Pediatric Annals

Special Issue Article 

Kikuchi-Fujimoto Disease in Children: An Important Diagnostic Consideration for Cervical Lymphadenitis

Emily Batton, MD; Muayad Alali, MD; Joseph R. Hageman, MD; Megan Parilla, MD; Karl O. A. Yu, MD, PhD

Abstract

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease that causes lymphadenopathy and has a characteristic histological appearance. The etiology of this disease is unknown, but a possible infectious trigger has been hypothesized. In the adult population this disease is more common in females; however, in the pediatric population it is more common in males. Descriptions in the pediatric literature are lacking, particularly in the United States. The authors report three cases of pediatric KFD that presented at the same institution in a 9-month time period. All three patients were male and of non-Asian descent who were diagnosed with KFD by histopathologic specimen after presenting with unilateral cervical lymphadenitis. Each patient had additional laboratory evidence of a possible bacterial infection at the time of diagnosis. These three cases highlight the importance of considering KFD early when a pediatric patient presents with unilateral cervical lymphadenitis. The authors discuss the epidemiology, etiology, clinical manifestations, diagnostic approaches, and treatment of KFD. [Pediatr Ann. 2019;48(10):e406–e411.]

Abstract

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease that causes lymphadenopathy and has a characteristic histological appearance. The etiology of this disease is unknown, but a possible infectious trigger has been hypothesized. In the adult population this disease is more common in females; however, in the pediatric population it is more common in males. Descriptions in the pediatric literature are lacking, particularly in the United States. The authors report three cases of pediatric KFD that presented at the same institution in a 9-month time period. All three patients were male and of non-Asian descent who were diagnosed with KFD by histopathologic specimen after presenting with unilateral cervical lymphadenitis. Each patient had additional laboratory evidence of a possible bacterial infection at the time of diagnosis. These three cases highlight the importance of considering KFD early when a pediatric patient presents with unilateral cervical lymphadenitis. The authors discuss the epidemiology, etiology, clinical manifestations, diagnostic approaches, and treatment of KFD. [Pediatr Ann. 2019;48(10):e406–e411.]

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease of unknown etiology that causes lymphadenopathy and has a characteristic histological appearance.1

Overlap in both clinical presentation and histological features with other diseases exist.2 The pathophysiology of KFD is unknown, but possible triggers such as infections or autoimmune diseases have been hypothesized.3 This disease is reported worldwide, although uncommonly in the United States, and it is particularly common in young adult women of Asian descent;4 however, the epidemiology of pediatric cases may differ. To increase awareness of KFD in the pediatric population, we describe three patients with KFD who presented to Comer Children's Hospital at the University of Chicago over a 9-month time period from April 2016 to January 2017 (Table 1). We also discuss the diagnosis, pathology, and management of KFD.

Patient Characteristics

Table 1:

Patient Characteristics

Illustrative Cases

Illustrative Case 1

A 15-year-old Hispanic boy presented with an enlarged cervical lymph node for 2 months but was otherwise asymptomatic. He had a positive PPD (purified protein derivative), positive tuberculosis (TB) test, negative AFB (acid-fast bacillus), and a lymph node biopsy consistent with KFD (see Table 2 for other laboratory findings). This case is presented in detail in an article by Alali et al.5

Laboratory Characteristics

Table 2:

Laboratory Characteristics

Illustrative Case 2

A 9-year-old Hispanic boy was transferred from a referring hospital with fever, headache, and weight loss for 1 month. He also endorsed night sweats, poor appetite, and intermittent migratory arthritis. He reported throat pain that started prior to admission and had since resolved. Physical examination revealed a febrile and uncomfortable boy with right anterior cervical lymphadenopathy. During the subsequent days he was intermittently diaphoretic with migratory arthritis in his hand and wrists. He required a short course of parenteral nutrition due to prolonged poor oral intake. The initial differential diagnosis included systemic juvenile idiopathic arthritis with or without macrophage activation syndrome, an infectious process, or a hematologic-oncologic process such as lymphoma.

Laboratory studies demonstrated pancytopenia, elevated serum transaminase, hyperferritinemia, and hypertriglyceridemia with a normal fibrinogen, erythrocyte sedimentation rate (ESR) in the range of 30 to 40 mm/h, and a C-reactive protein (CRP) of 6 mg/L. Bone marrow biopsy completed at the referring hospital demonstrated hemophagocytosis. A computed tomography (CT) scan of the chest, abdomen, and pelvis demonstrated hepatosplenomegaly and left axillary lymphadenopathy, and a CT scan of the neck showed extensive cervical lymphadenopathy (Figure 1). Anti-streptolysin O and anti-DNase B antibodies were elevated. All other infectious and rheumatologic testing remained negative (Table 2). An excisional right cervical lymph node biopsy was consistent with KFD (Table 2 and Figure 2). Lymph node culture was negative.

Coronal and axial planes of soft tissue neck imaging using computed tomography without contrast demonstrating cervical lymphadenopathy present in all three cases. (A) Illustrative Case 1: follow-up image 9 months after presentation with left lymph node at 1.1 × 1.3 cm. (B) Illustrative Case 2: largest right lymph node measuring 1.8 × 1.9 cm. (C) Illustrative Case 3: enlarged right lymph nodes at 1.9 × 1.1 cm.

Figure 1.

Coronal and axial planes of soft tissue neck imaging using computed tomography without contrast demonstrating cervical lymphadenopathy present in all three cases. (A) Illustrative Case 1: follow-up image 9 months after presentation with left lymph node at 1.1 × 1.3 cm. (B) Illustrative Case 2: largest right lymph node measuring 1.8 × 1.9 cm. (C) Illustrative Case 3: enlarged right lymph nodes at 1.9 × 1.1 cm.

Hematoxylin and eosin stain stains of lymph node biopsy samples from each patient. (A) Lymph node with sheets of histiocytes and focal necrotic areas in Illustrative Case 1. (B) Histiocytes with crescent-shaped nuclei in Illustrative Case 1. (C) Focal apoptotic debris in Illustrative Case 2. (D) Histiocytes with crescent-shaped nuclei and focal necrotic areas in Illustrative Case 3.

Figure 2.

Hematoxylin and eosin stain stains of lymph node biopsy samples from each patient. (A) Lymph node with sheets of histiocytes and focal necrotic areas in Illustrative Case 1. (B) Histiocytes with crescent-shaped nuclei in Illustrative Case 1. (C) Focal apoptotic debris in Illustrative Case 2. (D) Histiocytes with crescent-shaped nuclei and focal necrotic areas in Illustrative Case 3.

The patient was discharged with a 10-day course of penicillin V potassium for group A streptococcal infection and naproxen daily for symptomatic relief and KFD treatment. Group A streptococcal throat culture performed prior to starting penicillin remained negative. His symptoms resolved within 1 month and laboratory testing at that time was unremarkable. Rheumatology continues to observe him closely due to concern he may develop systemic lupus erythematosus (SLE).

Illustrative Case 3

A 14-year-old African American boy was transferred from another hospital with progressive neck and back pain, right neck swelling, vomiting, fever, fatigue, night sweats, and a 10-lb weight loss all occurring over a “few weeks.” He had been exposed to an iguana 2 weeks prior to symptom onset but denied diarrhea and abdominal pain. He denied any travel history. Physical examination demonstrated a tender right posterior lymph node with diffuse right neck swelling. Laboratory testing revealed elevated ESR and CRP, mild leukopenia, anemia, and elevated lactate dehydrogenase (Table 2). CT scan and ultrasound of the neck demonstrated right cervical lymphadenopathy (Figure 1, whereas CT scan of the abdomen and chest were largely unremarkable. Ceftriaxone and clindamycin were started on hospital day 1 for a presumed bacterial lymphadenitis. A bone marrow biopsy was deferred due to a higher likelihood of an infectious process. Lymph node biopsy completed on day 4 of hospitalization was consistent with KFD, although the lymph node gram stain and culture were negative. His fevers, neck swelling, tenderness, and oral intake significantly improved. The laboratory testing for an infectious agent remained negative at discharge; however, results of Salmonella serologies had not yet returned.

The patient was discharged with cefdinir to empirically cover Salmonella and clindamycin to cover gram-positive and anaerobic organisms. Ibuprofen every 6 hours was continued to treat his KFD. Several days after discharge, the Salmonella serology showed a positive response to the Vi capsular polysaccharide and an equivocal response to H antigen types b and d. The patient was seen in the infectious disease clinic shortly after discharge and all symptoms had resolved. He was assessed 6 months later to ensure he had not developed SLE given his KFD diagnosis. He was asymptomatic at that time and his lymphadenopathy had resolved.

Discussion

KFD is a benign, self-limited disease characterized by cervical lymphadenopathy that has traditionally been associated with young adult women of Asian descent. However, an increasing number of cases in children have been reported with an apparent male predominance in the pediatric population (a ratio of about 1.4:1 as reported by Kim et al.2). The three pediatric cases described here occurred in non-Asian, preadolescent boys from two large ethnic populations (African American and Hispanic), which support a male predominance and ethnic variability in the pediatric population.

Clinical Manifestations

Unilateral posterior cervical lymphadenopathy is commonly reported as a presenting symptom in KFD. The lymph node can be large, with reported sizes ranging from 0.5 to 7 cm in diameter.6 Other clinical manifestations can be nonspecific and represent signs of systemic inflammation including fever, fatigue, joint pain, and rashes. Leukopenia, anemia, and elevated ESR are not uncommon and many manifestations overlap with those of SLE.7 Clinical manifestations in children with KFD may be distinct from those in adults. Fever, rash, tender lymphadenopathy, and leukopenia occur more commonly in children whereas generalized lymphadenopathy is uncommon in the pediatric presentation.2

Etiology

Although the etiology and pathophysiology of KFD remain unknown, several authors have proposed a possible infectious trigger. Kucukardali et al.7 propose that T-cell–mediated hyperresponsiveness to antigenic stimuli in susceptible people may result in CD8 T-cell–induced cell necrosis and nuclear debris seen in KFD. The most common infectious triggers reported include viral infections (7%) such as Epstein-Barr virus, cytomegalovirus, varicella zoster virus, human herpesvirus-6, and HIV, and bacteria such as Mycobacterium tuberculosis, Yersinia enterocolitica, and Toxoplasma.8

The testing for infectious agents for these cases suggests a concurrent infection was present at the time of KFD diagnosis, possibly representing an infectious trigger (summarized in Table 2). Illustrative Case 1 demonstrates the most convincing evidence of a bacterial infection with a positive PPD and TB test along with a pertinent travel history, which supports the presence of a latent TB infection at the very least. However, it is difficult to determine whether this patient's lymphadenitis was TB in origin or if latent TB in another location triggered KFD. The elevated Group A streptococcal blood tests in Illustrative Case 2 and positive Salmonella antigen responses in Illustrative Case 3 may represent a carrier state or past infection rather than true pathologic disease.

Differential Diagnosis

Although KFD is self-limited, it presents a diagnostic dilemma because it mimics many serious illnesses including TB, lymphoma, and SLE, all of which are important to consider in the differential diagnosis of unilateral cervical lymphadenitis. A complex relationship between KFD and SLE has been established due to the clinical and histopathological overlap and the fact that some patients with KFD go on to develop SLE later in life.6

Diagnoses other than KFD were considered as the leading diagnoses in all three cases described (Table 1 and Table 3).

Treatment and Outcome

Table 3:

Treatment and Outcome

Diagnosis

KFD is most accurately diagnosed by histopathology from an excisional lymph node biopsy. A characteristic histological appearance of lymphoid tissue in KFD includes focal apoptotic coagulation necrosis (Figure 2), proliferation of histiocytes and CD8 T cells, karyorrhexis, and the absence of neutrophils.9 Histiocytes typically demonstrate eccentric crescent-shaped nuclei (Figure 2) and stain positively for the CD68 antigen.9 Less invasive methods of diagnosis such as fine needle aspiration and imaging have been explored but remain inferior.10,11

Treatment

No treatment guidelines for KFD exist at this time, and current recommendations are largely based on expert opinion. Temporary courses of nonsteroidal anti-inflammatory drugs and steroids are frequently used. Steroids have been shown to be particularly helpful in the case of prolonged fever and symptom duration.3

Recurrence

Despite the self-limited nature of KFD, this disease has been known to recur. The recurrence rates range from 3% to 4% in some studies12 to 15% in a more recent review.13 Recurrence has been observed as long as 8 years after initial presentation,13 making close and prolonged follow-up necessary. Of our cases, only the patient described in Illustrative Case 1 has developed symptomatic recurrence thus far. His recurrence occurred while on anti-tuberculosis treatment and resolved after a trial of scheduled ibuprofen.

Conclusion

Although rare, KFD should be considered in the differential diagnosis of fever of unknown origin and tender lymphadenopathy in otherwise healthy children. Infectious, rheuma tologic, and oncologic processes require careful consideration; however, it is essential that pediatricians consider KFD early as well. Our cases demonstrate the importance of a timely lymph node biopsy and histological diagnosis to prevent additional laboratory testing, procedures, and medications as well as to avoid delaying treatment. All three of our cases had positive infectious testing, supporting the hypothesis that an infectious trigger exists. More research to determine the etiology of KFD, including possible infectious or rheumatologic triggers, is needed to better direct therapies and follow-up.

References

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Patient Characteristics

Characteristic Case 1 Case 2 Case 3
Age 15 years 9 years 14 years
Gender Male Male Male
Ethnicity Hispanic Hispanic African American
Month of presentation April December January
History of the present illness Enlarged right cervical lymph node Fever, headache, weight loss, arthralgias, night sweats, decreased oral intake Neck pain and swelling, fever, fatigue, night sweats, weightloss
Past medical history Asthma Resolved isolated thrombocytopenia Migraine headaches
Physical examination Enlarged right mobile cervical lymph node Enlarged right anterior cervical lymph node, hand joint swelling Enlarged right posterior cervical lymph node, right neck swelling and tenderness

Laboratory Characteristics

Laboratory Parameter Case 1 Case 2 Case 3
White blood cell (per mcL) 5,300 1,400 (low) 3,000 (low)
Erythrocyte sedimentation rate (mm/h) 21 (high) 37 (high) 55 (high)
C-reactive protein (mg/L) 1 6 (high) 29 (high)
Hemoglobin (g/dL) 14.8 10.1 (low) 11.8 (low)
Platelets (per mcL) 210,000 120,000 (low) 155,000
Alanine aminotransferase (U/L) 13 121 (high) 13
Anti-nuclear antibody Negative Negative -
Anti-double stranded DNA - Negative -
Lactate dehydrogenase (U/L) - 925 (high) 636 (high)
Ferritin (ng/mL) - 1,694 (high) -
Triglycerides (mg/dL) - 164 (high) -
NK cell function - Decreased -
Soluble IL-2 receptor (pg/mL) - 494 -
Streptolysin O antibody (IU/mL) - 400 (high) -
Anti-DNase B antibody (U/mL) - 549 (high) -
Salmonella Vi antigen antibody - - Positive
Purified protein derivative Positive Negative Negative
QuantiFERON-TB Gold Positive Negative Negative
Othera Negative Negative Negative
Blood culture - Negative Negative
Respiratory virus panel Rhinovirus/enterovirus Negative Negative
Lymph node biopsy Histiocytic lymphadenitis Apoptotic debris Histiocytic necrotizing lymphadenitis, Kikuchi vs. lupus lymphadenitis Histiocytic necrotizing lymphadenitis Apoptotic debris and necrotic cells
Lymph node Gram stain Moderate white blood cells Predominantly mononuclear cells Many white blood cells Predominantly mononuclear cells Moderate white blood cells Predominantly mononuclear cells
Lymph node cultureb Negative Negative Negative
Bone marrow biopsy - Hypocellular Marked stromal damage Left shifted myelopoiesis -

Treatment and Outcome

Criterion Case 1 Case 2 Case 3
Symptom-to-diagnosis interval 2 months 5 weeks 16 days
Associated infection Mycobacterium tuberculosis Rhinovirus/enterovirus Streptococcus pyogenes Salmonella enterica (Vi positive)
Management Rifampin, isoniazid, pyrazinamide, and ethambutol for 8 weeks Rifampin and isoniazid for another 4 months Penicillin, naproxen Cefdinir, clindamycin, ibuprofen
Follow-up Lymphadenopathy recurrence Symptom resolution Symptom resolution
Authors

Emily Batton, MD, is a Resident in Pediatrics, Comer Children's Hospital, Pritzker School of Medicine, The University of Chicago. Muayad Alali, MD, is a Fellow in Pediatric Infectious Disease, Comer Children's Hospital. Joseph R. Hageman, MD, is a Senior Clinician Educator, Pritzker School of Medicine, The University of Chicago. Megan Parilla, MD, is a Hematopathology Fellow, Department of Pathology, The University of Chicago. Karl O. A. Yu, MD, PhD, is a Clinical Assistant Professor of Pediatrics, Division of Infectious Diseases, Department of Pediatrics, University at Buffalo.

Address correspondence to Emily Batton, MD, Comer Children's Hospital, Pritzker School of Medicine, The University of Chicago, 5721 S. Maryland Avenue, Chicago, IL 60637; email: embatton@gmail.com

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20190920-01

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