INTRODUCTION:

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is an extremely uncommon, idiopathic, and frequently self-limiting form of lymphadenitis¹. Kikuchi and Fujimoto et al. were the first to detect this disease in Japan in 1972^1,2. The populations most likely to contract this disease are those in Japan and other parts of Asia. Most of the occurrences (92%) are in Asian countries, whereas only 22 cases (7%) occurred in the United States³.

The presence of histiocytic necrotizing lymphadenitis on lymph node biopsy can be used to primarily diagnose this disease⁴^,5. The most trustworthy laboratory finding is leukopenia¹. Fever and cervical lymphadenopathy distinguish it from other benign illnesses⁶. It is also marked by signs of an upper respiratory infection, less frequent chills, nocturnal perspiration, arthralgia, a rash, and weight loss. Splenomegaly, hepatomegaly, and peripheral and central neurologic involvement may occur infrequently³. Lymph nodes are frequently the source of uncomfortable and sensitive feelings³.

KFD is caused by one or more unknown agents, most likely viruses. The agents initiate a self-limiting autoimmune process in people genetically predisposed to an autoimmune response⁷. As a result, it is possible to misdiagnose this clinical picture as malignant lymphoma, systemic lupus erythematosus (SLE), bacterial adenitis (most commonly TB or cat scratch disease), or viral infection (such as mononucleosis)⁸.

Females, namely younger than 30 years old were most commonly affected with Kikuchi’s disease^8,9. In most cases, KFD resolves itself within one to four months. According to studies, 3–4% of people might still experience a disease recurrence. In addition, there is a possibility of developing SLE, which may manifest years later. There is no evidence that KFD poses a genetic risk^3,10.

The aim of this review is to provide a comprehensive overview of Kikuchi-Fujimoto disease (KFD), including its epidemiology, clinical features, diagnostic methods, prognosis, and potential long-term complications, to raise awareness of this uncommon form of lymphadenitis and improve its diagnosis and management.

AFFECTED POPULATION:

KFD is a rare condition that primarily affects East Asian and Japanese populations¹¹, but cases have been reported in other parts of the world. It was first observed in young Japanese women, but later cases have affected people of different racial and ethnic origins^1,2. Individuals from diverse ethnic and racial backgrounds, including White or Caucasians, Hispanics, African Americans, and Asians, have been found to be affected by KFD¹². There is substantial evidence from multiple studies^4,13,14 indicating the occurrence of KFD in individuals belonging to diverse racial and ethnic groups worldwide.

SIGNS AND SYMPTOMS:

KFD is characterized by fever and lymphadenopathy. Cervical lymphadenopathy is the most prevalent symptom and occurs in up to 80% of patients. It is frequently unilateral (88.5% of the time) and consists primarily of painful lymph nodes in the posterior cervical triangle^10,13. Lymph nodes are typically between 0.5 and 4 centimeters in diameter, but on rare occasions, they may have a diameter of 6 centimeters or more^15,16. As a result of their illness, up to 59% of individuals will experience painful lymphadenopathy^15,16,17. According to research, between 1% and 22% of individuals have been observed to develop generalized lymphadenopathy^{10,13,15, 16,17} and can be unpleasant or uncomfortable^1,6.

Patients may experience fever that may last from one to seven weeks, with temperatures ranging from 38.6 degrees Celsius to 40.5 degrees Celsius¹⁸. Additional nonspecific signs and symptoms include upper respiratory symptoms, persistent low-grade fever or high-grade fever^19,20, malaise, arthralgia, myalgia, nausea, vomiting, fatigue, sore throat²¹, parotid gland enlargement, interstitial lung disease, and diarrhoea. The likelihood of experiencing night sweats and weight loss is relatively low⁸.

Kikuchi's disease can manifest as extranodal involvement affecting the skin. Skin-related extranodal involvement includes erythematous macules, maculopapular rashes^22,23, papules, and plaques^22,24. Despite being a rare condition, KFD can result in neurological involvement of both the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves responsible for movement and sensation)³. The patients may exhibit changes in their cognitive function attributed to neurological signs and symptoms, namely somnolence, disorientation, amnesia, and impaired consciousness²⁵. While not common, a limited number of KFD patients have demonstrated ocular involvement. This ocular involvement has been evidenced by papillary conjunctivitis and unilateral/bilateral uveitis²⁶.

ETIOLOGY AND PATHOGENESIS:

The etiology has been associated with infectious factors. KFD exhibits a clinical profile resembling that of a viral illness. Furthermore, similar to a viral infection, antibiotics are inappropriate treatment option for this condition¹⁷. Human immunodeficiency viruses, Epstein-Barr virus, rubella, cytomegalovirus (CMV), parvovirus B19, human herpesvirus, histoplasmosis, Brucella, Bartonella henselae, Yersinia enterocolitica, Toxoplasma gondii, as well as various other fungi, might be potential etiological agents for this disease²⁷. Based on positive serologic test results, Yersinia enterocolitica and Toxoplasma gondii are identified as likely causes of the disease⁴. Nevertheless, there is a lack of evidence to substantiate that any of the aforementioned viruses are responsible for the onset of Kikuchi disease²⁸.

Genetic and autoimmune factors may also play a role in developing KFD²⁹. An ultrastructural analysis was conducted on tissue samples taken from individuals with KFD, which revealed similarities to the histopathological findings seen in patients with SLE. While there appears to be a potential association between Kikuchi disease and SLE, the link has not yet been definitively established³⁰.

There is evidence to suggest that KFD has a genetic predisposition, with certain HLA class II genes being more common among KFD patients, particularly in Asians³¹. It has been hypothesized that specific compounds may be produced during the initial infection or from damaged host cells, leading to heightened T-cell-mediated immune responses to various antigens in KFD patients⁴. These compounds can attach to cells inside target organs, leading to inflammation in pathological lesions³². Certain HLA class II alleles, specifically HLA-DPA1 and HLA-DPB1, are more prevalent in KFD patients compared to the general population, with some alleles being more frequent in Asians and rare or non-existent in other populations⁴.

Several case reports have described KFD alongside a variety of pathologic illnesses such as meningitis³³, status epilepticus³⁴, interstitial lung diseases, myocarditis, acute renal failure³⁵, hemophagocytic syndrome³⁶, sickle cell anemia³⁷, malignancies^38,39, patients with breast implants⁴⁰, and pacemakers¹³. These findings suggest that foreign bodies may trigger the development of disease.

RELATED DISORDERS:

Although KFD is rare, it should be considered a differential diagnosis for "lymph node enlargement" in Western nations. The reason is that the course and treatment of KFD differ significantly from those of lymphoma, tuberculosis, and SLE⁴. Kikuchi disease can be clinically misdiagnosed with various conditions, including infectious mononucleosis, CMV disease, toxoplasmosis, cat scratch disease, sarcoidosis, mycobacterial disease, systemic lupus lymphoma, malignant tumors, lupus lymphadenitis, Hodgkin or non-Hodgkin lymphoma, and solid metastatic malignancy with necrosis^16,41. Several studies have indicated that distinguishing KFD from tuberculosis (TB) can be challenging due to their similar symptoms² ^,8^,42.

Individuals with SLE may develop a type of lymphadenitis that resembles necrotizing Kikuchi-Fujimoto disease (KFD) but has distinct characteristics⁴. When clinicians examine lymph nodes affected by SLE, they can identify two distinct characteristics: the Azzopardi phenomenon and the HE bodies. The Azzopardi phenomenon refers to the accumulation of nuclear material on the walls of blood vessels, while the HE bodies are believed to be dead cell nuclei that have reacted with autoantibodies. KFD does not exhibit these characteristics⁴.

When examining samples, the presence of a limited number of cytotoxic T cells suggests a higher probability of an association between lymphadenitis and SLE, which is in contrast to the previous report of abundant CD8+ cells in the lymph nodes of individuals with KFD⁴³. Finally, SLE-related lymphadenitis is more likely to develop when several plasma cells in a specific lymph node exhibit the KFD-associated characteristics¹⁵.

Diagnosing Kikuchi-Fujimoto disease (KFD) is crucial because it can be misdiagnosed as malignant lymphoma, which can result in inappropriate treatment and fatal consequences. KFD can present multiple immunoblasts that resemble diffuse large cell lymphoma, but histiocytes are easily distinguishable due to their weak nuclear membrane. The polymerase chain reaction for T-cell gene rearrangement can also help distinguish KFD from peripheral T-cell lymphoma^14,15. The term "Signet-ring histiocyte" denotes a specific subtype of histiocyte that bears resemblance to signet-ring cells and is commonly associated with Kikuchi-Fujimoto disease. Occasionally, the similarity between the histiocyte and metastatic adenocarcinoma cells can lead to a misdiagnosis, although this occurrence is infrequent¹⁴.

Earlier investigations have indicated an association between Kikuchi-Fujimoto disease and systemic autoimmune diseases including arthritis⁴⁴, adult Still's disease⁴⁵, polymyositis⁴⁶, interstitial lung disease⁴⁷, scleroderma⁴⁸, and drug hypersensitivity⁴⁹.

DIAGNOSIS:

Kikuchi disease is typically diagnosed through lymph node biopsy, histology, and immune histochemistry. The hallmark feature of this disease is histiocytic necrotizing lymphadenitis, which serves as a critical diagnostic criterion^4,5,9,50. Although an excisional biopsy of the affected lymph nodes may facilitate diagnosis^19,51, it is imperative to conduct a thorough assessment to rule out alternative etiologies of fever and lymphadenitis⁵².

In the diagnostic evaluation of Kikuchi disease, adjunctive measures such as magnetic resonance imaging, cerebrospinal fluid analysis, and electroencephalogram may contribute to avoiding unnecessary therapeutic interventions⁵⁰. It is noteworthy that excisional lymph node biopsy is more effective than fine-needle aspiration cytology in establishing a cytologic diagnosis of Kikuchi disease. However, if fine-needle aspiration cytology provides a conclusive diagnosis, the need for a surgical biopsy may be eliminated^14,53.

In cases where dural involvement is suspected, a dural biopsy can be undertaken to reveal histiocytic necrotizing inflammation that bears a resemblance to the characteristic histologic features of Kikuchi disease⁵². Furthermore, a dermoscopy study of skin lesions may represent an efficacious diagnostic modality by facilitating the analysis of the histological architecture of the cutaneous lesions⁵⁵.

Although ultrasonography and computed tomography (CT) scans do not exhibit any distinctive clinical manifestations of Kikuchi-Fujimoto disease, patients with the condition present a distinctive lymphadenopathy pattern on CT and magnetic resonance imaging (MRI)^{56, 57}. This pattern encompasses a tightly arranged configuration of diminutive lymph nodes. Nevertheless, careful consideration is essential in the interpretation of these results owing to the limited scale of the sample. Moreover, it should be noted that CT and MRI findings similar to those in Kikuchi-Fujimoto disease can be encountered in various nodal diseases with necrosis, such as tuberculosis and metastasis^56,57.

An abdominal ultrasound scan (USS) has the potential to reveal hepatomegaly and fatty liver disease. In addition, several other diagnostic tests, such as bone marrow biopsy, cervical lymph node biopsy, skin biopsy, neck ultrasound, chest X-ray, bone marrow aspirate, chest radiograph, and chest CT scan, can aid in diagnosing Kikuchi-Fujimoto disease⁵⁸. When making a differential diagnosis, other conditions such as lymphoma, SLE, infectious mononucleosis, Kawasaki disease, sarcoidosis, tuberculosis, and syphilis should also be considered¹⁶.

LABORATORY FINDINGS:

The diagnosis of KFD presents a considerable challenge to clinicians, largely due to the absence of well-defined serological markers²³. Nonetheless, a heightened level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)^4,8,59, thrombocytopenia⁸, leukopenia¹⁹, and atypical lymphocytes in the peripheral blood have been posited as potential indicators of the condition⁸. Diagnostic evaluations typically include a comprehensive blood count, white blood cell differential, liver enzyme analysis, and lactate dehydrogenase assessment⁶⁰. Necrosis of the lymph nodes was detected in approximately a third of KFD patients, and granulocytopenia emerges as a common complication of the disease⁸. Importantly, the bone marrow of these patients was observed to contain fewer granulocyte precursor cells, and while T lymphocytes may not substantially suppress the formation of colony-forming units in culture (CFU-C), inhibitory factors could be incriminated in this regard⁶¹. Additionally, certain patients may exhibit non-specific effects such as elevated levels of aminotransferases, transaminitis, and lactate dehydrogenase and ferritin levels^51,62.

HISTOPATHOLOGY:

Certain histopathologic characteristics are necessary to diagnose Kikuchi disease, including necrosis patches with karyorrhetic debris and histiocyte subtype diversity^4,63. It is important to note that atypia in the reactive immunoblastic component is common and may be mistaken for lymphoma. The immunophenotype of KFD is often characterised by a lack of B cells⁴, eosinophils, neutrophils, and plasma cell infiltration^1,2,64 an overabundance of T cells, and a higher proportion of CD8+ T cells compared to CD4+ T cells in the T cell population⁴. It is believed that Kikuchi disease is caused by an excessive T-cell immune response to a trigger, most likely a virus or an autoimmune condition⁴

Histopathological features include (a) Necrotizing lymphadenitis (b) Extensive karyorrhexis inside the necrotic areas (c) Atypical lymphocytes in the necrotic areas (d) The presence of mostly mononuclear cells in the infiltrate, with only sporadic macrophages and no neutrophils^4,13,15.

The histopathological attributes of KFD comprise a triad of sequential histologic stages, namely xanthomatous, necrotizing, and proliferative, each of which manifests a distinct set of characteristics⁶⁵. During the proliferative phase, an array of histiocytes, plasmacytoid monocytes, and lymphoid cells of diverse types can be discerned⁶⁶. Of note, the lymphoid cells harbor eosinophilic apoptotic debris and karyorrhectic nuclear fragments, both of which are hallmarks of apoptosis^4,65. To ascertain the presence of necrotizing KFD, it is imperative to examine cellular aggregates in a specific lymph node for any degree of coagulative necrosis. On the contrary, if the KFD lesions are primarily constituted by foamy histiocytes, the case is classified as xanthomatous, irrespective of the existence or non-existence of necrosis⁶⁵. Notably, xanthomatous KFD is the most prevalent subtype, accounting for slightly over fifty percent of all instances⁴.

KFD is distinguished by the concurrent expression of CD68 and myeloperoxidase (MPO) in histiocytes, while plasmacytoid monocytes exhibit CD68 expression but not MPO⁶⁷. Additionally, histiocytes within KFD lesions harbor a limited number of plasma cells, active T cells, and minuscule lymphocytes⁶⁸. The predominant lymphocyte subset observed in KFD lesions is T cells, of which CD8-positive T cells are more prevalent than CD4-positive T cells, and a lack of CD20-positive B cells is observed in the lesions. Furthermore, CD3-positive staining is also prevalent^68,69.

Kikuchi's disease manifests in skin lesions with several distinct characteristics, including a general interface dermatitis, the presence of non-neutrophilic karyorrhectic debris, and necrotic keratinocytes in the epidermis²². The predominant infiltrates in affected tissues consist of histiocytic cells and CD68-positive lymphocytes, with only a small number of CD30-positive cells and CD3-positive lymphocytes present in the dermis^22,24. Dermoscopic examination of lesions reveals a regular pattern of linear veins and a strawberry-like appearance against a pink background, likely resulting from thick infiltrates in the top epidermis and dilated veins in the superficial dermis^22,55. Skin biopsy results further confirm the presence of granulocytes in the dermis and surrounding adnexae, alongside hyperkeratosis, acanthosis, clusters of histiocytes, crescentic histiocytes, eosinophils, lymphocytes, and nuclear debris²⁰.

The bone marrow biopsy indicates that the patient has cellular bone marrow with modest granulocytic hyperplasia and hemophagocytosis²⁰. Meanwhile, immunohistochemical analysis of the bone marrow aspirate shows that the marrow is reactive with a moderate lymphocyte population expressing CD20, CD79a, CD3, CD10, and TdT antigens⁷⁰. Additionally, there is a moderate plasma cell population expressing CD79a, and a small number of plasma cells are also present⁷⁰.

The development of a clear histologic distinction between SLE and KFD is challenging, given that the specific symptoms of these diseases may not always be apparent, and pathologic specimens may appear similar to one another⁷¹. However, KFD can be distinguished from lupus lymphadenitis in the absence of granulocytes, plasma cells, and hematoxylin bodies⁷².

STANDARD THERAPY:

The mainstay of treatment for patients requiring medical intervention for Kikuchi-Fujimoto disease involves steroid therapy or the use of steroid-sparing medications, such as hydroxychloroquine^6,27. In severe cases with significant clinical involvement and increased complexity, intravenous immunoglobulin or rituximab may be necessary⁷³. Symptomatic treatment typically involves the use of ibuprofen and naproxen^41,74. Acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) are sufficient treatments for many patients⁸.

Corticosteroids and/or hydroxychloroquine have been recommended for KFD patients exhibiting extra-nodal involvement, widespread illness, or recurrence⁷⁵. Moreover, corticosteroids have demonstrated potential benefits for patients with Kikuchi disease⁷⁶, attributed to their ability to mitigate overactive immune cell responses³². Early intervention with these medications at appropriate doses is considered crucial for the effective management of KNL⁵⁰. However, due to the potential side effects associated with their use, careful consideration must be given before recommending corticosteroid therapy⁷³. Glucocorticoids have also shown promise in the management of severe or recurring KFD cases⁷⁶. A case study reported successful treatment of Kikuchi disease with hydroxyzine and triamcinolone 0.1% cream, with resolution of the eruption occurring within a time frame of approximately three to four weeks²².

Kikuchi disease patients have been effectively treated with various doses and forms of prednisolone. Oral prednisolone has been prescribed at doses ranging from 30mg to 60mg per day, with gradual tapering of the dosage as symptoms subside⁷⁷. Methylprednisolone pulse treatment intravenously has also been administered in conjunction with oral prednisolone²⁰. Furthermore, a dosage of 2 milligrams per kilogram of prednisone for five days has been widely utilized in treating Kikuchi disease patients^63,78. Oral minocycline has demonstrated considerable improvement in KFD patients, indicating its potential effectiveness against the bacteria responsible for the disease^76,79. Additionally, lymph node removal has been identified as a therapeutic measure with diagnostic benefits, and some patients have reported quick symptom relief following excisional biopsy⁶⁴^,80.

Hemophagocytic lymphohistiocytosis (HLH), which is a complication of KFD, is conventionally managed using a combination of intravenous immunoglobulins and steroids. If this regimen fails to yield the desired therapeutic outcome, alternative interventions such as etoposide may be considered^81,82. In cases where KFD occurs concurrently with another medical condition or neurological symptoms, the administration of corticosteroids has been shown to potentially improve the patient's condition¹⁶.

COMPLICATIONS:

Kikuchi disease, a rare condition, is not commonly accompanied by the life-threatening complication of hemophagocytic lymphohistiocytosis (HLH)⁸³. Nonetheless, a limited number of instances of secondary HLH, also known as hemophagocytic syndrome (HS)^69,84,85, have been recorded in western nations, typically in situations characterized by highly activated immune systems, such as severe infections, cancer, autoimmune disorders, and metabolic irregularities^21,32. HS symptoms encompass hemophagocytosis, hepatosplenomegaly, fever, severe lymphadenopathy, hypertriglyceridemia, and hypofibrinogenemia^21,32.

While systemic lupus erythematosus develops only in 20% of individuals with KFD^6,8, the disease confers a higher likelihood of severe consequences^69,84,85. Recent investigations have reported that 11% of patients with meningitis or encephalitis experience neurological complications^{25, 41,86, 87}, with aseptic meningitis being the most frequently observed neurological complication^{41,87, 88}. Additional neurological manifestations of KFD may comprise mononeuritis multiplex, hemiparesis, brachial neuritis, and photophobia. Although rare, ocular complications have also been documented, including anterior uveitis, panuveitis, occlusive retinal vasculitis, papillary edema, and preretinal hemorrhage, as documented in various studies^{89,
90, 91}.

CONCLUSION:

Kikuchi-Fujimoto disease (KFD) is a rare lymphadenitis that mainly affects cervical lymph nodes. It primarily occurs in Japan and other parts of Asia but has been reported in various ethnic groups globally. Diagnosis requires lymph node biopsy as it can be mistaken for other benign conditions. Early treatment with corticosteroids and hydroxychloroquine is vital, but their side effects should be considered. Lymph node removal has shown therapeutic benefits, providing diagnostic value and symptom relief. More research is necessary to comprehend KFD's mechanisms and develop improved treatments to manage this condition effectively.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

REFERENCES:

1. Primrose WJ, Napier SS, Primrose AJ. Kikuchi-Fugimoto disease (Cervical Subacute Necrotising Lymphadenitis): an important benign disease often masquerading as lymphoma. Ulster Med J. 2009 May; 78(2):134-136.

2. Guadarrama MB, Guzmán-Aguilar OD, López-Ugalde AC, Navarro JS, Cruz-Ortíz H. Kikuchi-Fujimoto disease associated to the epstein-barr virus. a type of rare necrotizing lymphadenitis and its differential diagnosis. Open Journal of Pathology. 2013 Sep 18; 3(04):186. Available from: https://doi.org/10.4236/ojpathology.2013.34034.

3. Longaretti P, Savasta S, Caimmi D, Possenti I, Marseglia GL. Kikuchi-Fujimoto disease complicated by peripheral neuropathy. Pediatr Neurol. 2012 May; 46(5):319-321. doi:10.1016/j.pediatrneurol.2012.02.024.

4. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease: a comprehensive review. Am J Clin Pathol. 2004 Jul; 122(1):141-152. doi:10.1309/YF08-1L4T-KYWV-YVPQ.

5. Jasmine Kaur. Systemic Lupus Erythematous: A Case Study. Asian J. Nur. Edu. and Research 5(4): Oct.- Dec.2015; Page 501-504.

6. Dumas G, Prendki V, Haroche J, Amoura Z, Cacoub P, Galicier L, et al. Kikuchi-Fujimoto disease: retrospective study of 91 cases and review of the literature. Medicine (Baltimore). 2014 Nov; 93(24):372-382. doi:10.1097/MD.0000000000000220.

7. Lelii M, Senatore L, Amodeo I, Pinzani R, Torretta S, Fiori S, et al. Kikuchi-Fujimoto disease in children: two case reports and a review of the literature. Ital J Pediatr. 2018 Jul 18; 44(1):83. doi:10.1186/s13052-018-0522-9.

8. Kucukardali Y, Solmazgul E, Kunter E, Oncul O, Yildirim S, Kaplan M. Kikuchi-Fujimoto Disease: analysis of 244 cases. Clin Rheumatol. 2007 Jan; 26(1):50-54. doi:10.1007/s10067-006-0230-5.

9. Lin HC, Su CY, Huang CC, Hwang CF, Chien CY. Kikuchi's disease: a review and analysis of 61 cases. Otolaryngol Head Neck Surg. 2003 May; 128(5):650-653. doi:10.1016/S0194-59980223291-X.

10. Jamal AB. Kikuchi Fujimoto disease. Clin Med Insights Arthritis Musculoskelet Disord. 2012 Jul 3; 5:63-66. doi:10.4137/CMAMD.S9895.

11. Baenas DF, Diehl FA, Haye Salinas MJ, Riva V, Diller A, Lemos PA. Kikuchi-Fujimoto disease and systemic lupus erythematosus. Int Med Case Rep J. 2016 Jun 29; 9:163-167. doi:10.2147/IMCRJ.S106396.

12. Zar R, McClintock C. Kikuchi-Fujimoto disease: A case report and review of literature. Conn Med. 2006 Sep; 70(8):491-494.

13. Pepe F, Disma S, Teodoro C, Pepe P, Magro G. Kikuchi-Fujimoto disease: a clinicopathologic update. Pathologica. 2016 Sep; 108(3):120-129.

14. Tsang WY, Chan JK, Ng CS. Kikuchi's lymphadenitis. A morphologic analysis of 75 cases with special reference to unusual features. Am J Surg Pathol. 1994 Mar; 18(3):219-231.

15. Dorfman RF, Berry GJ. Kikuchi's histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin Diagn Pathol. 1988 Nov; 5(4):329-345.

16. Kusworini Handono, Nanda Rachmad Putra Gofur, Nurdiana, Handono Kalim, Cesarius Singgih Wahono, Sri Poeranto. Gingivitis on Systemic Lupus Erythematosus (SLE) patients: A Pilot study. Research J. Pharm. and Tech. 2020; 13(11):5466-5470. doi: 10.5958/0974-360X.2020.00954.3.

17. Perry AM, Choi SM. Kikuchi-Fujimoto Disease: A Review. Arch Pathol Lab Med. 2018 Nov; 142(11):1341-1346. doi: 10.5858/arpa.2018-0219-RA.

18. Lee BC, Patel R. Kikuchi-Fujimoto disease: a 15-year analysis at a children's hospital in the United States. Clin Pediatr (Phila). 2013 Jan; 52(1):92-95. doi:10.1177/0009922811436338.

19. Sharma V, Kumar M, Rastogi P, Kumar R, Sharma A, Dhir V. Kikuchi-Fujimoto disease with relapsing polychondritis. Rheumatology. 2019 Aug 1; 58(8):1512. doi:10.1093/rheumatology/key449.

20. Vithoosan S, Karunarathna T, Shanjeeban P, Piranavan P, Matthias T, Gamlaksha D, Liyadipita A, Kulatunga A. Kikuchi-Fujimoto disease associated with systemic lupus erythematosus complicated with hemophagocytic lymphohistiocytosis: a case report. J Med Case Rep. 2019 jun 6; 13(1):173. doi: 10.1186/s13256-019-2100-1.

21. Lee HY, Huang YC, Lin TY, Huang JL, Yang CP, Hsueh T, et al. Primary Epstein-Barr virus infection associated with Kikuchi's disease and hemophagocytic lymphohistiocytosis: a case report and review of the literature. J Microbiol Immunol Infect. 2010 Jun; 43(3):253-257. doi:10.1016/S1684-1182(10)60040-0.

22. Atwater AR, Longley BJ, Aughenbaugh WD. Kikuchi's disease: case report and systematic review of cutaneous and histopathologic presentations. J Am Acad Dermatol. 2008 May 7; 59(1):130-136. doi:10.1016/j.jaad.2008.03.012.

23. Crawshaw H, Rachakonda KS, Kim L, Enno A, Jegatheesan T. Intensive care management of a rare case of pyrexia of unknown origin (Kikuchi-Fujimoto disease). Anaesth Intensive Care. 2020 Jul 30; 48(4):318-323. doi:10.1177/0310057X20937314.

24. Mathew LM, Kapila R, Schwartz RA. Kikuchi-Fujimoto disease: a diagnostic dilemma. Int J Dermatol. 2016 May 21; 55(10):1069-1075. doi:10.1111/ijd.13314.

25. Shafqat S, Memon SB, Hyder S, Hasan SH, Smego RA Jr. Brainstem encephalitis with Kikuchi-Fujimoto disease. J Coll Physicians Surg Pak. 2003 Nov; 13(11):663-664.

26. Gómez-Mariscal M, Oleñik A, Arriba-Palomero P, García-Cosio M, Muñoz-Negrete FJ. Recurrent Bilateral Anterior Uveitis with Kikuchi-Fujimoto Disease. Ocul Immunol Inflamm. 2017 Jul 15; 25(6):866-869. doi:10.1080/09273948.2016.1188966.

27. Deaver D, Horna P, Cualing H, Sokol L. Pathogenesis, diagnosis, and management of Kikuchi-Fujimoto disease. Cancer Control J Moffitt Cancer Cent. 2014 Oct; 21(4):313-321. doi:10.1177/107327481402100407.

28. Chiu CF, Chow KC, Lin TY, Tsai MH, Shih CM, Chen LM. Virus infection in patients with histiocytic necrotizing lymphadenitis in Taiwan. Detection of Epstein-Barr virus, type I human T-cell lymphotropic virus, and parvovirus B19. Am J Clin Pathol. 2000 Jun; 113(6):774-781. doi:10.1309/1A6Y-YCKP-5AVF-QTYR.

29. Bezek S, Tucci V, Kalra S, Fisher A. State of the globe: time to revisit kikuchi fujimoto disease. J Glob Infect Dis. 2014 Oct; 6(4):139-140. doi:10.4103/0974-777X.145228.

30. Justin Jeya Amutha. Lupus Nephritis. Int. J. Adv. Nur. Management. 2017; 5(2):169-171. doi: 10.5958/2454-2652.2017.00036.1.

31. Tanaka T, Ohmori M, Yasunaga S, Ohshima K, Kikuchi M, Sasazuki T. DNA typing of HLA class II genes (HLA-DR, -DQ and -DP) in Japanese patients with histiocytic necrotizing lymphadenitis (Kikuchi's disease). Tissue Antigens. 1999 Sep; 54(3):246-253. doi:10.1034/j.1399-0039.1999.540305.x.

32. Lee KY. A common immunopathogenesis mechanism for infectious diseases: the protein-homeostasis-system hypothesis. Infect Chemother. 2015 Mar 30; 47(1):12-26. doi:10.3947/ic.2015.47.1.12.

33. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lymphadenitis (Kikuchi's disease) with aseptic meningitis. J Neurol Sci. 1999 Mar 1; 163(2):187-191. doi:10.1016/s0022-510x(99)00037-4.

34. Oumerzouk J, Jouehari A, Hssaini Y, Bourazza A. Un état de mal épileptique révélant la maladie de Kikuchi-Fujimoto: à propos d'un cas et revue de la littérature [Status epilepticus revealing Kikuchi-Fujimoto disease: a case report and review of the literature]. Revue neurologique. 2013; 169(12):1010–1012. Available from: https://doi.org/10.1016/j.neurol.2013.01.630.

35. Silva AF, Focaccia R, Oliveira AC, Sementilli A, Reis GF. Kikuchi-Fujimoto disease: an unusual association with acute renal failure. Braz J Infect Dis. 2010 Nov-Dec; 14(6):621-627. doi:10.1590/s1413-86702010000600012.

36. Lim GY, Cho B, Chung NG. Hemophagocytic lymphohistiocytosis preceded by Kikuchi disease in children. Pediatr Radiol. 2008 Jul; 38(7):756-761. doi:10.1007/s00247-008-0894-x.

37. Vencato E, Manfredi R, Zamò A, Chilosi M, Beccari S, De Franceschi L. A rare disorder in an orphan disease: Kikuchi-Fujimoto disease in a young-adult patient with sickle cell anemia. Am J Hematol. 2014 Jul 14; 89(12):1151-1152. doi:10.1002/ajh.23792.

38. Aqel NM, Peters EE. Kikuchi's disease in axillary lymph nodes draining breast carcinoma. Histopathology. 2000 Mar; 36(3):280-281. doi:10.1046/j.1365-2559.2000.0872a.x.

39. Ifeacho S, Aung T, Akinsola M. Kikuchi-Fujimoto Disease: A case report and review of the literature. Cases J. 2008 Sep 26; 1(1):187. doi:10.1186/1757-1626-1-187.

40. Sever CE, Leith CP, Appenzeller J, Foucar K. Kikuchi's histiocytic necrotizing lymphadenitis associated with ruptured silicone breast implant. Arch Pathol Lab Med. 1996 Apr; 120(4):380-385.

41. Gonçalves LF, Debelenko LV, Bhambhani KJ, Scheid A, Altinok D. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) with CNS involvement in a child. Pediatr Radiol. 2014 Feb; 44(2):234-238. doi:10.1007/s00247-013-2786-y.

42. Nayak HK, Mohanty PK, Mallick S, Bagchi A. Diagnostic dilemma: Kikuchi's disease or tuberculosis? BMJ Case Rep. 2013 Jan 29; 2013:bcr2012008026. doi:10.1136/bcr-2012-008026.

43. Sowmya Annavarapu, Merry Raphael, Vijayanarayana K, Girish Thunga, Sreedharan N. A Study on Clinical Manifestations, Treatment Pattern and Outcome in Systemic Lupus Erythematosus Patients in Tertiary Care Hospital. Research J. Pharm. and Tech. 2017; 10(5): 1383-1388. doi: 10.5958/0974-360X.2017.00246.3.

44. Graham LE. Kikuchi-Fujimoto disease and peripheral arthritis: a first!. Ann Rheum Dis. 2002 May; 61(5):475. doi:10.1136/ard.61.5.475.

45. Cousin F, Grézard P, Roth B, Balme B, Grégoire-Bardel M, Perrot H. Kikuchi disease associated with Still disease. Int J Dermatol. 1999 Jun; 38(6):464-467. doi:10.1046/j.1365-4362.1999.00679.x.

46. Wilkinson CE, Nichol F. Kikuchi-Fujimoto disease associated with polymyositis. Rheumatology (Oxford, England). 2000 Nov; 39(11):1302-1304. https://doi.org/10.1093/rheumatology/39.11.1302.

47. Sharma OP. Unusual systemic disorders associated with interstitial lung disease. Curr Opin Pulm Med. 2001 Sep; 7(5):291-294. doi:10.1097/00063198-200109000-00007.

48. Laeng RH, Stamm B. Kikuchi's histiocytic necrotizing lymphadenitis driven by activated cytolytic T-cells: an example associated with systemic scleroderma. Histopathology. 1999 Apr; 34(4):373-374. doi:10.1046/j.1365-2559.1999.0669a.x.

49. Sierra ML, Vegas E, Blanco-González JE, GonzálezA, Martínez P, Calero MA. Kikuchi's disease with multisystemic involvement and adverse reaction to drugs. Pediatrics. 1999 Aug; 104(2):e24. doi: 10.1542/peds.104.2.e24.

50. Byun JH, Park SE, Nam SO, Kim YA, Kim YM, Yeon GM, Lee YJ. Three children of meningoencephalitis with Kikuchi necrotizing lymphadenitis. Brain Dev. 2018 Oct 16; 40(3): 251-255. doi:10.1016/j.braindev.2017.09.009.

51. Iio K, Matsuoka K. Visible lymphadenopathy in Kikuchi-Fujimoto disease. J Pediatr. 2020 Jun 8; 226:300. doi:10.1016/j.jpeds.2020.06.011.

52. Rosenberg TL, Nolder AR. Pediatric cervical lymphadenopathy. Otolaryngol Clin North Am. 2014 Jul 30; 47(5):721-731. doi:10.1016/j.otc.2014.06.012.

53. Viguer JM, Jiménez-Heffernan JA, Pérez P, López-Ferrer P, Gónzalez-Peramato P, Vicandi B. Fine-needle aspiration cytology of Kikuchi's lymphadenitis: a report of ten cases. Diagnostic cytopathology. 2001 Oct; 25(4):220-224. doi:10.1002/dc.2042.

54. Santos MV, Gallo P, Roked F, Nicklaus-Wollenteit I, Rodrigues D. Unusual presentation of Kikuchi-Fujimoto disease. J Neurosurg Pediatr. 2013 Jul 26; 12(3):266-269. doi:10.3171/2013.6.PEDS13118.

55. Sone Y, Namiki T, Nojima K, Hashimoto T, Hanafusa T, Tokoro S, Miura K, Yokozeki H. Kikuchi's disease: cutaneous involvement and dermoscopic features. Eur J Dermatol. 2017 Apr 1; 27(2): 212-213. doi:10.1684/ejd.2016.2958.

56. Na DG, Chung TS, Byun HS, Kim HD, Ko YH, Yoon JH. Kikuchi disease: CT and MR findings. AJNR. American journal of neuroradiology. 1997 Oct; 18(9):1729-1732.

57. Ogawa M, Ueda S, Ohto M, Fujita M, Kubosawa T. Ultrasonography of cervical lymphadenopathy in a patient with Kikuchi's disease. Acta Radiol. 1991 May; 32(3):260-261.

58. Altinel Açoğlu E, Sari E, Şahin G, Oğuz MM, Akçaboy M, Zorlu P, Senel S. Kikuchi-Fujimoto disease triggered by Salmonella enteritidis in a child with concurrent auto-immune thyroiditis and papilloedema. Paediatr Int Child Health. 2018 Jan 8; 38(4):298-301. doi:10.1080/20469047.2017.1420523.

59. Firooz N, Albert DA, Wallace DJ, Ishimori M, Berel D, Weisman MH. High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus. Lupus. 2011Mar 24; 20(6):588-597. doi:10.1177/0961203310393378.

60. Yaris N, Cakir M, Sözen E, Cobanoglu U. Analysis of children with peripheral lymphadenopathy. Clin Pediatr. 2006 Jul; 45(6):544-549. doi: 10.1177/0009922806290609.

61. Sumiyoshi Y, Kikuchi M, Minematu T, Ohshima K, Takeshita M, Minamishima Y. Analysis of herpesvirus genomes in Kikuchi's disease. Virchows Arch. 1994; 424(4):437-440. doi:10.1007/BF00190567.

62. Ruaro B, Sulli A, Alessandri E, Fraternali-Orcioni G, Cutolo M. Kikuchi-Fujimoto's disease associated with systemic lupus erythematous: difficult case report and literature review. Lupus. 2014 Apr 16; 23(9):939-944. doi:10.1177/0961203314530794.

63. Gerritsen A, Lam K, Marion Schneider E, van den Heuvel-Eibrink MM. An exclusive case of juvenile myelomonocytic leukemia in association with Kikuchi's disease and hemophagocytic lymphohistiocytosis and a review of the literature. Leuk Res. 2006 Feb 17; 30(10):1299-1303. doi:10.1016/j.leukres.2005.12.027.

64. Wang TJ, Yang YH, Lin YT, Chiang BL. Kikuchi-Fujimoto disease in children: clinical features and disease course. J Microbiol Immunol Infect. 2004 Aug; 37(4):219-224.

65. Kuo TT. Kikuchi's disease (histiocytic necrotizing lymphadenitis). A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol. 1995 Jul; 19(7):798-809. doi:10.1097/00000478-199507000-00008.

66. Pilichowska ME, Pinkus JL, Pinkus GS. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease): lesional cells exhibit an immature dendritic cell phenotype. Am J Clin Pathol. 2009 Feb; 131(2):174-182. doi:10.1309/AJCP7V1QHJLOTKKJ.

67. Pileri SA, Facchetti F, Ascani S, Sabattini E, Poggi S, Piccioli M, Rondelli D, Vergoni F, Zinzani PL, Piccaluga PP, Falini B, Isaacson PG. Myeloperoxidase expression by histiocytes in Kikuchi's and Kikuchi-like lymphadenopathy. Am J Pathol. 2001 Sep; 159(3):915-924. doi:10.1016/S0002-9440(10)61767-1.

68. Ioachim HL, Jeffrey Medeiros L. Ioachim’s Lymph Node Pathology. 4th ed. Lippincott Williams and Wilkins; 2009. Available from: https://pathology.lwwhealthlibrary.com/book.aspx?bookid=1418.

69. Hutchinson CB, Wang E. Kikuchi-Fujimoto disease. Arch Pathol Lab Med. 2010 Feb; 134(2):289-293. doi:10.5858/134.2.289.

70. Tchidjou HK, Macchiaiolo M, Ariganello P, Carducci FC, De Vito R, De Benedetti F, D'Argenio P. Kikuchi-Fujimoto disease in patient with systemic phacomatosis pigmentovascularis. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2014 Oct; 25(7):783–785. doi:10.1097/MBC.0000000000000129.

71. ErezBen–Menachem, Systemic Lupus Erthyematosus: A review for Anesthesiologists.2010; 111(3):686.

72. Kampitak T. Fatal Kikuchi-Fujimoto disease associated with SLE and hemophagocytic syndrome: a case report. Clin Rheumatol. 2008 May 9; 27(8):1073-1075. doi:10.1007/s10067-008-0902-4.

73. Sopeña B, Rivera A, Vázquez-Triñanes C, Fluiters E, González-Carreró J, del Pozo M, et al. Autoimmune manifestations of Kikuchi disease. Semin Arthritis Rheum. 2012 Dec 20; 41(6):900-906. doi:10.1016/j.semarthrit.2011.11.001.

74. Stimson L, Stitson R, Bahhadi-Hardo M, Renaudon-Smith E. COVID-19 associated Kikuchi-Fujimoto disease. Br J Haematol. 2021 Feb 7; 192(5):e124-e126. doi:10.1111/bjh.17292.

75. Kang HM, Kim JY, Choi EH, Lee HJ, Yun KW, Lee H. Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children. J Pediatr. 2016 Feb 4; 171:208-12.e1. doi:10.1016/j.jpeds.2015.12.064.

76. Jang YJ, Park KH, Seok HJ. Management of Kikuchi's disease using glucocorticoid. J Laryngol Otol. 2000 Sep; 114(9):709-711. doi:10.1258/0022215001906561.

77. Iwamoto N, Funahashi M, Shinohara K, Nakaya Y, Motobayashi H, Tochitani K, Yamamoto S, Shimizu T. Two Cases of Kikuchi Disease Presenting with Aseptic Meningitis and Encephalitis. Intern Med. 2022 Feb 19; 61(17):2687-2689. doi:10.2169/internalmedicine.7724-21.

78. Feder HM Jr, Liu J, Rezuke WN. Kikuchi disease in Connecticut. J Pediatr. 2014 Jan; 164(1):196-200.e1. doi:10.1016/j.jpeds.2013.08.041.

79. Takada K, Suzuki K, Hidaka T, Konishi T, Shinohara T, Kataharada K, Matsumoto M, Okada M, Ohsuzu F. Immediate remission obtained by minocycline in a patient with histiocytic necrotizing lymphadenitis. Internal medicine (Tokyo, Japan). 2001 Oct; 40(10):1055-1058. doi: 10.2169/internalmedicine.40.1055.

80. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics. 2004 Nov 15; 114(6):e752-e756. doi:10.1542/peds.2004-0485.

81. Chen CJ, Huang YC, Jaing TH, Hung IJ, Yang CP, Chang LY, Lin TY. Hemophagocytic syndrome: a review of 18 pediatric cases. J Microbiol Immunol Infect. 2004 Jun; 37(3):157-163.

82. Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004 Jan; 124(1):4-14. doi:10.1046/j.1365-2141.2003.04726.x.

83. Khan FY, Morad NA, Fawzy Z. Kikuchi's disease associated with hemophagocytosis. Chang Gung Med J. 2007 Jul-Aug; 30(4):370-373.

84. Cheng CY, Sheng WH, Lo YC, Chung CS, Chen YC, Chang SC. Clinical presentations, laboratory results and outcomes of patients with Kikuchi's disease: emphasis on the association between recurrent Kikuchi's disease and autoimmune diseases. J Microbiol Immunol Infect. 2010 Oct; 43(5):366-71.

85. Sykes JA, Badizadegan K, Gordon P, Sokol D, Escoto M, Ten I, Vyas S, Torres A, Levine AM. Simultaneous acquired self-limited hemophagocytic lymphohistiocytosis and Kikuchi necrotizing lymphadenitis in a 16-year-old teenage girl: a case report and review of the literature. Pediatr Emerg Care. 2016 Nov; 32(11):792-8. doi: 10.1097/PEC.0000000000000560.

86. Jasti DB, Naveen Prasad SV, Naveen T, Vengamma B. Kikuchi-Fujimoto disease presenting as brainstem encephalitis with secondary blepharospasm. J Neurosci Rural Pract. 2016 Jan-Mar; 7(1):157-160. doi:10.4103/0976-3147.165395.

87. Khishfe BF, Krass LM, Nordquist EK. Kikuchi disease presenting with aseptic meningitis. Am J Emerg Med. 2016 Mar 26; 32(10):1298.e1-1298.e2. doi:10.1016/j.ajem.2014.03.029.

88. Komagamine T, Nagashima T, Kojima M, Kokubun N, Nakamura T, Hashimoto K, et al. Recurrent aseptic meningitis in association with Kikuchi-Fujimoto disease: case report and literature review. BMC Neurol. 2012 Sep 29; 12:112. doi:10.1186/1471-2377-12-112.

89. Akhavanrezayat A, Cooper JD, Hassan M, Pham BH, Nguyen QD, Farr AK. Bilateral preretinal hemorrhage associated with Kikuchi-Fujimoto disease. Am J Ophthalmol Case Rep. 2021 Mar 2; 22:101041. doi:10.1016/j.ajoc.2021.101041.

90. Zou W, Wen F. Bilateral occlusive retinal vasculitis in Kikuchi-Fujimoto disease. Clin Exp Ophthalmol. 2007 Dec; 35(9):875-877. doi:10.1111/j.1442-9071.2007.01637.x.

91. Rocher F, Pelosse B, Momtchilova M, Laroche L. Maladie de Kikuchi et atteinte ophtalmologique. A propos d'un cas [Kikuchi's disease and ocular manifestation]. J Fr Ophtalmol. 2006 Oct; 29(8):932-936. doi:10.1016/s0181-5512(06)70116-4.

Received on 06.06.2023 Modified on 18.09.2023

Asian J. Res. Pharm. Sci. 2024; 14(2):129-136.

DOI: 10.52711/2231-5659.2024.00019