A 27-year-old Cambodian woman with fever, lymphadenopathy, and arthritis



A 27-year-old woman presented to the emergency department for evaluation of fever, chills, and drenching night sweats of a duration of approximately 1 month. The patient had not taken her temperature but described intermittent periods in which she felt febrile. These episodes occurred without any particular pattern. Three weeks before her presentation, the patient noted a painful neck lump that slowly increased in size. This was followed by additive joint pain of her feet, hands, wrists, knees, and elbows; 1 hour of morning stiffness; fatigue; anorexia; and a 6-pound weight loss. The patient took ibuprofen, with minimal relief. The development of lightheadedness, nausea, and headaches forced her to seek medical attention.

The patient denied oral ulcers, rashes, photosensitivity, Raynaud's phenomenon, cough, chest pain, dyspnea on exertion, thrombotic events, seizures, and dry eyes or dry mouth. She also denied sore throat, any known infections, recent travel, sick contacts, tick bites, tattoos, and blood transfusions.

Past medical history

She had no known medical conditions or previous surgeries. Two years before presentation she had refused isoniazid prophylaxis after being found to have a positive tuberculin skin test on occupational screening. The patient had 4 previous pregnancies, with 2 normal vaginal deliveries and 2 elective abortions. There was no history of sexually transmitted diseases. Medications on admission included ibuprofen, calcium, and vitamin D. No drug allergies were reported.

Social and family history

She had emigrated from Cambodia at age 13 years, was married, and had 2 healthy children. She had been monogamous with her husband for 10 years. She worked as a medical assistant at an outpatient clinic. She denied consumption of alcohol, tobacco, or illicit drug use. She had owned a cat until 1 year before presentation, but owned no pets at the time of the evaluation. Her mother had died of breast cancer. There was no family history of autoimmune disease or hematologic malignancy.

Physical examination

The patient appeared uncomfortable and weak. She was febrile to 38.0°C and had chills. Her blood pressure was 110/70 mm Hg and her heart rate was 110/minute. She had a mobile, tender, 4-cm lymph node in the left cervical region. The overlying skin was warm and diffusely erythematous (Figure 1). Additional smaller tender lymph nodes were present in the right axilla, the right epitrochlea, and the bilateral inguinal region. There was no facial erythema. Her oropharynx was clear. The cardiopulmonary examination was unremarkable, and her abdomen had no tenderness, masses, or organomegaly. The neurologic examination was nonfocal. The musculoskeletal examination revealed mild synovitis and tenderness of the shoulders, elbows, wrists, knees, and proximal interphalangeal (PIP) and metatarsophalangeal joints.

Figure 1.

Left cervical tender 4-cm lymph node with overlying erythema.

The patient's laboratory evaluation is shown in Table 1. An assay for antinuclear antibodies (ANAs) was negative. Antibodies directed against double-stranded DNA (dsDNA), Ro/SSA, La/SSB, RNP, and Sm were negative, as were assays for rheumatoid factor (RF), anticardiolipin antibodies, and lupus anticoagulant. The serum complement components C3 and C4 were normal. Parvovirus IgG and IgM were both <0.2 (normal index <0.9) and testing for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was negative. Screening for hepatitis B and C, the human immunodeficiency virus (HIV), antistreptolysin O, and a rapid plasma reagin test were negative. The ferritin level was 71 ng/dl (normal range 10–240). The erythrocyte sedimentation rate and C-reactive protein level were normal. Three sets of blood and urine cultures were negative. Examination of a peripheral blood smear showed 2+ microcytes, 1+ schistocytes, and 1+ ovalocytes. Her chest films were clear, with no evidence of lymphadenopathy, granulomas, or cavitary lesions. Hand radiographs showed subtle soft tissue swelling surrounding the second and third PIP joints of the left hand. There was no periarticular osteopenia or bony erosions (Figure 2). A diagnostic test was performed.

Table 1. Hematology and chemistry test results on admission
VariableValueNormal value
Hematocrit, %36.532–45
Hemoglobin, gm/dl12.211–15
White cell count, 1,000/μl2.24–11
Differential count, %  
 Band forms140–10
 Atypical lymphocytes20
Platelet count, 1,000/μl196150–400
Prothrombin time, seconds12.610.7–13.2
Partial thromboplastin time, seconds33.62–34
International normalized ratio1.10.9–1.1
Glucose, mg/dl13260–150
Sodium, mmoles/liter136135–145
Potassium, mmoles/liter3.73.6–5.1
Chloride, mmoles/liter10498–110
Urea nitrogen, mg/dl126–24
Creatinine, mg/dl0.660.4–1.3
Alkaline phosphatase, units/liter5740–130
Aspartate aminotransferase, units/liter3710–42
Alanine aminotransferase, units/liter205–40
Lactate dehydrogenase, units/liter30050–175
Creatinine kinase, units/liter7720–165
Red blood cells, per high-power field40–5
White blood cells, per high-power field80–5
Specific gravity1.0081.001–1.035
Figure 2.

Hand films showing subtle soft tissue swelling over the second and third proximal interphalangeal joints. No erosions are noted.


This previously healthy Cambodian woman had a subacute illness characterized by fever, constitutional symptoms, diffuse lymphadenopathy, and a symmetric additive polyarthritis. Notable laboratory findings included leukopenia, lymphopenia, and atypical lymphocytes.


The differential diagnosis encompasses infections, malignancies, and autoimmune conditions associated with systemic inflammation (Table 2).

Table 2. Differential diagnosis*
  • *

    HIV = human immunodeficiency virus; EBV = Epstein-Barr virus; CMV = cytomegalovirus.

  Tuberculous arthritis
  Poncet's disease
Streptococcal adenitis
  Parvovirus B19
Systemic inflammatory disorders with autoimmunity
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Still's disease
 Kikuchi-Fujimoto disease


Streptococcal pharyngitis is a frequent cause of cervical lymphadenitis to be considered. This disorder usually seen in children predominantly presents with fever, sore throat, and painful swallowing associated with pharyngeal erythema with or without exudates, which were not present in this patient. A negative antistreptolysin O titer more than 3 weeks after the onset of symptoms excludes this possibility.

The patient's country of origin and her known history of purified protein derivative (PPD) positivity suggest that tuberculosis (TB) is a diagnostic consideration. Interpretation of her positive PPD was challenging because of a previous BCG vaccination. Mycobacterial infection that affects the cervical lymph nodes, a condition known as scrofula, is a common presentation of TB among immigrant populations in the US (1). Approximately three-fourths of the patients who present in this fashion with TB do so without accompanying systemic symptoms (2). In most cases, primary TB is mild and self-limited and frequently results in latent disease after being contained by the host's defenses, explaining a possible unnoticed infection in this patient. In some cases, radiographic evidence of a healed primary infection in the form of calcified granulomas, mediastinal lymph nodes, or apical fibrotic disease may present. Our patient's chest radiograph had no such findings, nor was there a miliary pattern consistent with disseminated mycobacterial infection. Tuberculous arthritis typically presents as an insidious large-joint monarthritis involving the knee or hip rather than subacute, symmetric, small-joint inflammation, and therefore seems unlikely (3).

Poncet's disease, a rare reactive arthritis–like condition associated with TB infection elsewhere in the body, is like an acute symmetric polyarthritis involving large and small joints without evidence of active infection of the involved joints (4). This disease tends to occur with active extrapulmonary, pulmonary, or miliary TB, all of which are scenarios not present in this patient. Although the probabilities appear to argue against TB, further testing is necessary to exclude this possibility for certain.

This patient's history of exposure to a cat and the finding of bulky lymphadenopathy in the neck make a Bartonella henselae infection and cat scratch disease (CSD) a plausible diagnosis. CSD presents with fever, arthralgias/ arthritis (5.5%), and lymphadenitis that is usually regional and almost invariably related to a cat bite or scratch (5). Generalized lymphadenopathy, although described, seldom occurs. The incubation period for this infection is typically 7–12 days. The first cutaneous sign is a primary pustular skin lesion that appears at the site of the scratch. This is followed by the development of lymphadenopathy between 5 and 50 days later. Our patient reported no such skin lesions and her history of cat exposure was remote, making CSD improbable.

Another cat-related infection to consider is Toxoplasma gondii, acquired from exposure to cat feces. Acute toxoplasmosis is asymptomatic in the majority of immunocompetent hosts. When symptomatic infection occurs, the most common manifestation is bilateral, symmetric, nontender cervical adenopathy (6). Approximately 20–30% of symptomatic individuals have generalized lymphadenopathy. Constitutional symptoms such as fever, chills, and sweats are mild, if present at all. Patients may have evidence of a slight lymphocytosis or atypical lymphocytes in the blood, usually less than 10% of the total leukocyte count. Our patient's clinical features make toxoplasmosis unlikely. She also has no history of travel that would have taken her to regions endemic for deep fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis.

A host of viral infections could cause fever, arthritis, lymphadenopathy, and hematologic abnormalities, either directly or indirectly. Viral infections that cause mononucleosis-like symptoms and must be considered include HIV, EBV, and CMV. Primary HIV infection usually presents as an illness that resembles mononucleosis, with fever, pharyngitis, lymphadenopathy, headache, and myalgias (7). Laboratory findings may include elevations of the serum hepatic transaminases, leukopenia with lymphocytosis (and often atypical lymphocytes), and thrombocytopenia. Despite the presence of a few of these findings in our patient, she had no risk factors for HIV infection and a test for this condition was negative.

Infections with EBV or CMV are associated with a mononucleosis-like illness similar to acute HIV infection. Cardinal hematologic abnormalities related to mononucleosis include 50% or more lymphocytes and monocytes and 10% or more atypical lymphocytes (8). In contrast, our patient had primarily leukopenia without a significant proportion of lymphocytes. Moreover, the percentage of atypical lymphocytes was not as strikingly high as expected for a mononucleosis-like syndrome, and viral serologies for CMV, EBV, and the heterophil antibody were negative. A parvovirus B19 infection was also excluded on the basis of negative IgM antibodies to that pathogen (9).


The presence of marked constitutional symptoms in a person with prominent lymphadenopathy raises the concern for a lymphoproliferative disorder. “B symptoms” and the elevated serum lactate dehydrogenase level that our patient had are observed at variable frequencies among different types of lymphoma (10, 11). Arthritis associated with various malignant disorders is not well described in the literature and may include arthralgias and musculoskeletal pain related to tumor infiltration (12–14). Angioimmunoblastic T cell lymphoma, a rare type of non-Hodgkin's lymphoma, is characterized by fever, weight loss, lymphadenopathy, hepatosplenomegaly, rash, vasculitis, serositis, hemolytic anemia, and polyclonal hypergammaglobulinemia (15). This condition can present with a nonerosive, nondeforming, symmetric, seronegative polyarthritis that commonly presents in the hands (16, 17). Although this patient did not fit this clinical picture, certain features present in this patient may suggest a malignancy-associated process. Tissue sampling for morphologic examination, immunologic marker studies, and cytogenetic analysis appeared essential to exclude a malignancy.

Autoimmune and inflammatory disorders

Systemic lupus erythematosus (SLE), adult-onset Still's disease, and sarcoidosis were all strong possibilities as the explanation for our patient's presentation.

SLE associated with lupus lymphadenitis is an appealing explanation for the constellation of systemic symptoms, symmetric nonerosive small-joint arthritis, diffuse lymphadenopathy, leucopenia, and lymphopenia seen in this young woman. As many as two-thirds of patients with SLE have lymphadenopathy, and 12% of patients with SLE have generalized lymphadenopathy. The most common lymph node chains involved are the cervical (43%), mesenteric (21%), axillary (18%), and inguinal lymph nodes (17%). Patients with lymphadenopathy tend to be younger than those without lymphadenopathy and more likely to have fatigue, fever, weight loss, cutaneous abnormalities, hepatomegaly, splenomegaly, and higher titers of antibodies to dsDNA (18).

In order to be classified as a lupus patient for the purpose of inclusion in a research study, a patient must fulfill at least 4 of the 11 American College of Rheumatology (ACR) criteria for the classification of SLE (19). These criteria are often employed for the purpose of diagnosis, although they were not intended for this purpose (20). Our patient had lymphopenia and leukopenia documented on a single occasion and symmetric small-joint arthritis. These findings would be insufficient for classification of the patient as having SLE. Although the ACR criteria fail to capture the entire clinical spectrum of this protean disease and a patient can have a firm clinical diagnosis of SLE yet fail to fulfill the ACR criteria, our patient's negative ANAs and the absence of other key laboratory and clinical features typical of SLE provided evidence against this diagnosis.

The existence of subacute symmetric arthritis involving the hands and wrists with significant morning stiffness raises the concern of rheumatoid arthritis (RA) as a diagnostic possibility. However, elevation of inflammatory markers in the serum, the finding of a positive RF, and the radiographic presence of periarticular demineralization and/or erosions expected in RA were not seen in this case. In addition, febrile lymphadenopathy at the onset of mild inflammatory arthritis would be distinctly unique for RA.

A pertinent autoimmune condition that exhibits fever, arthritis, and lymphadenopathy to be considered in this young adult population is adult-onset Still's disease. High quotidian fever, the sine qua non of this disease, was not appreciated in this patient. Other factors that are inconsistent with a diagnosis of Still's disease are the absence of an evanescent rash, leukocytosis, elevated acute-phase reactants, or an elevated serum ferritin level, which is seen in 70% of cases (21).

A remaining diagnostic consideration in the rheumatic realm is sarcoidosis. This multisystem granulomatous disease of uncertain etiology predominantly affects young adults, and shows increased incidence in women (22). Patients with sarcoidosis are frequently asymptomatic and diagnosed incidentally on routine chest radiography. Organ system involvement can vary broadly in any given patient. Systemic symptoms such as fever, weight loss, fatigue, and malaise are the presenting symptoms in 25% of patients. Peripheral lymphadenopathy, one of the most common manifestations of sarcoidosis, occurs in 75% of cases (23), but erythematous, tender adenopathy would be distinctly unique of sarcoidosis. Sarcoid arthropathy, detected in up to 15% of patients (but significantly lower in most series), has varying patterns. Lofgren's syndrome, characterized by erythema nodosum, bilateral hilar adenopathy, and acute polyarthritis, usually involves the knees and ankles. Other chronic forms of osteoarticular sarcoid, which mainly involve the knees, ankles, and PIP joints, are not consistent with this patient's presentation. The explosive onset of symptoms without the classic distribution of arthritis and the absence of distinctive pulmonary findings make this granulomatous disease a doubtful diagnosis.

A more esoteric entity to be included in the differential diagnosis of lymphadenitis in a young woman is Kikuchi-Fujimoto disease (KFD). This is a rare, idiopathic, self-limited condition that shares many epidemiologic and clinical features with SLE. Although KFD has a predilection for patients of Asian descent, cases involving all ethnic groups have been described. The disease presents with low-grade fevers of a duration of approximately 1 week and cervical lymphadenopathy that is often unilateral (24). Other features of this disease also displayed in this patient are pronounced systemic symptoms, generalized lymphadenopathy, arthritis, leukopenia, atypical lymphocytes, and negative serologies for ANAs and RF.

Morphologic examination of the lymph node

The diagnostic test consisted of an excisional biopsy of a cervical lymph node. Examination of the node revealed patchy, irregular paracortical lesions composed of mononuclear cells associated with remarkable karyorrhectic debris (Figure 3). The mononuclear cells included phagocytic macrophages (tingible body macrophages), histiocytes, lymphocytes, and so-called plasmacytoid monocytes, now known to represent a population of immature dendritic cells. Neither neutrophils nor eosinophils were present in significant quantities. The cortical portion of the lymph node was markedly attenuated without reactive lymphoid follicles.

Figure 3.

Excisional biopsy of the lymph node showing paracortical expansion with patchy pale lesions composed of mononuclear cells, including phagocytic histiocytes (tingible body macrophages), lymphocytes, plasmacytoid dendritic cells, and karyorrhectic debris.


KFD, also referred to as histiocytic necrotizing lymphadenitis, was first described in Japan in 1972 in independent reports by Kikuchi and Fujimoto et al (25). The incidence of KFD varies widely across different ethnic groups but has a predilection for young women of Asian descent. The women to men ratio is 1:4, and the mean age range at presentation is 25–30 years (26).

The most common presentation is unilateral posterior cervical lymphadenopathy accompanied by low-grade fever, night sweats, fatigue, nausea, weight loss, and diarrhea. Involved lymph nodes are often firm, smooth, tender, and mobile. An analysis of 244 cases of KFD reported the following manifestations: lymphadenomegaly (100%), generalized lymphadenopathy (5%), fever (35%), rash (10%), arthralgias (7%), and arthritis (5%). Less common manifestations of KFD included hepatomegaly, splenomegaly, xerophthalmia, and aphthous lesions. The presence of leukopenia and atypical lymphocytes range in different series from 3–29% and 3–35%, respectively (26–28). The percentage of patients who are ANA positive appears to be higher among patients from Asia compared with Europe (23% versus 3%). KFD is a benign, self-limited disorder that usually resolves spontaneously within 6 months of presentation (24, 29). Anecdotal cases with fatal outcomes have been reported (27).

The etiology of KFD remains enigmatic. However, the identification of immature dendritic cells within the lymph nodes of patients with KFD as the lesional cells has illuminated some aspects of the pathogenesis. It appears to date that unknown triggering events activate an immune response leading to the recruitment or local proliferation of precursor dendritic cells (30). Putative triggering events include infectious organisms such as EBV, CMV, varicella-zoster virus, human herpesvirus 6, human herpesvirus 8, HIV, parvovirus B19, Yersinia enterocolitica, and Toxoplasma, among others (31–33).

Lymph node biopsy is required for the diagnosis of KFD to also exclude lymphoproliferative disorders and infectious lymphadenitis. The differential diagnosis of KFD includes SLE, Hodgkin's disease, toxoplasmosis, CSD, acquired immunodeficiency syndrome, angioimmunoblastic lymphadenopathy, and infectious mononucleosis (34).

KFD is characterized morphologically by nodal paracortical and cortical patchy lesions with karyorrhectic nuclear debris. A mononuclear cell response composed of histiocytes, lymphoid cells, and a striking population of mononuclear cells with plasmacytoid morphology is typical of the disease. In contrast, plasma cells and neutrophils are not a feature of KFD. Depending on the time course, karyorrhexis or a mononuclear reaction with variable cellular composition may predominate (30).

Despite numerous reports associating KFD with SLE, the precise relationship between these 2 conditions has yet to be defined. Reports of KFD have described this disease preceding, coinciding with, or occurring after a diagnosis of SLE (24, 35). The epidemiologic, clinical, and pathologic similarities between these 2 disorders have raised the consideration of KFD heralding SLE or reflecting a self-limited SLE-like autoimmune condition (a “forme fruste” of SLE).

The histopathologic features of Kikuchi's lymphadenitis are sufficiently distinctive to justify its recognition as a specific entity. However, the histopathologic findings of necrotic types of Kikuchi's lymphadenitis are indistinguishable from lupus lymphadenitis in the absence of hematoxylin bodies or abundant plasma cells, both of which are customarily present in lupus (26, 34).


Kikuchi-Fujimoto disease.


The patient was prescribed ibuprofen as needed. Her fever and hematologic abnormalities subsided approximately 1 week after presentation without any other intervention. At a followup visit 4 weeks later, the patient reported occasional night sweats and arthralgias of her hands. Her cervical lymphadenopathy decreased. Lymph node cultures were negative for mycobacteria at 8 weeks. A repeat ANA assay 8 weeks after presentation was negative. The patient was well and symptom free 12 months after diagnosis.


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Yinh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acquisition of data. Yinh.

Analysis and interpretation of data. Yinh, Pilichowska, Kalish.