Kikuchi-Fujimoto Disease

Etiology

The etiology of Kikuchi-Fujimoto disease remains uncertain and is generally categorized into 2 theories—infectious and autoimmune. Various infectious agents, including viral and bacterial, have been proposed as potential triggers for the disease. However, despite an extensive list of viral suspects, such as Epstein-Barr virus (EBV), herpes simplex virus (HSV) types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus (HHV-6, 7, and 8), parvovirus B19, human papillomavirus (HPV), hepatitis B virus (HBV), human T-lymphotropic virus 1 (HTLV-1), rubella, paramyxovirus, and parainfluenza, no conclusive evidence of a direct viral cause has been firmly established.[9][10][11] A definitive causative link has not been established despite extensive research into the potential association between EBV and Kikuchi-Fujimoto disease.[12] 

Bacterial triggers have also been suspected, including Brucella, Bartonella henselae, Toxoplasma gondii, Yersinia enterocolitica, Entamoeba histolytica, and Mycobacterium species.[11][13] Nevertheless, it is noteworthy that cultures and infectious investigations in Kikuchi-Fujimoto disease typically produce negative results.

Regarding the autoimmune hypothesis, specific human leukocyte antigens (HLAs) have been identified in populations with a higher susceptibility to Kikuchi-Fujimoto disease. Specifically, HLA class II alleles, including HLA-DPA1 and HLA-DPB1, are more prevalent in Asian populations, with a higher disease prevalence.[14]

Kikuchi-Fujimoto disease has been associated with various autoimmune conditions, including SLE, Sjögren syndrome, granulomatosis with polyangiitis, rheumatoid arthritis, and Still disease.[13] Among these autoimmune conditions, SLE is most commonly associated with Kikuchi-Fujimoto disease due to its resemblance with SLE and similar histological and epidemiological characteristics.

Individuals with Kikuchi-Fujimoto disease typically have negative autoimmune serological markers, and the presence of positive markers casts doubt on an exclusive diagnosis of Kikuchi-Fujimoto disease. In cases where individuals already have preexisting SLE, differentiation between lupus lymphadenitis and Kikuchi-Fujimoto disease based solely on histology can be challenging. This indicates that autoimmune conditions may precede, occur simultaneously with, or develop after a diagnosis of Kikuchi-Fujimoto disease.[11]

In addition to the infectious and autoimmune hypotheses, case reports have linked Kikuchi-Fujimoto disease to various other conditions and occurrences, including malignancies, central nervous system infections, renal failure, interstitial lung disease, foreign body implants, and even Roux-en-Y gastric bypass surgery.[11][15] However, among the various competing theories, the predominant explanation for Kikuchi-Fujimoto disease suggests that a viral or unidentified infectious trigger initiates an inflammatory process in a susceptible population.[16][17]

Epidemiology

Kikuchi-Fujimoto disease is extremely rare, and its exact incidence remains uncertain.[18] Typically, the disease affects individuals of any age group, including pediatric populations, but it most commonly manifests in those under 30.[6] Although there was initially a female predominance, more recent studies in Asian populations have suggested a nearly equal ratio of affected males to females.[11][12] 

Notably, Kikuchi-Fujimoto disease is most commonly observed in Asian populations, with only sporadic case studies in the United States and Europe. However, it has also been reported in individuals of various racial and ethnic backgrounds.[19] HLA genotypes in Asian populations have revealed associations with HLA-DPB1 and HLA-DPA1 alleles. However, routine testing for these alleles is not performed in the clinical setting.[20] Although there have been reports of familial associations, it remains unclear whether these cases have shared common genetic or environmental triggers.[21][22]

Pathophysiology

The underlying pathophysiology of Kikuchi-Fujimoto disease remains unclear,[23] but is believed to be triggered by an inflicting infection, autoimmune predisposition, or physical insult leading to an inflammatory cascade. This cascade ultimately results in T-cell–mediated apoptosis and the release of inflammatory cytokines.[24][25] Due to this intense inflammatory reaction, related sequelae, such as the development of SLE or malignancy, are possible.[5]

Histopathology

Diagnosing Kikuchi-Fujimoto disease necessitates an excisional biopsy of an enlarged lymph node, with immunohistochemistry playing a crucial role in excluding other potential differential diagnoses.[26] The condition is characterized by 3 histological stages—proliferative, necrotizing, and xanthomatous.

During the proliferative stage, there is follicular hyperplasia with infiltrates comprised of histiocytes and lymphocytes, with the notable absence of neutrophils and eosinophils. In the necrotizing stage, distinctive features include histiocyte nuclear breakdown (karyorrhexis) and multiple necrotic foci, while the overall lymph node architecture remains intact. Lastly, in the xanthomatous stage, there are foamy histiocytes with the regression of necrotic areas.

A notable absence of neutrophils or eosinophils is evident throughout all these stages, which serves as a crucial distinguishing feature between Kikuchi-Fujimoto disease and infectious etiologies.[17][27] Furthermore, microscopic examination and culture data typically yield negative results.[16]

Immunohistochemistry is crucial in confirming the diagnosis of Kikuchi-Fujimoto disease and differentiating it from other conditions, such as lymphoma.[4] The typical immunohistochemical profile involves positive staining for myeloperoxidase, lysozyme, CD68, CD163, and CD4. In addition, immunohistochemistry will reveal CD8-positive T cells, whereas CD20-positive B cells will be absent.[11] Other common features encompass the presence of CD123-positive plasmacytoid dendritic cells and positive nuclear reactivity for TCL1.[27] 

Although the histopathology of Kikuchi-Fujimoto disease may exhibit similarities to SLE lymphadenitis, distinctive histological characteristics aid in distinguishing between the two conditions. Biopsies in SLE may reveal hematoxylin bodies (collections of nuclear DNA), DNA deposits in vessel walls, and regions of vasculitis surrounding the zones of necrosis.[28] These histological characteristics are indicative of lupus lymphadenitis rather than Kikuchi-Fujimoto disease.[29] 

A distinct histological feature found in SLE lymphadenitis, but not in Kikuchi-Fujimoto disease, is the presence of hematoxylin bodies, which serve as a specific marker for SLE lymphadenitis.[11] Considering these histological differences and taking into account the patient's clinical presentation and serological profile, it becomes feasible to distinguish between Kikuchi-Fujimoto disease and SLE.

History and Physical

Symptoms of Kikuchi-Fujimoto disease typically manifest gradually over several weeks, with an acute to subacute onset. The most prevalent manifestation is unilateral tender posterior cervical lymphadenopathy, observed in 60% to 90% of cases, with occasional involvement of the supraclavicular and axillary nodes.[4][30] In approximately half of cases, the affected lymph nodes are typically mobile, solitary, nonsuppurative, and painful. Generally, these nodes are enlarged to a diameter of 1 to 2 cm, although larger sizes of up to 7 cm have been reported in the literature.[31] 

Bilateral or symmetric lymphadenopathy is also a potential presentation, and in up to 22% of cases, lymphadenopathy can become generalized.[32] Other associated symptoms may include a B-symptom-like presentation, with fever occurring in 36% to 77% of cases, often accompanied by weight loss, night sweats, fatigue, headaches, arthralgias, sore throat, upper respiratory symptoms, nausea, and vomiting.[7] In some instances, splenomegaly and hepatomegaly may be present in 5% of cases, possibly involving the bone marrow and nervous system.[11][16][31] 

Skin involvement is observed in 40% of individuals with Kikuchi-Fujimoto disease, and it can manifest as a nonspecific rash with diverse presentations. These may include maculopapular, morbilliform, nodular, or papular rashes, along with resemblances to erythema multiforme, mucosal ulcerations, diffuse alopecia, malar erythema, and other cutaneous lupus-like skin findings.[15][31] In more acute cases, patients may present with purpura or petechial rashes, which indicate vasculitis upon biopsy.[17][27] 

The clinical presentation of Kikuchi-Fujimoto disease may vary between children and adults. Children are more prone to experiencing severe and prolonged periods of fever and have a higher probability of lymph node necrosis than adults.[12] Therefore, the symptomatology can vary between these 2 age groups.

Evaluation

Due to the rarity and variable presentation of Kikuchi-Fujimoto disease, there are no standardized diagnostic criteria.[16] To establish a diagnosis, clinicians must initially exclude other potential causes of lymphadenopathy, including infectious, malignant, and autoimmune origins.

In the initial assessment, laboratory tests may indicate slightly elevated inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate, and ferritin. Furthermore, there may be elevated levels of aminotransferases and serum lactate dehydrogenase. Leukopenia may be detected in 20% to 58% of cases, whereas leukocytosis is uncommon and may occur in only 2% to 5% of cases. Atypical peripheral lymphocytes may be present in roughly 25% of cases.[11][31] 

Notably, no laboratory findings are specific or pathognomonic for Kikuchi-Fujimoto disease.[17] When evaluating a patient for Kikuchi-Fujimoto disease, it is essential to initiate an infectious workup guided by the patient's medical history, including any recent infectious illnesses, travel history, animal and potential tuberculosis exposures, or current antibiotic use.

Serological testing for various viral causes of lymphadenitis, including acute EBV, CMV, HBV, HSV, HIV, parvovirus B19, and viral respiratory pathogens such as parainfluenza, should be conducted. Testing for other infectious causes of lymphadenitis, such as B henselae, T gondii, E histolytica, and Y enterocolitica, should be considered based on exposure history and clinical presentation. For suspected tuberculous causes of lymphadenitis, the evaluation can include a tuberculin skin test (TST) or an interferon-gamma release assay (IGRA).

Typically, patients may pursue an evaluation for Kikuchi-Fujimoto disease after receiving empiric antibiotic treatment for prevalent bacterial causes of lymphadenitis, such as Staphylococcus aureus or Streptococcus pyogenes. Consequently, these common bacteria should still be considered in the differential diagnosis during the assessment.

Conducting an autoimmune workup is crucial to evaluating patients with suspected Kikuchi-Fujimoto disease. Specifically, evaluation for SLE should include testing for antinuclear antibodies, antibodies to double-stranded DNA, anti-Smith, anti-Ro, and anti-La antibodies. If the patient exhibits positive lupus serological markers, it becomes essential to scrutinize the histology carefully to distinguish between Kikuchi-Fujimoto disease and lupus lymphadenitis.

Furthermore, assessing the serum angiotensin-converting enzyme (ACE) level may be pertinent, although it is not a definitive diagnostic marker for sarcoidosis. A comprehensive evaluation of the patient's and their family's history of autoimmune disease is also essential. Peripheral flow cytometry may be contemplated in cases with a suspicion of malignancy. Histological and immunohistochemical analyses are paramount for excluding malignancy as a potential diagnosis.

Regarding imaging, it is advisable to conduct an ultrasound of the affected lymph node(s), which may reveal hypervascularity and node enlargement, typically ranging from 1 to 2 cm, although some cases have been reported in the literature with sizes up to 7 cm.[27][31] In addition, an abdominal ultrasound and chest radiograph can be utilized to assess for additional lymphadenopathy and organomegaly in the abdomen and chest regions.[16] 

Although CT scanning is unnecessary for diagnosing Kikuchi-Fujimoto disease, distinctive imaging findings from prior CT studies of biopsy-confirmed Kikuchi-Fujimoto disease can provide additional support for the diagnosis. These findings include homogenous nodal contrast enhancement in 83% of cases, low attenuation suggestive of necrosis in 16% of cases, cervical lymphadenopathy ranging from 0.5 to 3.5 cm, and frequent perinodal infiltration. These imaging findings may provide additional evidence to support the diagnosis of Kikuchi-Fujimoto disease and aid in distinguishing it from other possible alternatives.[33]

The definitive diagnosis of Kikuchi-Fujimoto disease relies on an excisional lymph node biopsy. The distinctive histological features observed during the biopsy are unique and crucial in confirming the diagnosis of Kikuchi-Fujimoto disease. Occasionally, a repeat biopsy may be required if the initial biopsy proves inconclusive, often due to the prevailing necrotic tissue.[29] Moreover, a skin biopsy can offer valuable insights, particularly when there is a suspicion of accompanying vasculitis, such as leukocytoclastic vasculitis, or when skin involvement is observed as part of the disease process.[17][27]

Treatment / Management

No specific treatment is available for Kikuchi-Fujimoto disease, as it typically follows a self-limited course with spontaneous resolution occurring within 1 to 4 months or 1 to 6 months.[10]

Supportive management is the mainstay of treatment and involves using antipyretics and analgesics to alleviate symptoms. Patients with severe disease may require a prolonged corticosteroid taper after ruling out infectious etiology. Other treatments that have been successful in the past include hydroxychloroquine, minocycline, or intravenous immunoglobulin.[29][31] (B3)

Kikuchi-Fujimoto disease is usually monophasic; in adults, the recurrence rate is around 3% to 4%. However, in children, the recurrence rate may be higher, reaching 31% to 39% in some studies.[12][34] (B2)

Patients with Kikuchi-Fujimoto disease require close monitoring to observe for the resolution of symptoms and to screen for the development of autoimmune disease (particularly SLE) after the resolution of Kikuchi-Fujimoto disease symptoms.[35](B3)

For patients who have a co-diagnosis of Kikuchi-Fujimoto disease and other autoimmune diseases (with SLE being the most common), appropriate treatment for the secondary autoimmune disorder is required. This may involve using agents such as corticosteroids and hydroxychloroquine.[29][36] (B3)

Long-term follow-up by the primary care provider and a rheumatologist is crucial to monitor for any potential recurrence of Kikuchi-Fujimoto disease and appropriately manage any underlying autoimmune conditions.

Differential Diagnosis

The potential differential diagnosis for Kikuchi-Fujimoto disease includes several conditions, including infectious lymphadenitis, autoimmune etiologies such as SLE, and malignancies, particularly lymphoma.[11] Especially in pediatric populations, it is essential to consider benign sources of lymphadenopathy, such as pharyngitis, otitis media, and upper respiratory tract infections, as they frequently manifest with enlarged lymph nodes.[16] When considering infectious differentials, it is essential to include lymphadenitis secondary to tuberculosis, leprosy, histoplasmosis, cat-scratch disease, syphilis, infectious mononucleosis, HSV, Y enterocolitica, as well as more common bacterial etiologies such as S aureus or S pyogenes.[37] 

To differentiate Kikuchi-Fujimoto disease from infectious causes, cultures, stains for acid-fast bacilli and fungi, as well as microbiological data, are scrutinized, and the results generally turn out negative in cases of Kikuchi-Fujimoto disease. Moreover, the clinical presentation and histological examination can reduce the likelihood of infectious etiologies. The absence of eosinophils, neutrophils, and viral inclusions in histology also contributes to ruling out infectious etiology in Kikuchi-Fujimoto disease. Moreover, negative results in infectious serology and cultures can further bolster the evidence that the histological findings are inconsistent with infectious causes.[11] Several autoimmune differentials should be considered, including SLE, sarcoidosis, and Kawasaki disease, when assessing a patient with suspected Kikuchi-Fujimoto disease.

SLE is the primary consideration in the differential diagnosis of Kikuchi-Fujimoto disease, and the 2 conditions can share similar histological findings. However, the presence of hematoxylin bodies is a specific histological feature in SLE but not in Kikuchi-Fujimoto disease. Serological markers, clinical manifestations, and additional diagnostic criteria in distinguishing between the 2 conditions, as positive SLE autoimmune markers would be notably absent in Kikuchi-Fujimoto disease. Another autoimmune differential, such as sarcoidosis, usually presents with non-necrotizing granulomas and can be screened through ACE levels, chest imaging, and the presence of a cough.[31] 

In the pediatric population, another potential differential diagnosis is Kawasaki disease. This condition is characterized by cervical lymphadenopathy described as a "cluster of grapes" on ultrasound, bilateral conjunctival injection, rash, and mucosal involvement.[31]

Notably, autoimmune pathologies can be co-diagnosed with Kikuchi-Fujimoto disease, and there are case reports of Kikuchi-Fujimoto disease co-diagnosed with primary Sjögren syndrome manifesting as necrotizing lymphatic granulomas. In addition, there have been cases of Kikuchi-Fujimoto disease co-diagnosed with relapsing polychondritis, resulting in bilateral pinnae inflammation and lymphadenopathy, and instances of Kikuchi-Fujimoto disease in conjunction with Still disease and mixed connective tissue disease.[13][31][38] Thus, simultaneous testing for other autoimmune diseases should be initiated when symptoms do not align with the typical Kikuchi-Fujimoto phenotype. Overall, the relationship between Kikuchi-Fujimoto disease and other autoimmune diseases is not fully understood, and the involvement of a rheumatologist is imperative.

Lymphoma is a significant consideration in the differential diagnosis of Kikuchi-Fujimoto disease. A thorough examination of histology and immunostaining of the biopsy sample, along with peripheral bloodwork, can aid in ruling out malignant etiologies.

In histological examination, the absence of CD20-positive B cells in Kikuchi-Fujimoto disease diminishes the likelihood of B-cell lymphoma. In contrast, the lack of positive stains for myeloperoxidase in Kikuchi-Fujimoto disease assists in distinguishing it from T-cell lymphomas. The absence of Reed-Sternberg cells, the lack of staining for CD30 and CD15, and unremarkable results in peripheral flow cytometry can also be employed to exclude lymphoma.[31] Furthermore, physical examination findings in lymphomas and other malignancies typically reveal painless, nonmobile lymphadenopathy and a more gradual progression of lymph node enlargement than the acute and tender lymphadenopathy observed in Kikuchi-Fujimoto disease.[37]

Prognosis

Kikuchi-Fujimoto disease is generally a benign and self-limited inflammatory condition that resolves without specific treatment within a few months. The relapse rate in adults is approximately 3% to 4%. Treatment options for a relapse may include corticosteroids, intravenous immunoglobulins, or hydroxychloroquine.[27][31] 

Predicting the likelihood of relapse is challenging, but some studies have suggested that relapse is associated with a high peripheral absolute lymphocyte count in cases of recurrent Kikuchi-Fujimoto disease, even in the presence of leukopenia. The relapse rate in children seems to be higher, potentially reaching up to 38.5%.[34] 

Another study reported that an excisional lymph node biopsy offers diagnostic and therapeutic advantages, with patients frequently experiencing rapid improvement following the procedure.[39] 

The prognosis for Kikuchi-Fujimoto disease is generally favorable despite its initial diagnostic challenges. Although rare, some studies indicate the development of SLE months or years after a Kikuchi-Fujimoto disease diagnosis, potentially attributed to the generation of autoantibodies during the clearance of cell debris following Kikuchi-Fujimoto lymphadenitis. Although the incidence of SLE development appears to be low, reported in 2 out of 61 patients in one study and 4 out of 169 patients in another study,[37] it still warrants rheumatology follow-up for surveillance.[27][37] A routine follow-up with a primary care provider and a rheumatologist is highly recommended to monitor for resolution or recurrence of this typically benign, self-limited condition.

Complications

In extremely rare cases, the immunological stress associated with Kikuchi-Fujimoto disease can potentially trigger HLH—a severe immunological response characterized by histiocytic proliferation, hemophagocytosis, systemic inflammatory response, and disseminated intravascular coagulation. HLH can be life-threatening and is linked to a mortality rate of 20% to 42%. HLH management typically involves using intravenous immunoglobulin and methylprednisolone to suppress the immune response. Pediatric patients with HLH generally experience more favorable outcomes compared to adults.[16][40]