A 36-year-old woman with recurrent high-grade fevers, hypotension, and hypertriglyceridemia

INITIAL CLINICAL PRESENTATION

Chief symptom

A 36-year-old white woman was transferred for evaluation of a 6-month history of recurrent high-grade fevers and episodic hypotension.

History of the present illness

The patient had been admitted 6 months earlier to an outside hospital with a high-grade fever, an erythematous rash on her lower extremities, and pain in her legs. She had a history of bipolar disorder and schizoaffective disorder, and had been treated with the antipsychotic medications ziprasidone and quetiapine fumarate. An initial evaluation for infections was negative, and broad-spectrum antibiotics failed to relieve the fever. The patient's fevers were attributed to the neuroleptic malignant syndrome (Table 1). Her fevers continued unabated to temperatures as high as 103°F, despite discontinuation of her antipsychotic medications and treatment with bromocriptine. She was transferred to another hospital for further evaluation and management.

Table 1. Patient's clinical features on each hospital admission

Admission	Clinical features on admission	Discharge diagnosis
First outside hospital	High-grade fever, transient localized rash on lower legs, leg pain	Neuroleptic malignant syndrome due to use of antipsychotics
Second outside hospital	High-grade fever, transient localized rash on lower legs, transient increase in creatine kinase level	Presumed dermatomyositis
Third outside hospital	High-grade fever	Urinary tract infection due to Escherichia coli
Fourth outside hospital	High-grade fever, sinus tachycardia, hypotension, low hematocrit at 20%	Neuroleptic malignant syndrome and anemia of chronic disease
Our hospital	High-grade fever, sinus tachycardia, hypotension

At the transfer hospital, the patient exhibited a transient increase in her creatine kinase level to 1,389 units/liter (normal value <240). Assays for antinuclear antibodies, antibodies to double-stranded DNA, and extractable nuclear antigens (Ro, La, Sm, and RNP) were negative, as were anti–Jo-1 antibodies. A magnetic resonance image of the lower leg showed muscle edema with localized infarction. A muscle biopsy showed perivascular inflammatory infiltrates consistent with an inflammatory myopathy. Prednisone 60 mg/day was started and azathioprine was considered, but the patient's localized rash and leg pain resolved spontaneously before treatment with azathioprine was started. The patient was prescribed a tapering course of prednisone for presumed dermatomyositis, and did not experience recurrent episodes of fever, rash, or leg pain while receiving glucocorticoids (Table 1). No photographic record of the patient's original rash exists.

Within one week of discharge, the patient developed recurrent fevers and was readmitted to a third hospital. Her dose of prednisone at that time was unknown. She was later found to have a urinary tract infection caused by Escherichia coli and was treated with trimethoprim/sulfamethoxazole. Despite antibiotic treatment, the patient continued to have intermittent high-grade fevers and episodes of hypotension, with blood pressure as low as 70/40 mm Hg (Table 1). She was transferred to a fourth hospital. Upon transfer, the patient had a temperature of 104°F, sinus tachycardia (140–160 beats/minute), hypotension, and a hematocrit of 20%. There was no rash despite the development of intermittent high-grade fever.

Multiple cultures were negative for infection. The patient underwent a bone marrow biopsy that showed a hypercellular marrow, and a peripheral smear showed some dysplastic myeloid forms and blasts. These were interpreted as being consistent with reactive changes associated with anemia of chronic disease. A second muscle biopsy finding showed mild perivascular inflammatory infiltrates in the endomysium, consistent with an inflammatory myopathy. However, further analysis by electron microscopy and immunohistochemical staining demonstrated no definitive evidence of such a condition. Antibodies against the membrane attack complex of complement, the major histocompatibility complex, CD20, CD3, laminin α, Brown-Brenn stain, and NADH reductase were negative. The final interpretation of the muscle biopsy finding was nonspecific and possibly the result of trauma or ischemia at needle entry sites.

The patient continued receiving prednisone without a diagnosis, and bromocriptine was reinitiated for the possibility of the neuroleptic malignant syndrome. The patient responded to these interventions with resolution of the fevers and episodic hypotension. She received 2 units of packed red blood cells for her anemia and was discharged with a presumptive diagnosis of recurrent fever due to bromocriptine withdrawal (Table 1).

FURTHER EVALUATION

Within one month after discharge, the patient was admitted to our hospital (her fifth) for recurrent high-grade fever and hypotension (Table 1). Additional history was taken, but no new information about her past medical history emerged. Both of her parents were alive but she had no siblings. The family history was noncontributory. Her medications on admission included bromocriptine, clonazepam, esomeprazole, and calcium carbonate with vitamin D.

On physical examination, the patient was alert, oriented, and cooperative. She was febrile (102°F), had a pulse of 100 beats/minute, and had a blood pressure of 80/65 mm Hg. Her respiratory rate was 18 breaths/minute and unlabored. Her oxygen saturation was 98% on room air. Examination of her heart revealed a regular tachycardia but no murmurs, rubs, or gallops. The lungs were clear to auscultation. There was no evidence of hepatosplenomegaly, skin rash, focal motor weakness, sensory deficits, or arthritis.

The initial laboratory evaluation is shown in Table 2. The serum alanine aminotransferase and aspartate aminotransferase concentrations were elevated ∼4-fold and the creatine kinase level was slightly elevated (178 units/liter, normal value 40–150). The patient's serum triglycerides level was 610 mg/dl (normal range 40–150). The serum ferritin level was markedly increased at 9,770 ng/ml (normal range 10–200), and the patient had a pronounced anemia, with a hematocrit of 20.6% (normal range 36.0–46.0). A peripheral leukocytosis was present, with a white blood cell count of 20,900/mm³ (normal range 4,500–11,000). The erythrocyte sedimentation rate (ESR) was >140 mm/hour (normal value 1–25) and the C-reactive protein (CRP) level was 218 mg/liter (normal value <5).

Table 2. Results of laboratory tests upon admission to the Massachusetts General Hospital*

Variable	Value	Normal value
* ALT/SGPT = alanine aminotransferase/serum glutamic pyruvic transaminase; AST/SGOT = aspartate aminotransferase/serum glutamic oxaloacetic transaminase; N/A = not applicable.
Plasma sodium, mmoles/liter	136	135–145
Plasma potassium, mmoles/liter	4.2	3.4–4.8
Plasma chloride, mmoles/liter	98	100–108
Plasma CO2, mmoles/liter	30.3	23.0–31.9
Plasma urea nitrogen, mg/dl	13	8–25
Plasma creatinine, mg/dl	0.5	0.6–1.5
Plasma glucose, mg/dl	126	70–110
Liver function tests
ALT/SGPT, units/liter	117	7–30
AST/SGOT, units/liter	107	9–32
Alkaline phosphatase, units/liter	126	30–100
Total bilirubin, mg/dl	0.8	0–1
Direct bilirubin, mg/dl	0.2	0–0.4
Total protein, gm/dl	6.6	6.0–8.3
Albumin, gm/dl	2.5	3.3–5.0
Globulin, gm/dl	4.1	2.6–4.1
Cardiac enzymes
Creatine kinase, units/liter	178	40–150
Creatine kinase isoenzymes, ng/ml	11.1	0.0–6.9
Lactic dehydrogenase, units/liter	293	110–210
Cholesterol panel
Total cholesterol, mg/dl	195	N/A
Triglycerides, mg/dl	610	40–150
High-density lipoprotein, mg/dl	10	35–100
Anemia-related studies
Iron, μg/dl	62	30–160
Total iron binding capacity, μg/dl	153	228–428
Ferritin, ng/ml	9,770	10–200
Vitamin B12, pg/ml	589	>250
Folic acid, ng/ml	11.4	3.1–17.4
Hematologic studies
Hematocrit, %	20.6	36.0–46.0
Hemoglobin, gm/dl	7.0	12.0–16.0
Mean corpuscular volume, μm^3	89	80–100
Platelet count, per mm^3	261,000	150,000–350,000
White blood cell count, per mm^3	20,900	4,500–11,000
Differential counts, %
Neutrophils	82	40–70
Band forms	9	0–10
Lymphocytes	3	22–44
Monocytes	5	4–11
Eosinophils	0	0–8
Basophils	0	0–3
Acute-phase reactants
Erythrocyte sedimentation rate, mm/hour	>140	1–25
C-reactive protein, mg/liter	218	<5
Haptoglobin, mg/dl	591	16–199
Myositis-specific antibodies
Jo-1	Negative
PL-7	Negative
PL-12	Negative
EJ	Negative
OJ	Negative
Mi-2	Negative
Signal recognition particle	Negative
PM-Scl	Negative
Ku	Negative
U1 RNP	Negative
U2 RNP	Negative
Ro	Negative

Assays for antinuclear antibodies, antibodies to double-stranded DNA, rheumatoid factor, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, and cryoglobulins were negative. The serum C3 and C4 levels were normal. A serum protein electrophoresis test showed normal levels of all immunoglobulins and no monoclonal spike. Blood cultures and a tuberculin test were negative.

Initial diagnostic studies were performed to rule out infectious causes, including blood cultures, a chest radiograph, and computed tomographic scans of the abdomen and pelvis. Each of these studies was unremarkable. Her fever did not respond to acetaminophen, and she had several episodes of severe hypotension that required admission to the medical intensive care unit. To control those symptoms, it was necessary to increase the patient's glucocorticoid dose again.

CASE SUMMARY

This 36-year-old woman had been ill for at least 6 months. The dominant features of her illness were recurrent high-grade fevers, hypotension, and anemia. She also had a transient, localized rash on her lower leg and an elevated creatine kinase level early in her course, but her overall syndrome was not consistent with an idiopathic inflammatory myopathy. The patient's striking leukocytosis and elevated acute-phase reactants, ferritin level, and triglycerides were consistent with an infection, but repeat and thorough infectious evaluations did not reveal compelling evidence of a microbial pathogen. Her anemia had been attributed to the anemia of chronic disease, and the bone marrow biopsy interpretation appeared to support that diagnosis. Her recurrent fever and hypotension resolved several times on high doses of glucocorticoids and appeared to have recurred following tapered removal of glucocorticoid treatment.

DIFFERENTIAL DIAGNOSIS

In a patient who presents with high grade-fevers and hypotension, infection must be excluded expeditiously. In this patient, infection was ruled out through extensive evaluation on each hospital admission. Multiple computed tomography and magnetic resonance imaging scans appeared to exclude malignancies. Several serologic analyses and 2 muscle biopsies were not consistent with an idiopathic rheumatic disorder.

The patient's syndrome calls to mind 3 major diagnoses: adult-onset Still's disease (AOSD), macrophage activation syndrome (MAS), and an autoinflammatory syndrome such as cryopyrin-associated periodic syndrome. Each of these possibilities is considered in turn.

Adult-onset Still's disease

AOSD is a rare systemic inflammatory disease of unknown etiology that often presents as a fever of unknown origin. Based on a meta-analysis of the 5 largest retrospective studies performed between 1966 and 2005, the overall incidence of fever in AOSD patients was 96% (1). The fever often exceeds 102°F, is transient, and rarely lasts more than 4 hours. The next two most common features of AOSD are a characteristic rash, present in 73% of patients, and arthralgia (or arthritis). The classic rash associated with AOSD is an evanescent, salmon-pink, maculopapular eruption found predominantly on the proximal extremities and trunk. This rash recurs with fever and is often mildly pruritic, resembling that of a drug reaction.

Patients with AOSD usually exhibit a striking leukocytosis and elevations of the hepatic transaminases and acute-phase reactants. In addition, extremely high serum levels of ferritin, ranging up to 30,000 ng/ml, are not uncommon in AOSD. The serum ferritin level often corresponds to disease severity. These ferritin level elevations are out of proportion to the elevations observed in other acute-phase reactants. Hyperferritinemia has a high sensitivity for AOSD (∼80%) but has a low specificity (40%). High levels of ferritin have limited diagnostic value for AOSD because they are also characteristic of hemochromatosis, systemic infections, malignancies, and MAS.

AOSD is a diagnosis of exclusion and its treatment is largely empiric (1). Nonsteroidal antiinflammatory drugs are often the first therapy employed, but most patients require glucocorticoids to control their disease. An interleukin-1 (IL-1) antagonism, e.g., with the IL-1 receptor antagonist anakinra, is the standard of therapy for the exacerbations of acute disease rather than increasing steroid use (2).

Macrophage activation syndrome

MAS is a rapidly fatal illness of unknown etiology that is characterized by fever, rash, hepatosplenomegaly, lymphadenopathy, and central nervous system dysfunction. In addition, MAS patients have striking laboratory test results, including anemia, thrombocytopenia, hypertriglyceridemia, hypoalbuminemia, elevated serum concentrations of hepatic transaminases and lactate dehydrogenase, markedly elevated ferritin levels, and hyponatremia. MAS often occurs as a complication of systemic juvenile idiopathic arthritis (JIA) (3, 4).

The etiology of MAS remains unclear, and conditions associated with MAS include infections, malignancies (both hematologic and solid tumors), autoimmune diseases, and inborn error of metabolism, etc. (5). Proposed guidelines for the diagnosis of MAS are predicated on the clinical presentation (i.e., fever, tachycardia, etc.), the characteristic laboratory profile outlined above (serum ferritin level >10,000 ng/ml, etc.), and the histopathologic findings on bone marrow biopsy (3, 5). The presence within the bone marrow of well-differentiated macrophages that are actively engaged in the phagocytosis of hematopoietic elements is considered a hallmark of MAS (4, 5). Because most of the primary forms of MAS are genetically defined and occur earlier in life, a diagnosis of MAS in this 36-year-old patient will warrant further investigation for secondary causes of MAS, such as infection, solid tumors, hematologic malignancy, or a consequence of rheumatologic disorder, most commonly Still's disease (5).

Recent studies have suggested that abnormalities of natural killer cells mediate the MAS. For example, JIA patients with MAS have depressed natural killer cell function (5, 6). Other studies have shown that IL-18 levels are elevated in JIA patients with MAS (5, 7). IL-18, which stimulates neutrophils and macrophages to produce proinflammatory cytokines, has been implicated in a variety of inflammatory rheumatic diseases (8–10).

Patients are often dependent on high doses of parenteral glucocorticoids at the time of their MAS diagnosis (4, 5). Despite treatment with high doses of glucocorticoids, some patients with MAS die (11, 12). Other studies indicate that cyclosporine, intravenous immunoglobulins, anti–IL-1 therapy, or etoposide may be an effective therapeutic approach for MAS that is resistant to glucocorticoids (5, 13–15).

This patient presented clinical features and laboratory findings consistent with MAS. These features included a fulminant, treatment-refractory disease course, recurrent high-grade fever, dependence on high doses of glucocorticoids, anemia, hypertriglyceridemia, hypoalbuminemia, elevated serum concentrations of hepatic transaminases and lactate dehydrogenase, markedly elevated ferritin levels, increases in acute-phase reactants, and hyponatremia. A more direct approach to the diagnosis is a bone marrow biopsy to demonstrate the presence of hemophagocytosis or hematologic abnormalities causing secondary MAS. However, hemophagocytosis is not required for a diagnosis of MAS.

Autoinflammatory syndromes

The autoinflammatory syndromes, frequently referred to as cryopyrin-associated periodic syndromes, generally respond to glucocorticoid treatment and could conceivably account for our patient's symptoms. The salient characteristics of the hereditary familial syndromes, as part of the autoinflammatory syndromes that present with fever and rash, are shown in Table 3. At the present time, several disorders are known: familial cold-induced autoinflammatory syndrome 1 (FCAS1); FCAS2; familial Mediterranean fever (FMF); hyperimmunoglobulinemia D with periodic fever syndrome; Muckle-Wells syndrome; neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome; Schnitzler syndrome (SS); syndrome of pyogenic sterile arthritis, pyoderma gangrenosum, and acne; and tumor necrosis factor receptor–associated periodic syndrome (TRAPS).

Table 3. Features of hereditary periodic fever syndromes (part of the autoinflammatory syndromes)*

	FCAS1	MWS	NOMID/CINCA syndrome	FCAS2	FMF	HIDS	PAPA	TRAPS
* Adapted, with permission, from ref.21 and OMIM. FCAS1 = familial cold-induced autoinflammatory syndrome 1; MWS = Muckle-Wells syndrome; NOMID/CINCA syndrome = neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome; FMF = familial Mediterranean fever; HIDS = hyperimmunoglobulinemia D with periodic fever syndrome; PAPA = syndrome of pyogenic sterile arthritis, pyoderma gangrenous, and acne; TRAPS = tumor necrosis factor receptor–associated periodic syndrome. MK = mevalonate kinase; TNF = tumor necrosis factor; IL-1 = interleukin-1; NSAIDs = nonsteroidal antiinflammatory drugs.
Autosomal inheritance	Dominant	Dominant	Dominant	Dominant	Recessive	Recessive	Dominant	Dominant
Gene	CIAS1 (NLRP3)	CIAS1 (NLRP3)	CIAS1 (NLRP3)	NLRP12	MEFV	MVK	PSTPIP1	TNFRSF1A
Protein	Cryopyrin	Cryopyrin	Cryopyrin	NALP12	Pyrin	MK	Cryopyrin	p55 TNF receptor
Ethnicity	Mainly European	Northern European	None	2 patients from Guadeloupe reported	Arab, Armenian, Italian, Jewish, Turkish	Dutch, northern European	None	Irish, Scottish, Danish, Ashkenazi Jewish
Duration of attacks	<24 hours	1–2 days	Continuous but with flares	2–3 days	1–3 days	3–7 days	Variable	Often >1 week
Skin disease	Maculopapular rash	Urticarial rash	Persistent rash	Urticaria	Rare erysipeloid erythema	Rare erysipelas	Acne, cystic skin lesion, pyoderma gangrenosum	Localized rash overlying myalgia
Musculoskeletal involvement	Myalgia and polyarthritis after cold exposure	Myalgia and polyarthralgia	Arthralgia, patellar/epiphyseal overgrowth	Myalgia and polyarthralgia after cold exposure	Arthritis	Arthralgia	Sterile pyogenic arthritis	Myalgia, arthralgia
Other features	Childhood onset, rare late-onset renal amyloidosis, leukocytosis may be present	Abdominal pain, sensorineural hearing loss, amyloidosis in 10–50%	Neonatal disease, chronic meningitis, growth and mental retardation, hepatosplenomegaly, sensorineural hearing loss, vision defect	Newborn or childhood onset, abdominal pain and vomit, headache and sensorineural hearing loss	Sterile peritonitis, pleurisy, recurrent pericarditis, abdominal pain, frequency of amyloidosis varied among ethnic groups	Prodromal headache, abdominal pain, tender lymph nodes; rare renal amyloidosis; high serum IgD levels and elevated IgA levels; leukocytosis	Childhood onset, destructive muscle and joint disease	Abdominal pain, lymphadenopathy, anemia, leukocytosis, meningitis, skin lesions with infiltrating T lymphocytes
Treatment	Avoidance of cold, anti–IL-1, stanozolol, NSAIDs, rilonacept	Anti–IL-1, rilonacept	Anti–IL-1	Avoidance of cold, NSAIDs, anti–IL-1	Colchicine for treatment and prophylaxis, steroids	NSAIDs, statins, steroids, anti-TNFα	Steroids, anti-TNFα, anti–IL-1	Anti-TNFα, anti–IL-1, steroids

The clinical features of this patient, including initial localized rash overlying myalgia, anemia, leukocytosis, and fever responsiveness to glucocorticoids, suggest that the patient may have TRAPS. TRAPS usually presents in childhood or adolescence, but it can also be diagnosed in adults. Although TRAPS is not known to present with such fulminant characteristics, genetic testing for TRAPS is warranted in this patient based on the clinical features of her disease. Two points arguing compellingly against an autoinflammatory syndrome are the patient's age (somewhat old for a new diagnosis of TRAPS) and the presence of severe, recurrent hypotension, which is not characteristic of these conditions.

SS is a very rare disease of unknown etiology that is characterized by a chronic urticarial eruption, recurrent fever, bone pain, arthralgia, or arthritis (16, 17). SS occurs in adult or elderly populations, and the average age of diagnosis is approximately 55 years. The molecular mechanisms and pathogenesis of SS are unknown, but SS is strongly associated with a monoclonal IgM gammopathy. Recent findings also suggested dysregulation of IL-1α in SS (18), which is supported by the efficacy of anti–IL-1 therapy (19, 20).

Conclusive diagnosis of the autoinflammatory syndromes requires genetic analysis and the detection of the gene mutation specific for each disorder (OMIM) (21, 22). The hereditary familial syndromes are each associated with single-gene mutations (Table 3). Altered function of these proteins causes aberrant production of IL-1β, dysregulation of downstream pathways, and induction of periodic fevers.

CLINICAL DIAGNOSIS

Macrophage activation syndrome.

CLINICAL COURSE

The patient failed multiple attempts to taper her glucocorticoid dose and had multiple episodes of fever and hypotension. Before a diagnosis of MAS was established, the patient was put on a trial of etanercept therapy (25 mg twice a day) for a possible diagnosis of TRAPS. However, subsequent genetic testing for the detection of TRAPS-associated mutations (Gene Dx, Gaithersburg, MD) was negative for all common gene mutations in the TNF p55 receptor gene. The patient was also tested for the V726A mutation in FMF and the mutations of 4 other common FMF genes. Each of these was negative. The patient's levels of IgD and IgA were normal.

Soon after beginning etanercept therapy, the patient experienced recurrent high-grade fevers and hypotension during a taper of the glucocorticoid dose (Figure 1). Subsequently, etanercept was discontinued and sequential courses of azathioprine, mycophenolate mofetil, cyclosporine, and colchicine were administered. The administration of each of these medications appeared to result in the transient symptomatic remissions (Figures 1 and 2), but the patient remained dependent on high doses of glucocorticoids for the maintenance of systolic blood pressure and the control of fevers.

Figure 1. Correlation between the use of immunosuppressants and prednisone doses during hospitalization. IV = intravenous; PO = prednisone orally.

Figure 2. Correlation between the use of immunosuppressants and daily maximum body temperatures during hospitalization. IV = intravenous; PO = prednisone orally.

Prior to the initiation of anakinra treatment, a bone marrow biopsy was performed to investigate new-onset pancytopenia and possible diagnosis of MAS. The patient's transient leukopenia and thrombocytopenia later resolved on their own, and were thought to be related to the use of immunosuppressants. On the other hand, her anemia did not improve throughout multiple treatment courses. On hospital day 133, the patient began anakinra 100 mg twice a day for possible MAS. Her mean arterial blood pressure stabilized and her fevers remitted (Figure 2). The patient remained afebrile and hemodynamically stable for 2 months while receiving intravenous or subcutaneous treatment of anakinra, and tolerated a glucocorticoids taper down to oral prednisone (40 mg daily). In addition, her CRP level returned to normal and her ESR decreased from 123 to 65 mm/hour while receiving the anakinra treatment.

PATHOLOGIC FINDINGS

The bone marrow biopsy sample, clot section, and aspirate smears were all adequate for evaluation. Examination of the biopsy sample and clot section revealed marrow that was variably cellular but on average hypocellular for the age of the patient (Figures 3A and B). The overall cellularity was 20%. The myeloid to erythroid ratio appeared increased. Myeloid elements showed a leftward shift. Maturation of erythroid elements was difficult to assess because of the paucity of erythroid precursors. Megakaryocytes were decreased in number, and some of those present were small, hypobolated, and dysplastic (Figure 3B). Stains for acid-fast bacilli and fungi on sections of the marrow biopsy sample were negative. A 200-cell differential count of the aspirate smears revealed 46% neutrophils and neutrophil precursors, 13% erythroid cells, 20% lymphocytes, 1% monocytes, 1% eosinophils, 7% promyelocytes, and 12% blasts. The myeloid maturation was left-shifted, with an increase in blasts and promyelocytes. Erythroid maturation showed nuclear irregularities and lobation, and basophilic cytoplasmic stippling (Figure 3C). Scattered hemosiderin-laden histiocytes were seen in both the marrow biopsy (Figure 3B) and on the aspirate smear. In a few histiocytes, a small amount of cellular debris was present along with hemosiderin (Figure 3D), but no population of hemophagocytic histiocytes was identified. A Prussian blue–stained aspirate smear revealed abundant storage iron. Ringed sideroblasts were not identified.

Figure 3. Bone marrow biopsy and aspirate smear. A, Bone marrow core biopsy sample (hematoxylin and eosin stained; original magnification × 100). In this area, the marrow is markedly hypocellular and the marrow space is mainly occupied by fat. B, Bone marrow core biopsy sample (hematoxylin and eosin stained; original magnification × 250). In this area, the marrow is more cellular. The megakaryocytes are small and hypolobated, consistent with dysplastic megakaryocytes. Histiocytes containing golden-brown hemosiderin are scattered among the hematopoietic elements. C, Bone marrow aspirate smear (Wright stained; original magnification × 1,000). Increased numbers of myeloblasts (arrows), primitive cells with round nuclei, prominent nucleoli, and scant agranular cytoplasm are present. The erythroid elements show highly abnormal nuclear morphology with frequent nuclear irregularity and lobation (arrowheads). D, Bone marrow aspirate smear (Wright stained; original magnification × 1,000). Histiocyte with cellular debris is shown.

Flow cytometric analysis revealed a population of CD33+, CD13−, CD117+, CD34+, CD14−, and myeloperoxidase cells, consistent with myeloid blasts (21% of the cell population). There was no evidence of an abnormal B lymphocyte or T lymphocyte population. Cytogenetic analysis revealed an abnormal karyotype: 46XX, t(2;3)(p23;q26) [cp14]/46,XX [6] (Figure 4). Because the breakpoint at 2p was in the area of the activin receptor–like kinase (ALK) gene at 2p23, fluorescence in situ hybridization was performed on interphase nuclei using a probe for ALK. No ALK rearrangement was identified in 100 of 100 cells examined.

Figure 4. Partial GTG-banding karyotype showing the t(2;3)(p23;q26). Arrows show the abnormal chromosomes, der(2) and der(3).

The combination of morphologic abnormalities in all 3 hematopoietic cell lines, increased numbers of myeloblasts, and a clonal cytogenetic abnormality was interpreted as a myelodysplastic syndrome (MDS) known as refractory anemia with excess blasts 2 (RAEB-2). Although 21% of blasts were found by flow cytometry and the presence of more than 20% of myeloblasts was used to establish a diagnosis of acute myeloid leukemia, fewer blasts (12%) were found by direct count of the aspirate smear. The latter is the value typically used in subclassification of myeloid neoplasms.

The t(2;3) has been reported in at least 50 patients with a broad spectrum of myeloid malignancies, including refractory anemia, RAEB, chronic myelogenous leukemia, and acute myeloid leukemia (23). The translocation was seen as the sole chromosome aberration in the majority of the cases, but it was also noted in association with total or partial loss of chromosomes 5 and/or 7. A high degree of heterogeneity of breakpoints on chromosome 2 has been demonstrated by both conventional and molecular cytogenetic analysis, most often clustering to 2p15-p21 and 2p21-p23 regions. In contrast, the chromosome 3 breakpoint maps to 3q26 in the vicinity of the locus for the putative EVI1 oncogene. It has been suggested that the t(2;3) myeloid malignancies could belong to the group of patients with other 3q26 rearrangements, e.g., inv(3)(q21q26), t(3;3)q21;q26), ins(3;3)(q26;q21q26), t(3;12)(q26;p13), and t(3;21)(q26;q22), because ectopic expression of EVI1 and trilineage dysplasia and dysmegakaryopoiesis are common features of these patients as well.

PATHOLOGIC DIAGNOSIS

Myelodysplastic syndrome (refractory anemia with excess blasts).

DISCUSSION

MDS is a heterogeneous group of neoplastic clonal stem cell disorders. The pathogenesis of MDS, which remains to be fully elucidated, is thought to be related to cytogenetic abnormalities of the hematopoietic stem cells resulting in single-or multiple-lineage deficiency of hematopoietic cell lines (24–26). Myeloid neoplasms associated with the t(2;3) translocation, as in this case, have heterogeneous clinical and pathologic features. The clinical and hematologic features of most cases are described in little or no detail; therefore, it is difficult at this time to assess the prognostic significance of t(2;3) in general, much less the specific breakpoint clusters on 2p.

MDS primarily occurs in an elderly population with a median age between 60 and 75 years, but can also be found in younger adults and children. The main clinical features of MDS are fatigue and exertional dyspnea over a prolonged period of time, which are often misinterpreted as cardiopulmonary diseases, especially in elderly patients. Approximately half of the patients are asymptomatic, and a suspicion for MDS is raised only after a routine blood count. Recent case reports have demonstrated autoimmune phenomena in patients with MDS (27). These patients presented with autoimmune disorders such as vasculitis, arthritis, polyneuropathy, connective tissue diseases, lupus, Sjögren's syndrome, or Raynaud's phenomenon, etc. To date, a fulminant course of MAS that requires multiple intensive care unit admissions, as seen in our patient, has not been reported for MDS. Therefore, this may be the first report of a patient with MDS presenting with features so strongly reminiscent of MAS.

A common paradox in patients with MDS is the coexistence of normal or increased cellularity in the bone marrow, with decreased cell counts in the peripheral blood. This paradox could be explained by an increase in apoptosis counterbalancing the observed increased cellular proliferation of hematopoietic stem cells in the bone marrow (25). In support of this hypothesis, the overexpression of CD95 and TRAIL death receptors has been shown in MDS patients (28–31). In addition, other cytokines such as IL-6, IL-18, and IL-23 have also been shown to be either up-regulated or dysregulated in MDS patients, and could contribute to the modulation of hematopoietic cell proliferation and apoptosis (32–34). Recent studies have also implicated interferon regulatory factor 1 in the pathogenesis of autoimmunity in MDS, such that expression of high levels of interferon regulatory factor 1 messenger RNA in bone marrow mononuclear cells from patients with MDS was associated with systemic vasculitis (35).

Treatment for MDS is supportive care, and patients often receive packed red blood cell transfusion for symptomatic anemia. Allogeneic bone marrow transplantation is the only potentially curative therapy for MDS. The efficacy of other treatment modalities such as demethylating agents, immunosuppressive agents, and cytotoxic treatments depends on the MDS subtype and patient characteristics (36).

This patient presented with a striking anemia to both an outside hospital and ours. The report of the negative bone marrow biopsy finding from the outside hospital and the working diagnosis of anemia of chronic disease delayed her ultimate diagnosis, partly because the presentation of MDS with a fulminant course characterized by high-grade fevers and hypotension is virtually unprecedented. The clinicians caring for the patient at our hospital also believed that her anemia was initially part of her overall clinical syndrome rather than its direct cause. It is also likely that the transient rash and features of an inflammatory myopathy with which she presented early in her course were also part of the autoimmune expression of her MDS. We anticipate that more autoimmune features of MDS will be uncovered in the future.

AUTHOR CONTRIBUTIONS

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. Chou 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. Chou, Dinarello, Dal Cin.

Acquisition of data. Chou, Dinarello, Ferry, Dal Cin.

Analysis and interpretation of data. Chou, Ferry.