Baffled with fever and lymphadenopathy: neither infection nor malignancy, think Kikuchi disease

  1. Ali Hussain 1,
  2. Mohsin Gondal 2,
  3. Hira Yousuf 3 and
  4. Mubashar Iqbal 4
  1. 1 Acute Medicine, Hull Royal Infirmary, Hull, Kingston upon Hull, UK
  2. 2 Cardiology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  3. 3 Oncology, Pinderfields General Hospital, Wakefield, UK
  4. 4 Respiratory, Sheffield Teaching Hospital, Sheffield, UK
  1. Correspondence to Dr Ali Hussain; ali.hussain14@nhs.net

Publication history

Accepted:13 Jan 2021
First published:28 Jan 2021
Online issue publication:28 Jan 2021

Case reports

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Abstract

Kikuchi disease is a rare, benign condition of unknown aetiology, which usually involves young women and is characterised by cervical lymphadenopathy and fever. Herein, we are reporting a case of a young Asian woman, who presented with fever and lymphadenopathy raising possibility of either infection or malignancy but after appropriate clinical investigations including lymph node biopsy, it turned out to be Kikuchi disease. She made an uneventful complete recovery with only symptomatic treatment.

Background

Kikuchi disease (KD) is a self-limiting disease of undetermined cause and often pose diagnostic challenge as its clinical presentation may mimic serious infections, autoimmune disorders and sinister pathologies like lymphoma. The diagnosis of Kikuchi disease is almost always made by lymph node biopsy which typically shows coagulative necrosis with histiocytic proliferation and absence of granulocytes. Anti-nuclear antibodies are mandatory in the work-up as few patients initially diagnosed with Kikuchi disease, may subsequently develop systemic lupus erythematosus (SLE). Symptomatic treatment with antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) is the only required treatment in majority of such cases. There is scanty literature available for this entity and is mainly limited to few case reports/series. We describe the case of a 25-year-old woman, presenting as fever with lymphadenopathy who was diagnosed on lymph node biopsy as Kikuchi disease and recovered completely with simple antipyretic medications.

Case presentation

A 25-year-old married, non-pregnant woman, presented to the emergency department with 3 weeks’ history of left-sided neck swelling associated with pain, neck spasm and fever. Prior to her presentation, the patient was seen twice by general physician and prescribed oral amoxicillin 500 mg three times per day, but there was no improvement in her symptoms. The fever was documented to be around 39°C, mainly at night and associated with rigours and profuse sweating. There was no history of headache, joint pain, skin rash, sore throat, tooth ache or any ear discharge. She denied any history of cough, weight loss, nausea, vomiting, diarrhoea, burning micturition or any genital discharge. Moreover, there was no account of recent contact with a sick person, ingestion of unpasteurised milk or Page 5 of 12 foreign travel. The patient did not have any significant past medical history. She was not on any regular medications. There was no history of any drug allergies. On initial assessment in emergency department, the patient was febrile 39°C, blood pressure 125/70 mm Hg, heart rate 110 bpm and respiratory rate 20 per min with oxygen saturation 98% (on room air). On examination, there was tender left-sided cervical (postauricular) lymphadenopathy. Lymph nodes were matted and firm in consistency with normal overlying skin. Apart from enlarged cervical lymph nodes, there was no other palpable lymph nodes or hepatosplenomegaly. Rest of systemic examination was unremarkable.

Investigations

Her baseline laboratory reports are shown in (table 1). She had a high erythrocyte sedimentation rate (ESR) 60 mm/hour (normal; 0 to 10 mm/hour), C-reactive protein (CRP) 52 mg/L (normal; 0 to 10 mg/L), haemoglobin 9.4 gm/dL (normal; 11 to 14.5 gm/dL), leucopenia 3.1×109/L (normal; 2.4 to 9.5×109/L with mild lymphopenia 1.0×109/L (normal; 1.2 to 3.8×109/ L). Blood, urine, genital and sputum cultures were all negative. Lactate dehydrogenase (LDH) 260 U/L (normal; 100 to 250 U/L) was minimally elevated.

Table 1

Illustrates laboratory parameters of the patient

Parameters Normal range (units) Patient results (on admission)
ANA, antinuclear antibodies; anti-dsDNA, anti-double stranded DNA; CRP, C-reactive protein; ENA, extractable nuclear antigen; ESR, erythrocyte sedimentation rate; TB, tuberculosis.
Haemoglobin 11.0–14.5 g/dL 9.4
Mean corpuscular volume 78.0–95.0 fL 64
Platelets 150–450 x 109/L 365
White blood count 2.4–9.5 x 109/L 3.1
Neutrophils 1.0–4.8 x 109/L 1.8
Lymphocytes 1.2–3.8 x 109/L 1
Eosinophils 0.1–0.5 x 109/L 0
Basophils 0.1–0.2 x 109/L 0
ESR 0–10 mm/hour 60
CRP 0–10 mg/L 52
Urea 2.8–8.1 mmol/L 4.8
Creatinine 45–84 µmol/L 61
Sodium 135–145 mmol/L 138
Potassium 3.5–5.1 mmol/L 4.4
Chloride 98–107 mmol/L 104
Bicarbonate 22–29 mmol/L 19
Alanine aminotransferase (ALT) 0–33 U/L <5
Aspartate aminotransferase (AST) 0–33 U/L 14
Albumin 35–52 g/L 22
Bilirubin 0–17 µmol/L 10
Rheumatoid factor   7
ANA Negative 1/80 speckled pattern
Weakly positive
Anti-dsDNA 0–45 IU/mL  26
ENA panel Negative Negative
Toxoplasmosis Ab (IgG and IgM) Negative Negative
Infectious mononucleosis Ab Negative Negative
HIV 1 and 2 antibodies Negative Negative
Hepatitis B and C serologies Negative Negative
Interferon gamma TB Negative Negative
GeneXpert MTB/RIF (lymph node biopsy) Negative Negative
Tissue culture (Lowenstein-Jensen) for Mycobacterium tuberculosis Negative Negative
Brucella - melittins and abortus Negative Negative
Blood cultures Negative Negative
Urine microscopy and culture Negative Negative
Genital swab and cultures Negative Negative
Malarial parasite Not Seen Not seen

Differential diagnosis

The main important diagnostic challenge is to distinguish SLE and lymphoma from Kikuchi disease. SLE and Kikuchi disease share similar clinical presentations for instance fever and lymphadenopathy. However, autoimmune antibodies are typically absent in Kikuchi disease as compared with SLE. Furthermore, Kikuchi disease has predominant T lymphocyte in histological sections. Lymphoma is often challenging to differentiate from Kikuchi. However, absence of cytological atypical and immunohistiological negative stain for CD3 and CD20 and positive stain for CD68, as in our case exclude lymphoma. Glandular fever present in similar fashion to Kikuchi disease but absence of antibodies help to exclude them. Toxoplasmosis usually remains asymptomatic and often causes symptoms in immunocompromised patients and can be diagnosed by antibodies and demonstration of typical protozoa in blood and tissue samples. Sarcoidosis typically have bilateral hilar lymphadenopathy on chest X-ray and non-caseating granuloma is a prototype of sarcoidosis on histological sections. Similarly, Castleman disease shows changes in germinal centres with hypervascularity and predominant follicular dendritic cells which distinguish it from Kikuchi disease.

Treatment

Patient’s antibiotics were stopped and was commenced on antipyretics (paracetamol 1 g four times per day and ibuprofen 400 mg three times per day). About 1 week later, fever subsided and she had remarkable improvement in her symptoms. Patient was initially very concerned about malignancy but felt much relieved after clear explanation and reassurance provided about the diagnosis. Later, she was discharged and given an appointment to follow-up in medical outpatients’ clinic.

Outcome and follow-up

On routine follow-up at 3 months and 6 months, she remained afebrile with regression in her cervical lymphadenopathy and no new symptoms were reported.

Discussion

KD is an infrequently encountered self-limiting disease of unknown aetiology characterised by fever and cervical lymphadenopathy in otherwise healthy young individuals. It was first described by Masahiro Kikuchi, a Japanese pathologist, in 1972.1 Initially, KD was thought to be a disorder of Asian ancestry, however, Pileri et al 2 described the first case series in the European cohort. Thereafter, KD has been reported worldwide in a variety of ethnic backgrounds.3 In the Arabian population, 0.5% of lymph node biopsies from Saudi Arabian descent showed changes of KD4 as compared with 5.7%, as reported by Kuo in nodal specimens from Taiwan.5 KD typically affects young adults and has female predominance, with a male to female ratio of 1:1.9.6 However, it also has been reported in patients aged from 6 to 80 years.7 Lymph node involvement is present in almost all cases which typically involves neck nodes.

In the USA among a series of 108 patients, 83 had lymphadenopathy localised to one site, usually cervical and particularly posterior cervical.8 The nodes were usually moderately enlarged (1 to Page 8 of 12, 2 cm in diameter).4 They were typically firm, smooth, discrete and mobile. The nodal enlargement was associated with dull or acute pain. In our patient, posterior cervical lymph nodes were enlarged up to 3 cm in size, firm in consistency and associated with a dull ache.

Fever is present in 30% to 50% of the patients and is usually low-grade, which persists for about a week and rarely up to a month. Other less common clinical findings include weight loss, malaise, chills, night sweats and gastrointestinal symptoms.9

In terms of laboratory findings, leucopenia is seen in up to 43%,10 followed by atypical lymphocytosis in 25 per cent of the patients.11 Other reported findings of complete blood count include thrombocytopenia and pancytopenia. In those with severe illness, anaemia of chronic disease is also demonstrated.12–14

ESR can be normal but was elevated to more than 60 mm/hour in 70% of the patients in one series.15 Other non-specific findings include elevated serum LDH.16 Generally, antinuclear antibodies (ANA), rheumatoid factor and lupus erythematosus antibodies are negative. However, a transient rise in anti-DNA and antiribonuclear protein antibody levels have been described.10 It is noteworthy that few patients initially diagnosed with Kikuchi disease may subsequently develop SLE.8 Therefore, an ANA test is mandatory to exclude SLE in patients with KD and such cases should be followed carefully to ensure complete resolution of their symptoms. Serology for hepatitis B, C, Epstein-Barr virus, cytomegalovirus, HIV, toxoplasmosis, cat-scratch disease and other infectious agents are often performed, since these infections are considered in the differential diagnosis of fever and lymphadenopathy.

CT imaging of the affected lymph nodes typically shows perinodal infiltration and homogenous nodal contrast enhancement. This may help to differentiate Kikuchi disease from nodal reactive hyperplasia and tuberculous lymphadenopathy.

The diagnosis of Kikuchi disease is almost always made by lymph node biopsy. Biopsy should be performed, despite the self-limiting nature of this disease, to exclude more serious conditions requiring aggressive therapy such as lymphoma. There are also few reports of patients of KD misdiagnosed as having lymphoma and treated with cytotoxic agents.8

Histologically, three main patterns of KD have been described: proliferative, necrotising and xanthomatous.9 Presence of coagulative necrosis with histiocytic proliferation and the absence of granulocytes is mandatory for diagnosis of KD with proliferative pattern. Cellular necrosis, karyorrhexis and cellular debris are hallmarks of necrotising pattern of KD. Additionally, SLE or reactive lymphadenopathy can be distinguished from KD by the absence of granulocytes in necrotising stage.

On immunohistochemistry, histiocytes in KD are positive for lysozyme, myeloperoxidase, CD68, CD163 and CD4. The lymphocytes in the lesions are mostly CD3-positive T cells demonstrating a predominance of CD8 as compared with CD4, with very few CD20-positive B cells. In our case, there was a necrotising histiocytic change and absence of granulation which favoured Kikuchi disease.

There is no established treatment protocol or guidelines for Kikuchi disease. In majority of the patients, symptomatic management with antipyretics and NSAIDs is sufficient to control symptoms. Complete recovery is usually observed within 1 month but may extend up to 4 months.17 However, patients having severe or persisting symptoms, may be treated with glucocorticoids18 or intravenous immune globulin19 with apparent benefit. In Page 9 of 12 there have been reports of recurrence of Kikuchi disease, successfully treated with hydroxychloroquine monotherapy or in combination with glucocorticoids.20–22

Learning points

  • Kikuchi disease (KD) is an uncommon disease, which often masquerades as systemic lupus erythematosus (SLE), lymphoma and systemic infectious disease, that is, tuberculosis.

  • Lymph node biopsy will aid accurate diagnosis.

  • It is mostly a self-limiting disease but affected patients should be followed for some years because they can develop SLE, and recurrences of KD can occasionally continue for many years.

Footnotes

  • Contributors Dr AH is directly involved in active management and diagnosis of patient. Drs MG, HY and MI helped in editing manuscript and searching the published data on Kikuchi disease and final review of the case for any mistakes.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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