A 21-year-old man with a history of adult-onset Still's disease (AOSD) presented to the emergency room with a 10-day history of fever with a maximum temperature of 40°C, headaches, joint pain, rash, and vomiting. His rheumatologist advised him to stop taking adalimumab until any underlying infection was ruled out. He was thought to have a flare of Still's disease and was advised to continue methotrexate (MTX) and prednisone 60 mg daily. He did not improve and after 3 days was admitted and given intravenous methylprednisolone (IVMP). He initially felt better, but when the dose of IVMP was decreased, joint pain, fever, and rash returned. Laboratory tests from the initial admission are shown in Table 1. Peripheral blood smear showed atypical lymphocytes. Creatine kinase, hepatitis panel, and chest radiograph were unremarkable.
He was diagnosed with AOSD at age 19 years. His initial presentation consisted of symmetric polyarthritis, a macular rash on his chest and face, leukocytosis, and fever. He was treated initially with high-dose steroids and was taking prednisone until 5 weeks prior to this admission. He had been treated with anakinra in the past, and for the past 1 year he had been taking oral MTX 15 mg weekly and adalimumab 40 mg every other week.
The patient is a college student in southern Ohio majoring in theater. He reported that he had worked in caves for recent productions. He reported no history of travel outside of Ohio since 2006.
Medications prior to hospitalization
His medications prior to admission were prednisone (60 mg/day), celecoxib (200 mg twice a day), esomeprazole (20 mg/day), and MTX (15 mg/week).
On transfer to our hospital, his temperature was 38°C. He had a faint malar rash and a macular, non-blanching rash on the anterior chest, and no synovitis. On abdominal examination, there was tenderness in the right upper quadrant and no hepatosplenomegaly. IVMP was restarted. However, he continued to spike high temperatures, with a maximum of 40°C. Additional laboratory testing is shown in Table 1. He had anemia, leukopenia, thrombocytopenia, and elevated liver enzymes, D-dimer, and ferritin, with a normal erythrocyte sedimentation rate (ESR).
The patient is a 21-year-old man with a previous history of AOSD, recently taking adalimumab and MTX, and presenting with recurring fever, rash, and cytopenias.
Flare of Still's disease
His daily fevers, evanescent rash, arthritis, hyperferritinemia, and liver dysfunction were consistent with a flare of Still's disease (1, 2), but his low ESR, thrombocytopenia, and lack of response to steroids were not.
High fever, rash, cytopenias, liver dysfunction, and elevated D-dimer and ferritin can be consistent with sepsis, especially in an immunocompromised host. Endocarditis should also be considered.
Opportunistic infections, such as disseminated histoplasmosis, aspergillosis, Mycobacterium tuberculosis, nontuberculous mycobacterial infection, or Pneumocystis jiroveci, should be considered in an immunocompromised patient, especially one taking tumor necrosis factor (TNF) inhibitors with continued high fevers despite high-dose steroids (3, 4).
Cytopenias and possible disseminated intravascular coagulation with prior TNF inhibitor therapy suggests the possibility of underlying malignancy (5).
Macrophage activation syndrome
Macrophage activation syndrome (MAS) may be either due to Still's disease or secondary to an infection (bacterial, viral, or fungal).
A possible diagnosis of MAS due to Still's disease was made based on the thrombocytopenia, hyperferritinemia, elevated D-dimer and liver enzymes, and a low ESR. A bone marrow biopsy was done, and prior to the results, anakinra 100 mg subcutaneously twice a day was started along with IVMP. Despite treatment, he continued to have high fever, rash, and joint pains. A computerized tomography scan of the chest showed tiny nodules that were more confluent at the lung bases, producing diffuse hazy ground-glass opacities.
Serologic testing for cytomegalovirus, Toxoplasma, Epstein-Barr virus, and human immunodeficiency virus was negative, as were the blood cultures. A transthoracic echocardiogram was normal. A serum fungal antibody panel was positive for the Histoplasma antibody by complement fixation. A revised diagnosis of disseminated histoplasmosis leading to MAS was made. A positive urine Histoplasma antigen test and positive fungal blood cultures confirmed the diagnosis of disseminated histoplasmosis. He was treated with IV lipid amphotericin B at 4 mg/kg/day. Steroids and anakinra were continued for the MAS.
On day 8, the bone marrow biopsy showed hemophagocytosis and rare intracellular budding yeast compatible with Histoplasma capsulatum (Figures 1 and 2). He was transferred to the medical intensive care unit for respiratory distress and a bronchoscopy was performed. The bronchoalveolar lavage showed many budding yeasts. On day 9, his urine output was decreasing and the creatinine level rose from 1.0 mg/dl to 2.8 mg/dl. Treatment with IV fluids was started.
On day 10, he was afebrile and the urine output and shortness of breath improved. By day 11 of the hospital stay and 3 days after staring lipid amphotericin B, his liver function tests and creatinine started to improve. He was discharged 10 days later on IV lipid amphotericin B at 4 mg/kg/day, oral prednisone, and anakinra (100 mg subcutaneously twice a day).
There are reports in the literature of histoplasmosis leading to MAS/hemophagocytic lymphohistiocytosis (HLH) (6, 7). There are many reports of patients developing disseminated histoplasmosis while receiving TNF inhibitors (3, 4). Patients with AOSD can develop MAS (8, 9). However, this is a prime example of MAS caused by disseminated histoplasmosis in a patient with AOSD taking adalimumab.
There are 2 forms of HLH: primary or familial HLH and secondary or acquired HLH (10). MAS is a term used to describe HLH that occurs in children with systemic juvenile idiopathic arthritis (JIA) or AOSD. It occurs in approximately 10% of patients with systemic JIA (11).
HLH is part of a clinical syndrome caused by increased activation of macrophages, histiocytes, and CD8+ T cells (12). Patients with systemic JIA and MAS have depressed natural killer cell numbers and activity, in part due to lack of phosphorylation in response to interleukin-18 (IL-18) (13), and this may cause uncontrolled macrophage activation (14). It is known that perforin, a cytotoxin protein secreted by lymphocytes, is deficient in both MAS and primary or familial HLH. This results in increased production of interferon-γ and granulocyte–macrophage colony-stimulating factor, both of which are important activators of macrophages (15). The activated macrophages then infiltrate tissues and cause elevated levels of TNFα, IL-1, and IL-6, all of which play an important role in the clinical symptoms and can cause tissue damage (14).
An early report of this entity was by Hadchouel et al in 1985, who described 7 patients with juvenile rheumatoid arthritis presenting acutely with mental status changes, hepatosplenomegaly, elevated liver enzymes, and a sharp fall in blood cell counts and ESR (16). The bone marrow aspirate of most of these patients revealed macrophages actively phagocytosing hematopoietic elements.
There are several triggers for MAS, including various rheumatic conditions, infections, and medications. Infectious triggers can be bacterial, viral, fungal, mycobacterial, or parasitic (7), the most common being Epstein-Barr virus (17, 18). The associated rheumatic conditions can be systemic JIA, systemic lupus erythematosus, sarcoidosis, or rheumatoid arthritis (7, 19). Reports of patients treated with drugs associated with cases of MAS include MTX (20), gold injections (especially the second injection), and sulfasalazine (9), although TNF inhibitors such as etanercept (21) have been described.
MAS can occur at any age with the constellation of clinical features, including persistent fevers (not intermittent), skin rash, hepatosplenomegaly, lymphadenopathy, arthralgias (with relatively minimal arthritis), central nervous system abnormalities, anemia, leukopenia, thrombocytopenia, elevated liver enzymes, hypofibrinogenemia, hypertriglyceridemia, prolonged prothrombin time, partial thromboplastin time, and evidence of hemophagocytosis in the bone marrow (22). Hyperferritinemia, with ferritin levels >10,000 ng/ml (23) and a precipitous fall in ESR (22), are important hallmarks and clinical clues in the diagnosis of MAS.
The preliminary diagnostic criteria for MAS were described by Ravelli et al and are outlined in Table 2 (24). Serum levels of soluble CD25, which is a subunit of IL-2 receptor complex and of soluble CD163, a monocyte/macrophage-restricted transmembrane protein, are elevated in MAS associated with systemic JIA. These levels return to normal with resolution of MAS. These markers may be helpful in identifying high-risk patients with systemic JIA (25).
Table 2. Preliminary diagnostic guidelines for MAS complicating systemic juvenile idiopathic arthritis*
Adapted, with permission, from ref.24. MAS = macrophage activation syndrome.
1. Decreased platelet count (≤262 × 109/liter)
2. Elevated levels of aspartate aminotransferase (>59 units/liter)
3. Decreased white blood cell count (≤4.0 × 109/liter)
4. Hypofibrinogenemia (≤2.5 gm/liter)
1. Central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures, coma)
Evidence of macrophage hemophagocytosis in the bone marrow aspirate
The diagnosis of MAS requires the presence of any 2 or more laboratory criteria or of any 2 or 3 or more clinical and/or laboratory criteria
A bone marrow aspirate for the demonstration of hemophagocytosis may be required only in doubtful cases
In the HLH treatment protocol (HLH-94) developed by the International Histiocyte Society (26), the combination of steroids, cyclosporin A, and etoposide form the major components of treatment. However, use of this protocol would be highly challenging in the setting of infection, as in our patient with fulminant disseminated histoplasmosis. Most cases of systemic JIA–related MAS respond to steroids (11, 18), and those that do not, respond to cyclosporin A (18). Those that do not respond to cyclosporin A are treated with the HLH-94 protocol.
In some patients, etanercept has been used to treat MAS (27). However, other case reports (14, 28) suggest that MAS occurred during treatment with etanercept. Since the majority of cases of MAS occur in the setting of an infection, the use of TNF inhibitors should be avoided until infection has been ruled out. IL-1 inhibitors have been used successfully in the treatment of many patients with systemic JIA (29). There is a single case report of MAS being treated successfully with anakinra, an IL-1 receptor antagonist (30), whereas another patient with systemic JIA developed MAS while being treated with anakinra (31). MAS can be fatal and 2 pediatric series of MAS reported a mortality of 8–22% (11, 18).
In patients with prolonged fever unresponsive to antibiotics, pronounced hepatosplenomegaly, cytopenias, elevated ferritin and triglycerides, low fibrinogen, and a low ESR, the diagnosis of MAS should be considered. In patients who do not respond to therapy for MAS, it is crucial to evaluate for underlying infection. However, even when MAS is triggered by infection, there is an exaggerated immune response, thus warranting the need to add immunosuppressive medications in addition to antimicrobial therapy. Awareness of this condition, early diagnosis, and prompt treatment are important in preventing life-threatening complications.
MAS secondary to disseminated histoplasmosis in a patient with AOSD receiving treatment with a TNF inhibitor.
Two weeks after discharge, his creatinine level, platelet count, and liver function tests had continued to improve. He had no fevers, but remained fatigued. One month later, IV lipid amphotericin B was changed to oral itraconazole after the liver function tests normalized, with an intended duration of therapy of at least 1 year. His fatigue was significantly improved and he was without fever or rash. Creatinine level, platelet count, and liver function tests had now returned to normal. Anakinra 100 mg daily was continued and the prednisone dose was tapered.
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. Deal 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.
Study conception and design. Mehta, Deal.
Acquisition of data. Mehta, Avery, Deal.
Analysis and interpretation of data. Mehta, Hashkes, Avery, Deal.