Case of recurrent fever with late lymphadenopathy: Think of Kikuchi’s disease


Kikuchi’s disease or histiocytic necrotizing lymphadenitis, a relatively uncommon and self-limiting entity of varied manifestations including prolonged fever, is diagnosed primarily by excluding other more common causes of fever and established finally by the typical histological finding on lymph node biopsy. The appearance of palpable lymph nodes may be delayed and become clinically detectable only after the initial fever subsides, and the patient having spent a few days without fever comes back with episodes of recurrent fever before the lymph nodes become clinically palpable. One such case is presented here to stress upon the importance of complete and thorough systematic clinical examination on each and every visit by the patient to the physician.

Keywords: Differential diagnosis for cervical adenitis and prolonged or recurrent pyrexia, histiocytic necrotizing lymphadenitis, histopathological confirmation, Kikuchi′s disease

How to cite this article:
Jaleel M A, Fathima FN, Jaleel BF. Case of recurrent fever with late lymphadenopathy: Think of Kikuchi’s disease. Ann Trop Med Public Health 2013;6:134-8
How to cite this URL:
Jaleel M A, Fathima FN, Jaleel BF. Case of recurrent fever with late lymphadenopathy: Think of Kikuchi’s disease. Ann Trop Med Public Health [serial online] 2013 [cited 2016 Aug 15];6:134-8. Available from:

Kikuchi’s disease is a relatively rare disease that presents predominantly in young persons in their 20s and 30s. The disease was first described in Japan in 1972 almost simultaneously by Kikuchi in his individual capacity and by Fujimoto, Kozima, and Yamaguchi jointly as a new clinicopathological entity of necrotizing cervical lymphadenitis along with its diverse clinical manifestations. This entity subsequently became to known as Kikuchi’s disease or Kikuchi-Fujimoto’s disease or simply as histiocytic necrotizing lymphadenitis. [1],[2]

Kikuchi’s disease is usually seen in young adults in their 20s and 30s. It is relatively more common in females with the male:female ratio reported as 1:1.76. [3] The disease is more common in the Far East, but sporadic cases are seen all over the world including the USA, Europe, Asia, Middle East, and South America. [4],[5],[6],[7]

Kikuchi’s disease needs to be differentiated from some other ominous conditions like malignant lymphoma and other lymph node malignancies and also from other causes of lymphadenopathies like toxoplasmosis, infectious mononucleosis, etc. Biopsy findings ultimately help in clinching the diagnosis of Kikuchi’s disease.

Kikuchi’s disease or histiocytic necrotizing lymphadenitis should be considered in the differential diagnosis of unexplained persisting or recurrent fever with cervical lymphadenitis in young adults with varied sign and symptoms such as sore throat, cough, rhinorrhea, chills, cephalgia, and nonspecific myalgias. Histopathological reports of fine needle aspiration or excision biopsy of accessible lymph node together with immune histochemistry, if available, are the means presently available for making a definitive diagnosis of Kikuchi’s disease. It usually runs a benign course, recurrences are very rare and the overall prognosis is generally favorable. Treatment is primarily symptomatic.

Case Report

A 27-year-young well-nourished male patient presented initially to his family physician and then to an ENT specialist complaining of fever for the past 3 days accompanied with chills, head ache, sore throat, general weakness, and vague aches and pain all over the body. He also complained of slight dry cough and reduced appetite and nausea; he did not feel any difficulty in passing urine and was able to attend to his daily chores albeit with less enthusiasm and vigor. There was no history of any substance abuse, blood transfusion, sexual misadventures, insect or animal bites, travels to endemics prone areas or contacts with persons with tuberculosis, jaundice, malaria, etc. His past, personal, and family history did not reveal any clinically significant data.

He was treated empirically with a course of amoxicillin+clavulanic acid and NSAIDs; and apparently had defervescence on the second day of treatment with reduction in most of his other complaints which with continued treatment lasted for about a week. But the patient again developed fever with chills, nausea, myalgias, general malaise, and sore throat. He was advised institutional management and investigated as an in-patient.


Apparently well built, well-nourished young male adult, nonicteric, not having any evidence of cyanosis, finger clubbing, dependent or pedal edema, but found to be slightly febrile with his oral temperature recorded as 100°F. His blood pressure, respiration, pulse and heart rates, and other parameters of general physical examination were within normal limits. ENT and skin examination did not reveal any abnormalities. There were no exanthematous changes in his skin. No lymph nodes were palpable in the neck, axillae, or the groin regions. Abdomen was soft, non-tender without any palpable abdominal organomegaly. Other systemic examinations too were all within normal limits.


Complete blood count showed hemoglobin, red blood cell (RBC) count, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and platelet counts all within normal range. There was relative leucopenia with the total white blood cell (WBC) count being 3800 cells/cumm, polymorphs 49% and the erythrocyte sedimentation rate (ESR) was elevated to 34 mm/hr. Liver function tests showed the serum Glutamic oxaloacetic transaminase (SGOT) also called aspartate aminotransferase (AST), serum glutamate pyruvate transaminase (SGPT) also called alanine aminotransferase (ALT), alkaline phosphatase, and gamma glutamyltransferase (GAMMA GT) levels as 48, 65, 72, and 94 U/L, respectively. Serum uric acid, creatinine, fasting plasma glucose (FPG), post-prandial plasma glucose (PPPG), and serum electrolytes such as sodium, chloride, calcium, and potassium were normal. Serological tests for HIV 1 and 2, HBsAg, cytoplasmic antineutrophil cytoplasmic antibody (cANCA), and perinuclear antineutrophil cytoplasmic antibodies (pANCA), were all negative. Mantoux test was reported as negative, and so also were the blood culture report and the screening tests for malaria, typhoid, dengue fever, leptospirosis, rickettsial fevers, and infectious mononucleosis. Throat culture yielded mere routine oropharyngeal commensals, and the angiotensin-converting enzyme levels were reported as 12.3 U/L well within the normal reference range value of 8-52 U/L.

Provisional diagnosis

The patient was diagnosed provisionally as suffering from nonspecific viral fever and put on conservative symptomatic treatment with non-steroid anti-inflammatory drugs (NSAID), IV fluids, and vitamin supplements. On the third day of hospitalization, the patient apparently showed total recovery, fever subsided, his appetite returned, sore throat was relieved, and myalgias reduced considerably. He remained afebrile and asymptomatic for the next 48 hours and was sent home in a clinically stable state with the advice to report whether there is any recurrence of fever and/or other earlier symptoms.

Recurrence of fever and other symptoms

After discharge from the hospital, the patient remained afebrile for 3 days and then his fever reappeared together with the other complaints like chills, myalgias, nausea sore throat, etc. He was readmitted to the ward and subjected to relevant laboratory tests as before which again were found to be inconclusive. Repeat detailed physical examination this time revealed a solitary small lymph node of size 1×1.5 cm in the right posterior triangle of the neck. It was slightly tender, freely mobile, and firm/rubbery in consistency. Chest X-ray and X-ray of the paranasal sinuses were normal; so also were CT chest and abdomeno-pelvis. CT study of the paranasal sinuses followed by multiplanar reconstructions reported a few subcentimeter lymph nodes at levels a1a, 11a, and 111. Fine needle aspiration cytology (FNAC) of the accessible cervical lymph node was performed but the results were inconclusive and hence excision biopsy of the lymph node was done and specimens sent for mycobacterium DNA polymerase chain reaction and gram stain. Both of these tests were negative. Histopathological report of the lymph node biopsy clinched the diagnosis as Kikuchi’s disease-histiocytic necrotizing lymphadenitis with the suggestive findings of crescentic histiocytes, plasmacytoid monocytes, and extracellular debris. Immunohistochemical studies were not undertaken due to non-availability of the same at our center.

Final diagnosis

Kikuchi’s disease: Histiocyticnecrotizing lymphadenitis.


Treatment of uncomplicated Kikuchi’s disease as in our case is primarily symptomatic with confident reassurance to the patient about the usually relatively benign nature of Kikuchi’s disease. Patient is well after lapse of over 6 months without any complaints.


Kikuchi’s disease or histiocytic necrotizing lymphadenitis is a relatively benign and self-limiting lymphadenitis primarily of the cervical glands but may involve supraclavicular, axillary, mediastinal, celiac, peripancreatic, or inguinal groups of lymph nodes singly or in groups. Histiocytic necrotizing lymphadenitis is accompanied with fever and other varied manifestations. So far, no single specific etiological factor has been identified as being responsible for causing Kikuchi’s disease. Many viral infections including Epstein-Barr virus (EBV), human herpes 6 virus, rubella, para-myxovirus, and para-influenza viruses were suspected at different times to be of etiological significance but their role if any could not be confirmed. Likewise, there were suggestions of toxoplasmosis and Yersina enterocolitica being responsible for it, but again there were no scientific confirmations to support such assumptions. [8],[9],[10]

The etiology of Kikuchi’s disease continues to remain unclear. It is probably the result of a hyperimmune action to different etiological agents of the microbial, chemical, physical, or neoplastic type. There are reports suggestive of a possible causative role of Epstein-Barr virus (EBV) in Kikuchi’s disease (KD), but the observations remain unconfirmed and unsubstantiated in scientific circles. [10]

The usual clinical presentation of KD is a relatively acute onset of cervical lymphadenitis preceded or accompanied with sore throat, fever, and vague flue like prodrome in otherwise healthy young adults in their 20s and 30s, slightly more common in females than in the males. [11],[12] Slightly tender lymph nodes in the neck with persistent mild fever and sore throat with or without other early complaints including nonproductive cough, rhinorrhea, head ache, general malaise, poor appetite, nausea, night sweating, slight restriction in neck mobility, myalgias, and arthralgias usually take the patients to their family physician, primary care physician, or the ENT specialist. [13],[14],[15]

Lymphadenopathy is considered by many to be the hall mark in the clinical presentation of Kikuchi’s disease. [3] The most common site of lymph node involvement is the posterior triangle of the neck followed by the anterior triangle of the neck, axillary-unilateral or occasionally bilateral-and at times supraclavicular, mediastinal, celiac, peripancreatic, and inguinal group of nodes may be affected. [4] Rarely, there might be generalized lymphadenopathy. The affected lymph nodes are usually tender but might be painless, usually less than 2 cm in diameter, multiple in number, discrete without any matting, and are firm to rubbery in consistency. [16]

Cutaneous manifestations of KD may lead to some perplexion in arriving at the clinical diagnosis. These changes are not seen in all persons affected with KD, may affect 3-30% of patients only; they are usually nonspecific such as macula-papular or morbilliform rash, nodules, urticaria, and a semblance of molar rash simulating that seen in lupus erythematosis. [13]

At present, histopathological, immunohistochemical, and transmission electron microscopy (TEM) study-where ever this is available-form the only means of establishing a definitive diagnosis of KD.

Fine needle aspiration cytology (FNAC)

Fine needle aspiration cytological examination findings from the affected lymph node can suggest the diagnosis of KD especially if there are other accompanying clinical findings in support of the same. Ideally, an excision biopsy of the involved lymph node if accessible may be required to confirm the diagnosis of Kikuchi’s disease. [14],[15],[16] Cytological findings suggestive of KD include crescentic histiocytes, plasmacytoid monocytes, and extracellular debris. [17]

The following finding of immunohistochemical studies helps in arriving at a diagnosis of KD with confidence: [4],[17] The immunophenotyping of Kikuchi’s disease is primarily composed of mature CD-8 positive and CD-4 positive T-lymphocytes.

Positive immunostaining result by the monoclonal antibody macrophage inflammatory protein K1-M1P is seen in Kikuchi’s disease.

The immunostaining with high endothelial cell antigen (HECA 452) (directed against cutaneous lymphocyte antigen) highlights numerous transformed lymphocytes and plasmacytoid monocytes.


Even though rare instances of fatalities have been reported, [18] Kikuchi’s disease is usually a relatively benign and self-limiting entity, and if mistaken for other more serious conditions would result in many avoidable psychological, physical, and financial strains for the patients and all others concerned with their care. There are many conditions that present with lymphadenopathy and other similar clinical manifestations especially prolonged mild fever and general malaise. Out of these, systemic lupus erythematosis (SLE) associated lymphadenopathy, Herpes simplex-associated lymphadenopathy, non-Hodgkin lymphoma, plasmacytoid T-cell leukemia, Kawasaki disease, and nodal colonization by AML need to be considered in all seriousness in the differential diagnosis of KD [Table 1]. [19],[20],[21],[22]

Table 1: Clues to differential diagnosis of  Kikuchi-Fujimoto disease More Details[22]

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Kikuchi’s disease is a relatively rare, usually benign and self-limiting entity of as yet obscure etiology presenting as prolonged fever and lymphadenitis in relatively young patients that needs to be given serious consideration in the differential diagnosis of all such presentations so that the condition is not mistaken for more serious and ominous conditions like lymphomas, tuberculosis, or SLE.

1. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes: A clinico-pathological study (in Japanese). Acta Hematol Jpn 1972;35:379-80.
2. Fujimoto Y, Kozima Y, Yamaguchi K. Cervical sub acute necrotizing lymphadenitis: A new clinico-pathological entity. Naika 1972;20:920-7.
3. Yu HL, Lee SS, Tsai HC, Huang CK, Chen YS, Lin HH, et al. Clinical manifestations of Kikuchi′s disease in southern Taiwan. J Microbiol Immunol Infect 2005;38:35-40.
4. Poulose V, Chiam P, Poh WT. Kikuchi′s disease: A Singapore case series. Singapore Med J 2005;46:229-32.
5. Rakic L, Arrese JE, Thiry A, Piérard GE. Kikuchi-Fujimoto lymphadenitis with cutaneous involvement. J Eur Acad Dermatol Venereol 1999;13:118-22.
6. Turner RR, Martin J, Dorfman RF. Necrotizing lymphadenitis. A study of 30 cases. Am J Surg Pathol 1983;7:115-23.
7. Mukta V, Jayachandran K, Hemapriya S. Kikuchi-Fujimoto′s disease: A report of five cases. J Assoc Physicians India 2011;59:183-4.
8. Amir AR, Amr SS, Sheikh SS. Kikuchi-Fujimoto′s disease: Report of familial occurrence in two human leucocyte antigen-identical non-twin sisters. J Intern Med 2002;252:79-83.
9. Onciu M, Medeiros LJ. Kikuchi-Fujimoto lymphadenitis. Adv Anat Pathol 2003;10:204-11.
10. Asano S, Akaike Y, Muramatsu T, Wakasa H, Yoshida H, Kondou R, et al. Necrotizing lymphadenitis: A clinicopathological and immunohistochemical study of four familial cases and five recurrent cases. Virchows Arch A Pathol Anat Histopathol 1991;418:215-23.
11. Hudnall SD. Kikuchi-Fujimoto disease: Is Epstein-Barr virus the culprit? Am J Clin Pathol 2000;113:761-4.
12. 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;113:774-81.
13. Yen A, Fearneyhough P, Raimer SS, Hudnall SD. EBV-associated Kikuchi′s histiocytic necrotizing lymphadenitis with cutaneous manifestations. J Am Acad Dermatol 1997;36:342-6.
14. Imamura M, Ueno H, Matsuura A, Kamiya H, Suzuki T, Kikuchi K, et al. An ultrastructural study of subacute necrotizing lymphadenitis. Am J Pathol 1982;107:292-9.
15. Ohshima K, Shimazaki K, Suzumiya J, Kanda M, Kumagawa M, Kikuchi M. Apoptosis of cytotoxic T-cells in histiocytic necrotizing lymphadenitis. Virchows Arch 1998;433:131-4.
16. 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;128:650-3.
17. Bhat NA, Hock YL, Turner NO, Das Gupta AR. Kikuchi′s disease of the neck (histiocytic necrotizing lymphadenitis). J Laryngol Otol 1998;112:898-900.
18. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease: A comprehensive review. Am J Clin Pathol 2004;122:141-52.
19. Updated clinical practice. Available from: [Last cited 2009].
20. 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;19:798-809.
21. Bataille V, Harland CC, Behrens J, Cook MG, Holden CA. Kikuchi disease (histiocytic necrotizing lymphadenitis) in association with HTLV1. Br J Dermatol 1997;136:610-2.
22. Santana A, Lessa B, Galrão L, Lima I, Santiago M. Kikuchi-Fujimoto′s disease associated with systemic lupus erythematosus: Case report and review of the literature. Clin Rheumatol 2005;24:60-3.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.115196


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