important tool for distinguishing Kikuchi-Fujimoto disease from lymphoma.

SUSCEPTIBILITY IN VITRO AND IN VIVO

The relationship of Kikuchi-Fujimoto disease with infections is controversial; therefore no in vitro or animal studies on drug susceptibility exist.

ANTIMICROBIAL THERAPY

Given the lack of in vitro and animal data, sparse reports of empirical antibiotic treatment in humans constitute the only data available. These include successful responses to minocycline (56) and ciprofloxacin (37). Therapeutic response to antibiotics has been used as supportive evidence for an infective etiology in Kikuchi-Fujimoto disease. Recognizing the significant limitations of the above data, we do not recommend an antibiotic regimen. No antiviral therapy has been used in clinical practice.

Underlying Diseases

There is no evidence that Kikuchi-Fujimoto disease is more prevalent in immunocompromised patients, or that treatment should be modified in this population.

ADJUNCTIVE THERAPY

The course of Kikuchi-Fujimoto disease is typically benign and self-limited; no specific therapy has therefore been established for Kikuchi-Fujimoto disease.

Treatment is generally symptomatic and supportive: non-steroidal anti-inflammatory drugs and acetaminophen are beneficial in relieving distressing local and systemic complaints. Adjunctive therapy has been focused on patients with recurrent, generalized or severe disease in order to prevent a fatal outcome. The majority of reports are of treatment with corticosteroids (mainly prednisone), to which some patients seem to respond (22, 25, 33, 47). Glucocorticoids have also been applied to patients with prolonged fever unresponsive to initial non-steroidal anti-inflammatory drugs (25, 30, 47). Due to variable responseadditional studies are needed for validating steroid treatment for this disease (25).

Empirical treatment include hydroxychloroquine, successfully used in a patient with recurrent Kikuchi-Fujimoto disease (49). There is a single case report describing intravenous immunoglobulin treatment (0.4 g/kg per day for 3 days) in a patient with severe Kikuchi-Fujimoto disease (44). Excisional lymph node biopsy for the purpose of confirming the diagnosis is the only surgery indicated in Kikuchi-Fujimoto disease.

ENDPOINTS FOR MONITORING THERAPY

No therapeutic endpoints have been established. Cessation of fever and general malaise is usually the first objective signs of improvement, followed by reduction of lymph nodes. Laboratory and histologic abnormalities lag behind the clinical gains.

VACCINES

There are no experimental or commercially available vaccines for prevention of Kikuchi-Fujimoto disease.

PREVENTION OR INFECTION CONTROL MEASURES

Since the relation between Kikuchi-Fujimoto disease and infections remains a matter of debate, no special prevention or infection control measures are advised.

CONTROVERSIES, CAVEATS OR COMMENTS

Several questions are worthy of further investigations. Which is the role of infections in Kikuchi-Fujimoto disease? Which is the relation between Kikuchi-Fujimoto disease and autoimmune disorders? Should Kikuchi-Fujimoto disease be treated with glucocorticoids? Does antibiotic therapy provide any additional benefit in Kikuchi-Fujimoto disease therapy?

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