Symptoms of Kikuchi disease develop over several weeks, with an acute to subacute presentation. The most common presentation is of unilateral tender posterior cervical lymphadenopathy in 60-90% of cases, with occasional involvement of the supraclavicular and axillary nodes. Affected lymph nodes are typically mobile, solitary, nonsuppurative, and are painful in approximately half of cases. The affected nodes are enlarged typically to 1-2cm in diameter, however up to 7cm has been reported in the literature [13].  Bilateral or symmetric lymphadenopathy can occur, and lymphadenopathy can be generalized in 1-22% of cases. Other associated symptoms include B-like presentation with fever in 36-77% of cases, accompanied by weight loss, night sweats, fatigue, headaches, arthralgias, sore throat, upper respiratory symptoms, nausea, and vomiting. Splenomegaly and hepatomegaly are present in 5% of cases and there can be bone marrow and nervous system involvement [1][5][1][13]. Notably, skin involvement occurs in 40% of Kikuchi disease cases and can present as a nonspecific rash which can be maculopapular, morbilliform, nodular/papular, as well as with the appearance of erythema multiforme, mucosal ulcerations, diffuse alopecia, malar erythema, and other cutaneous lupus-like skin findings [4][13]. More acute presentations include purpura or petechial rashes, and on biopsy are found to have vasculitis [6][11]. The clinical presentation can differ between children and adults, as children are more likely to have severe and prolonged durations of fever and have a higher likelihood of lymph node necrosis compared to adults [2]. Thus, the symptomatology can vary.

There are no set diagnostic criteria for Kikuchi disease, given its rarity and variable presentation [5]. Typically, infectious, malignant, and autoimmune etiologies of lymphadenopathy must be excluded, and excisional biopsy is required to make the diagnosis.

The initial lab work may reveal mildly elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, ferritin), elevated aminotransferases and elevated serum lactate dehydrogenase. Leukopenia occurs in 20-58% of cases; leukocytosis is rare and occurs in 2-5% of cases. There may be atypical peripheral lymphocytes present in 25% of cases [1][13]. However, there are no lab findings that are specific or pathognomonic for Kikuchi disease [6].

Infectious workup should be initiated, guided by the history of any recent infectious illnesses, travel, animal exposures, tuberculosis exposures, or recent antibiotic use. Serology for various viral causes of lymphadenitis including testing for acute EBV, CMV, Hepatitis B, Herpes simplex, HIV, parvovirus B19, and viral respiratory causes such as parainfluenza should be obtained. Testing for other infectious causes of lymphadenitis such as Bartonella henselae, Toxoplasma gondii, Entamoeba histolytica, and Yersinia enterocolitica should be performed depending on exposure history and clinical presentation. Testing for tuberculous causes of lymphadenitis can be initiated with tuberculin skin test (TST) or interferon-gamma release assay (IGRA). Typically, patients present for evaluation for Kikuchi disease after having already failed trial of empiric antibiotics for common bacterial lymphadenitis etiologies such as Staphylococcus aureus or Streptococcus pyogenes, however, these common bacteria may remain in the differential.

Autoimmune workup should be performed, particularly evaluation for SLE with antinuclear antibodies, antibodies to double-stranded DNA, anti-Smith, anti-Ro, and anti-La antibodies. If the patient has positive lupus serologic markers, the histology must subsequently differentiate Kikuchi disease from lupus lymphadenitis. Serum ACE level can be checked, although is nondiagnostic for sarcoidosis. A personal or family history of autoimmune disease should be elucidated. Peripheral flow cytometry can be performed if there his suspicion for malignancy, and histology and immunohistochemistry will be crucial to rule out this diagnosis.

In terms of imaging, ultrasound of the affected lymph node(s) should be performed and may show hypervascularity and node enlargement typically 1-2cm, up to 7cm in the literature [11][13][11]. Additionally, an abdominal ultrasound and chest radiograph can be used to evaluate for additional lymphadenopathy and organomegaly [5]. Further imaging such as CT scanning is not required, although prior CT studies of biopsy-confirmed Kikuchi disease showed homogenous nodal contrast enhancement in 83% of cases, low attenuation suggestive of necrosis in 16%, cervical lymphadenopathy in the range of 0.5-3.5cm, and frequent perinodal infiltration. This may help support the diagnosis and parse out alternatives [14].

Ultimately, excisional lymph node biopsy is required. The histological characteristics of Kikuchi disease are unique, as explained in the histopathology section of this paper, and will ultimately cinch the diagnosis. Occasionally, a repeat biopsy may be required if the initial biopsy is inconclusive due to the predominance of necrosis [12]. Additionally, skin biopsy can help identify concomitant vasculitis (such as leukocytoclastic vasculitis) or other skin involvement seen in the disease process [6][11].

There is no specific treatment available for Kikuchi disease. It is typically a self-limiting disease, and spontaneous resolution occurs within one to four, or one to six months. Treatment includes supportive management with antipyretics and analgesics, although some patients with severe disease may require a prolonged corticosteroid taper, after infectious etiology is ruled out. Other treatments that have been successful in the past include hydroxychloroquine, minocycline, or intravenous immunoglobulin [12][13][12]. Typically, Kikuchi disease is monophasic; in adults there is a recurrence rate of 3% to 4%, however, in children it is around 31-39% in some studies [2][15]. Patients require close monitoring for resolution of Kikuchi disease, and possible periodic testing for the development of autoimmune disease (particularly SLE) after resolution of Kikuchi symptoms. For patients with co-diagnosis of Kikuchi disease and other autoimmune diseases (SLE being most common), the appropriate treatment for the secondary autoimmune disorder with agents such as corticosteroids and/or hydroxychloroquine is required [12][16][12]. Patients should be followed long term for the recurrence of Kikuchi disease by their primary care provider as well as a rheumatologist.

The differential diagnosis of Kikuchi disease includes infectious lymphadenitis, autoimmune causes such as systemic lupus erythematosus, and malignancy, particularly lymphoma [1].

Particularly in the pediatric populations, sources of benign lymphadenopathy (such as pharyngitis, otitis media, upper respiratory infection) should be considered [5]. Other infectious differentials would include lymphadenitis secondary to tuberculosis, leprosy, histoplasmosis, cat-scratch disease, syphilis, infectious mononucleosis, herpes simplex, Yersinia enterocolitica, as well as more common bacterial etiologies such as Staphylococcus aureus or Streptococcus pyogenes [17]. Ultimately cultures and stains for acid-fast bacilli and fungi and microbiology data are negative in Kikuchi disease and the clinical picture will show infectious etiology as less likely. The absence of eosinophils, neutrophils, and viral inclusions on histology also helps rule out infectious etiology in Kikuchi disease, and negative infectious serology and cultures can help triangulate histological findings as being incompatible with infectious cause [1].

Autoimmune differentials include SLE, sarcoidosis, Kawasaki disease; SLE is highest on the differential. On histology, findings of SLE and Kikuchi disease may be similar, with hematoxylin bodies being unique to SLE on histology compared to Kikuchi disease. Additionally, the two diseases would be differentiated based on serology and clinical picture, as SLE autoimmune markers would be negative in Kikuchi disease alone. Another autoimmune differential such as sarcoidosis typically presents with non-necrotizing granulomas and can be screened for with ACE level, chest imaging, and symptomatology such as cough [13]. Kawasaki disease can be a differential in the pediatric population, and typically presents with cervical lymphadenopathy (on ultrasound described as ‘cluster of grapes’), bilateral conjunctival injection, rash, and mucosal involvement [13].

Of note, autoimmune pathologies can be co-diagnosed with Kikuchi disease. There are case reports of Kikuchi disease co-diagnosed with primary Sjogren’s syndrome manifesting as necrotizing lymphatic granulomas, Kikuchi disease co-diagnosed with relapsing polychondritis manifesting as bilateral pinnae inflammation and lymphadenopathy, and Kikuchi disease in Still’s disease and mixed connective tissue disease [3][13][18]. Thus, concomitant testing for other autoimmune diseases should be initiated for symptoms that otherwise do not fit the characteristic Kikuchi phenotype. Overall, the relationship between Kikuchi disease and other autoimmune diseases is incompletely understood and the involvement of a rheumatologist is important.

Lastly, lymphoma is in the differential in Kikuchi disease. Histology as well as immune staining of the biopsy sample can help rule out these malignant etiologies, as can peripheral bloodwork. On histology, the paucity of CD-20 positive B cells makes B cell lymphoma less likely, and positive stains for myeloperoxidase in Kikuchi disease are absent in T-cell lymphomas. The absence of Reed-Sternberg cells and CD30/CD15 staining, as well as unremarkable peripheral flow cytometry, can additionally be used to rule out lymphoma [13]. Additionally, physical exam findings of lymphomas and other malignancies typically show painless nonmobile lymphadenopathy, along with more slowly progressing lymph node enlargement compared to Kikuchi disease [17].

Kikuchi disease is typically a benign, self-limiting inflammatory process that resolves with supportive measures within months without any specific treatment.  The relapse rate is about 3-4% in adults and is treated with corticosteroids, intravenous immunoglobulins, or hydroxychloroquine [11][13]. Relapse is difficult to predict, although Yoo et. al. found that relapse is correlated with a high peripheral absolute lymphocyte count (ALC) despite leukopenia in recurrent Kikuchi disease, and the rate of relapse in children is higher, up to 38.5% [15]. Another study found that removal of the affected lymph node has both a diagnostic as well as therapeutic effect, as patients improve quickly after excisional lymph node biopsy [19]. Overall, the typical prognosis of Kikuchi disease is good, despite the diagnostic puzzle with which it may initially present. Rarely, some studies show the development of systemic lupus erythematosus months or years after diagnosis of Kikuchi disease, possibly caused by the generation of autoantibodies during the process of clearing cell debris following Kikuchi lymphadenitis. The rate of SLE development appears low, however, seen in two out of 61 patients in one study, and in four out of 169 patients in a second study [17]. Overall, however, rheumatology follow up for Kikuchi disease is strongly recommended for surveillance [11][17]. Thus, patients should follow with their primary care provider as well as rheumatologist routinely for monitoring for resolution or recurrence of this otherwise typically benign self-limiting condition.

Exceedingly rarely, the immunologic stress of Kikuchi disease can lead to hemophagocytic lymphohistiocytosis (HLH), which is a strong immunologic response associated with histiocytic proliferation, hemophagocytosis, systemic inflammatory response and disseminated intravascular coagulation that can be life-threatening with a mortality rate of 20-42%. HLH is managed with intravenous immunoglobulin and methylprednisolone, and pediatric outcomes are typically better than adults [5][20]. 

Given the rarity of the condition, patient education in Kikuchi disease is of paramount importance. Reassurance that this is a self-limiting condition can be comforting to patients and family members, especially as initial evaluation includes differentials such as malignancy and serious infection. However, the possible complications and correlation to autoimmune disease should be made clear. Management including symptomatic control with analgesics and antipyretics should be explained to patients and caregivers, and the lack of indication for antibiotics should be emphasized. The importance of follow up for symptom monitoring and resolution is key, and patients should be educated on the importance of following up with their primary care provider and rheumatologist for long-term monitoring.

Due to the rarity of the disorder, clinicians are often unfamiliar with the diagnosis of Kikuchi disease, and subsequently, there is a misdiagnosis rate estimated to be up to 40%. This is associated with inappropriate courses of antibiotic therapy and increase the time to diagnosis for this disorder [1][11][21]. As such, greater widespread education and awareness of the disease is imperative. Overall, the disease is best managed by an interprofessional team that includes an infectious disease expert, rheumatologist, internist, and pathologist, who can collaborate on managing this rare condition.