Hospital Medicine

Kikuchi Fugimoto

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Kikuchi-Fujimoto Disease

I. What every physician needs to know.

Kikuchi-Fujimoto disease (also known as Kikuchi disease or histiocytic necrotizing lymphadenitis), is a disease characterized by widespread lymphadenopathy. The disease derives its names from the two Japanese scientists who independently described the classical constellation of signs and symptoms in 1972. The disease is common in Japan but rare elsewhere.

The cause of the disorder is unknown. Infectious, autoimmune, and genetic etiologies have been proposed. A widely accepted theory is related to the triggering of a self-limited autoimmune process by an external agent. Proposed triggers include several environmental infectious agents (viral candidates such as cytomegalovirus, adenovirus, Epstein Barr Virus). None of these have been confirmed. The hallmark of the disease is self-limited, diffuse lymphadenitis.

II. Diagnostic Confirmation: Are you sure your patient has Kikuchi-Fujimoto disease?

The most common presentation of Kikuchi-Fujimoto disease is an acute or subacute onset, febrile illness that mimics a flu-like prodrome with associated localized lymphadenopathy. Cervical nodes are the most commonly affected site (80%). Generalized lymphadenopathy involving inguinal, axillary, retroperitoneal or mesenteric lymph nodes is rare. Half of all patients present with a flu-like syndrome including headache, fever, rash and myalgia.

A. History Part I: Pattern Recognition:

Kikuchi-Fujimoto is predominantly a disease of young women in their 20-30s. The disease presents with the classic triad of fever, rash and lymphadenopathy. Occasionally, weight loss, severe headaches, hepatomegaly, splenomegaly and meningitis occur.

B. History Part 2: Prevalence:

The disease is uncommon in the United States with isolated case reports. Think of Kikuchi-Fujimoto in patients who have recently immigrated from East Asia. The highest prevalence is reported in Japan.

C. History Part 3: Competing diagnoses that can mimic Kikuchi-Fujimoto disease.

Any form of diffuse lymphadenopathy competes with Kikuchi-Fujimoto for diagnosis. The hallmark of this diagnosis is the history and origin of the patient. Differentials include infectious agents (e.g., bacterial agents/STDs such as Gonococcus, tertiary syphilis, cat-scratch disease; viral agents such as CMV, EBV [mononucleosis], disseminated HIV; fungal diseases such as histoplasmosis or toxoplasmosis; typical and atypical mycobacterial infections such as disseminated tuberculosis or lepromatous leprosy, MAI, etc.; systemic lupus erythromatosis (SLE); thyroid metastasis; and hematological malignancies such as lymphomas.

D. Physical Examination Findings.

Kikuchi disease most frequently manifests as a relatively acute onset of cervical adenopathy associated with fever and a flu-like prodrome. Lymphadenopathy is usually found in one location, classically cervical in 80% of patients. The nodes are usually painless to mildly tender, firm, mobile (non adherent), and do not manifest fluctuation or drainage. Extranodal findings involving the skin in the form of a maculo-papular rash, nodules, urticaria or a malar rash resembling SLE have been reported in 5-30% of patients. Hepatosplenomegaly, aseptic meningitis, encephalitis are rare but more serious presenting findings. Widespread organ involvement has been reported in patients with solid organ transplants.

E. What diagnostic tests should be performed?

Diagnostic tests are useful to exclude other differentials. Routine laboratory tests should include: comprehensive metabolic panel, CBC, LDH, ESR, CRP, blood culture and urinalysis. The following serologic studies are also recommended: HIV, EBV, CMV, Toxoplasma, HHV6 and HHV8. ANA and RF are also helpful.

Fine needle aspiration of an enlarged lymph node may be suggestive of the diagnosis but is not confirmatory. The confirmatory diagnostic test of choice is excisional lymph node biopsy.

There are three histopathologic stages of the disease: proliferative, necrotic and xanthomatous. Characteristic findings on pathology include the presence of crescenteric histiocytes, plasmacytoid monocytes and extracellular debris. In addition, paracortical necrosis of affected lymph nodes to variable degrees may be present. Neutrophils, granulomas or plasma cells are rarely found in the lymph nodes of those affected with Kikuchi-Fujimoto disease. Immunohistochemical studies will show mature CD8 positive and CD4 positive T lymphocytes.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A CBC may show mild leukocytosis or leukopenia, atypical lymphocytes may be seen in 25% of patients. Inflammatory markers such as CRP and ESR may be elevated. Elevated LDH levels are indicative of hepatic involvement but do not rise otherwise.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging modalities are not helpful in establishing the diagnosis but may be used to evaluate the extent of lymphadenopathy in other areas when considering differentials such as lymphomas, mycobacterial infections, disseminated/tertiary syphilis, etc.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Imaging studies and laboratory studies should be used sparingly. In the right clinical scenario (young woman from East Asia with cervical lymphadenopathy and fever), excisional lymph node biopsy is the most cost-effective approach.

III. Default Management.

Treatment for this disease is primarily supportive. There are no established treatment guidelines for this disease. NSAIDs may be used to treat lymph node tenderness and fever. Rarely, corticosteroids may be useful in severe extra-nodal or generalized Kikuchi disease. Prednisone is specifically indicated in the treatment of:

1) Neurological system - aseptic meningitis, cerebellar ataxia

2) Hepatic involvement - with elevated LDH level

3) Severe lupus-like syndrome - e.g., excisional LN consistent with findings in Kikuchi disease with positive ANA titers.

Recommended doses of prednisone vary from 0.5mg/kg to 1mg/kg based on severity of disease.

A. Immediate management.

NSAIDs, analgesics and antipyretics for fevers, discomfort, pain or tenderness.

B. Physical Examination Tips to Guide Management.

Monitor symptom trends, size of lymphadenopathy, presence of neurologic or GI involvement by close neurological examination and/or serum LDH levels.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There is no evidence supporting laboratory testing to monitor disease. Jung et al. studied 44 patients with serial ESR and CRP to monitor disease course and found this had poor correlation with symptomatic improvement unless extra-nodal disease was present. When liver disease was present, serial LDH measurements correlated with disease activity and aided the tapering of systemic steroid treatment.

D. Long-term management.

Close follow-up is recommended in order to monitor for further manifestations of SLE. In general, the disease is self-limiting. Recurrence is rare but has been documented in 3-4% of patients. No long term management is indicated.

E. Common Pitfalls and Side-Effects of Management.

Always exclude other diagnostic considerations prior to Kikuchi-Fujimoto disease. It is imperative that thorough evaluation for diseases that may present with diffuse lymphadenopathy are investigated. Specific treatment may be warranted in those conditions, in contrast to this disease.

IV. Management with Co-Morbidities.

Neurologic disease confirmed by LP should be treated with systemic corticosteroids. The diagnosis is based on CSF findings consistent with aseptic meningitis, high clinical suspicion, and classical pathological findings on excisional lymph node biopsy.

Liver disease due to Kikuchi-Fujimoto - confirmed by elevated serum LDH levels - should also be treated with systemic steroids at 1mg/kg prednisone.

No other changes to standard management are warranted.

A. Renal Insufficiency.

No other changes to standard management are warranted. Caution with NSAIDs in this population.

B. Liver Insufficiency.

Monitor LDH to ensure absence of liver involvement; no specific changes are otherwise warranted.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Caution with systemic steroids in this population.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

Caution with steroids in this population.

V. Transitions of Care.

A. Sign-out Considerations While Hospitalized.

Most patients with this disease do not require hospitalization. When hospitalized, specific isolation and/or treatment is not usually warranted.

B. Anticipated Length of Stay.

Rarely hospitalized.

C. When is the Patient Ready for Discharge.

NA

D. Arranging for Clinic Follow-up.

Long-term follow up solely for this disorder is not warranted.

1. When should clinic follow up be arranged and with whom.

NA

2. What tests should be conducted prior to discharge to enable best clinic first visit.

NA

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

NA

E. Placement Considerations.

NA

F. Prognosis and Patient Counseling.

The disease rarely recurs and is usually benign and self-limiting. Supportive care and reassurance are the mainstays of treatment and counseling.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

No specific interventions or prophylactic measures exist.

VII. What's the Evidence?

Bosch, X1, Guilabert, A, Miquel, R, Campo, E. "Enigmatic Kikuchi-Fujimoto disease: a comprehensive review". Am J Clin Pathol. vol. 122. 2004 Jul. pp. 141-52.

(This review outlines the importance of keeping this disease on the differential when patients present with lymphadenopathy. In contrast to hematologic malignancies which carry significant burden, this condition in general has good prognostic outcome for the majority of patients.)

Chong, Y, Kang, CS. "Causative agents of Kikuchi–Fujimoto disease (histiocytic necrotizing lymphadenitis): A meta-analysis". International Journal of Pediatric Otorhinolaryngology. vol. 78. November 2014. pp. 1890-1897.

(Over the years there have many proposed causative agents for Kikuchi. This meta-analysis reviews the studies that have been performed to confirm correlation. Based on the conclusions in this study, there is still no definitive agent.)

Deaver, D, Horna, P, Cualing, H, Sokol, L. "Pathogenesis, diagnosis, and management of Kikuchi-Fugimoto disease". Cancer Control. vol. 21. 2014 Oct. pp. 313-21.

(This review focused on the pathogenesis of the disease. Diagnostic criteria are discussed in great detail including pathologic differentiations of phases of the disease as seen on histology.)

Dumas, G, Prendki, V, Haroche, J. "Kikuchi-Fugimoto disease: retrospective study of 91 cases and review of the literature". Medicine (Baltimore). vol. 93. 2014 Nov. pp. 372-82.

(This large retrospective study reviews the characteristics of a large number of patients diagnosed with this rare condition in Europe. There was discussion on severity based on presentation and how one may predict outcomes in these patients. Some risk factors for the developments of SLE were also investigated.)

Khishfe, BF, Krass, LM, Nordquist, EK. "Kikuchi disease presenting with aseptic meningitis". Am J Emerg Med. vol. 32. 2014 Oct. pp. 1298.e1-2.

(Although this case report is of a patient with an unusual presentation of Kikuchi, the authors do a great job of reviewing the literature, epidemiology, evaluation and management of patients with Kikuchi.)

Rakesh, P, Alex, RG, Varghese, GM. "Kikuchi-Fugimoto disease: clinical and laboratory characteristics and outcome". J Glob Infect Dis. vol. 6. 2014 Oct. pp. 147-50.

(This is a retrospective study that reviews histopathology of patients diagnosed with Kikuchi over a 5 year period in a tertiary institution in India. This authors correlate the pathology to the clinical data that had been documented.)

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