Macrophage activation syndrome and other systemic inflammatory conditions after BMT

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1 (2006), 1 6 & 2006 Nature Publishing Group All rights reserved /06 $ REVIEW Macrophage activation syndrome and other systemic inflammatory conditions after BMT A Sreedharan 1, S Bowyer 2, CA Wallace, MJ Robertson 4, K Schmidt 2, AE Woolfrey and RP Nelson Jr 4 1 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 2 Department of Pediatrics, Section of Rheumatology, Indiana University School of Medicine, Indianapolis, IN, USA; Division of Rheumatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; 4 Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA and Division of Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA Autologous hematopoietic cell transplantation (HCT) is being used to treat autoimmune diseases refractory to conventional therapy, including rheumatoid arthritis. Macrophage activation syndrome (MAS) is a descriptive term for a systemic inflammatory disorder that has been described in patients with juvenile rheumatoid arthritis (JRA). This case report describes a young adult with systemic JRA (sjra) who developed MAS on day # 12 post-autologous transplantation. The patient developed high fever, laboratory evidence of disseminated intravascular coagulation (DIC), hepatocellular injury, pancytopenia and hyper-ferritinemia. All viral, bacterial and fungal studies were negative and the patient improved with high-dose glucorticosteroid and cyclosporine therapy. Extreme elevation of serum ferritin was documented and helpful in monitoring response to therapy. A number of systemic inflammatory syndromes have been described in association with HCT. These include DIC, engraftment syndrome, infection-associated hemophagocytic syndrome and familial hemophagocytic lymphohistiocytosis. Macrophage activation syndrome presents with features of DICand is closely related or identical to infectionassociated hemophagocytic syndrome. The diagnosis needs to be established in a timely fashion because early and appropriate treatment may improve outcome. advance online publication, 27 February 2006; doi:10.108/sj.bmt.1700 Keywords: arthritis; macrophage activation syndrome; autoimmunity; engraftment syndrome; stem cell transplantation Correspondence: Dr RP Nelson Jr, Division ofhematology/oncology, Hematological Malignancy Program/Immunology, Indiana University School ofmedicine, Barnhill Dr., Suite 47, Indianapolis, IN 46202, USA. ronelson@iupui.edu Received and accepted 2 November 200 Introduction A variety ofsystemic inflammatory syndromes with both distinct and overlapping features occur in association with hematopoietic cell transplantation (HCT), including disseminated intravascular coagulation (DIC), capillary leak syndrome, engraftment syndrome, familial hemophagocytic lymphohistiocytosis (HLH), infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS). 1 Treatment ofthese conditions differs, and owing to their oftentimes-fulminant inflammatory nature must be initiated in a timely fashion. The following report describes a patient with MAS following autotransplantion for juvenile rheumatoid arthritis (JRA), and reviews the diagnostic and management issues of these syndromes in the context ofhct. Case presentation The patient is a 29-year-old Caucasian male with JRA diagnosed at 16 years ofage, who had failed multiple treatments including high-dose corticosteroids, methotrexate, intramuscular gold injections, intravenous immunoglobulin, azathioprine, sulfasalazine, hydroxychloroquine, cyclosporine, pulse cyclophosphamide, etanercept, infliximab, anakinra and thalidomide. At the time ofautotransplant, aside from severe polyarthritis, he suffered from obesity, diabetes, hypertension, pathologic fractures, infections and cataracts. Baseline laboratory data are shown in Table 1. Mobilized PBSC were collected in a single apheresis, and subsequent CD4 þ cell selection resulted in a product with CD4 þ cells/kg and CD cells/kg. Exacerbation ofjra was not observed during receipt of G-CSF. Following conditioning (using cyclophosphamide, ATG and 800 cgy oftotal body irradiation) and re-infusion of the cryopreserved CD4 þ cells, his course was complicated by fever and coagulase negative staphylococcal bacteremia on day þ, treated with ceftazidime and vancomycin. Peripheral granulocyte recovery (400/mm ) occurred on day þ 10 after transplant. He developed a

2 2 cough; computerized chest tomography on day þ 10 revealed no infiltrates, and transthoracic echocardiogram did not reveal any vegetations. Meropenum was added. The patient spiked a fever of 9.01C on day þ 12, and blood and urine cultures were negative. The patient developed a rash and vancomycin was switched to clindamycin on day þ 1. He then experienced daily fevers as high as 40.01C on days þ 12 to þ 19, associated with cough, increased somnolence, generalized arthralgias and fatigue. Physical exam revealed tachycardia, tachypnea and normal blood pressure. Cheeks were flushed. Extremities revealed 2 þ edema, and musculoskeletal examination revealed no evidence ofactive synovitis. Within a few days, pancytopenia developed, white blood count of1600/mm, hemoglobin 7.9 g/dl and platelet count /mm. He was treated with broad-spectrum antibacterials, acyclovir, IVIG and prophylactic inhalational pentamadine. Intensive monitoring ofliver function, clotting parameters and serum ferritin was initiated (see Figure 1). Platelet transfusion support was provided. Despite the generalized systemic inflammatory condition, erythrocyte sedimentation rate (ESR) was 4 on day þ 1. Prothrombin time was 12.6 s, INR, 1.09; D-dimer was elevated and fibrinogen was decreased. Serum ferritin was ng/ml (Table 1). Methylprednisolone, 0. mg/kg every 6 h (2 mg/ kg/day), was given on day þ 1 to day þ 19. Cyclosporine A was begun on day þ 17 and on days þ 20 to 22, he received pulse glucocorticosteroids (GCS), 1000 mg q.d. Glucocorticosteroids were reduced to 1 mg/kg/day by day þ 0. Fever began to resolve, ferritin peaked at Table 1 Laboratory and other testing/procedures Lab data Admission Day +12 Day +19 WBC 1 200/mm /mm 1600/mm Hemoglobin 11.7 g/dl 10.1 g/dl 7.9 g/dl Platelet count /mm /mm /mm Alkaline phosphatase 1 U/l 26 U/l 26 U/l AST 19 /l 204 U/l 29 U/l Total bilirubin 0.4 mg/dl 0.7 mg/dl 2.8 mg/dl D-dimers 1.49 mg FEU/ml mg FEU/ml.41 mg FEU/ml Fibrinogen 9 mg/dl 16 mg/dl 79 mg/dl Protime 12.6 s 1 s Ferritin ng/ml Pre-transplant VDRL and RPR: negative CMV IgG: negative Varicella zoster IgG Ab: detectable HIV ELISA: negative HTLV 1 and 2: negative Herpes simplex virus I and II: detectable Serum cryptococcal antigen: negative Toxoplaxmosis IgG: detectable Serum cryptococcal antigen: negative Day +19 post transplant Urine histoplasmosis antigen: negative Nasopharyngeal viral cultures: negative Serum histoplasmosis complement Fixation: negative Serum cryptococcal antigen: negative EBV PCR serum: negative Serum fungal gel diffusion: negative Abbreviations: AST¼ aspartyl transaminase; EBV ¼ Ebstein Barr virus. Temperature (degree C) Maximum daily temperature Post-transplant day number WBC count (K/mm ) White blood cell count Post-transplant day number Ferritin (ng/ml) Ferritin Post-transplant day number Figure 1 Temperature, white blood cell count and ferritin values before, during and after autologous hematopoietic cell transplantation.

3 ng/ml on day þ 17 and fibrinogen nadired at 79 mg/dl on day þ 19, whereas D-dimer remained elevated. Cryoprecipitate was given periodically. Over the next several days, the patient improved clinically and labs normalized. Histoplasmosis antigen (urine) and histoplasmosis complement fixation serology were negative. Cryptococcal antigen (serum), serum fungal gel diffusion, nasopharyngeal viral cultures and Ebstein Barr virus (EBV) qualitative polymerase chain reaction gene amplification from serum were negative. Following recovery, taper ofimmunosuppressive medications continued uneventfully. He is currently 2 months post-transplant off all medications, in remission, working full-time with normal blood counts, sedimentation rate, C-reactive protein, coagulation studies and serum ferritin. Discussion The systemic inflammatory syndromes include DIC, capillary leak syndrome, engraftment syndrome, familial HLH, infection-associated hemophagocytic syndrome and MAS (see Table 2). Disseminated intravascular coagulation is the prototypical cytokine-mediated systemic inflammatory syndrome. Interleukin (IL)-6, tumor necrosis factor-a (TNF-a), and IL-1 are the primary cytokines involved in the widespread activation ofthe coagulation cascade and microvascular fibrin deposition. 6 The resultant consumption ofcoagulation factors causes bleeding. Capillary leak syndrome is another cytokine-mediated entity that has been described in a wide variety ofdiseases and is most commonly seen in critically ill patients. Engraftment syndrome The term engraftment syndrome is sometimes used to describe a capillary leak syndrome that occurs during neutrophil recovery in bone marrow transplantation patients. Powles et al. 7 described a clinical syndrome associated with leaky capillaries in post-marrow transplant patients. In 1996, Cahill et al. 2 made the temporal connection between a capillary leak syndrome and engraftment. Both allogeneic and autologous bone marrow transplant patients were affected. Clinical manifestations include fever, rash, weight gain, ascites, edema, noncardiogenic pulmonary edema and kidney and liver abnormalities. High levels oftnf and IL-1 are implicated as mediators. Spitzer et al. developed major and minor criteria based on clinical impressions ofmultiple anecdotes. Major criteria include temperature 48.1C with no identifiable infectious etiology, erythroderma involving more than 2% ofbody surface area and non-cardiogenic pulmonary edema. Minor criteria include a total bilirubin X2 mg/dl or transaminases Xtwo times normal, serum creatinine Xtwo times baseline, weight gain of X2.% of baseline body weight and transient encephalopathy. 8 Three major criteria or two major criteria and one minor criterion are required for diagnosis. Maiolino et al. based criteria on a retrospective analysis ofpatients with fever and rash that occurred 24 h before or after neutrophil recovery, and concluded that diagnostic criteria for engraftment syndrome should include fever with either skin rash, pulmonary infiltrates or diarrhea. Gorek et al. 9 recently described engraftment syndrome in a cohort of patients after nonmyeloabltive HCT. Hemophagocytic lymphohistiocytic disorders Hemophagocytic lymphohistiocytosis is a collection of histiocyte disorders that can be divided into three groups: dendritic cell disorders, macrophage-related disorders and malignant disorders. 10 Hemophagocytic lymphohistiocytosis may be further subdivided into primary or familial lymphohistiocytosis and secondary HLH, previously known as IAHS. The diagnosis ofhlh, as defined by Henter et al., includes five major criteria: fever 48.1Cfor 7 or more days, splenomegaly, cytopenias involving two or more cell lines, hypertriglyceridemia or hypofibrinogenemia and hemophagocytosis. 4 A bone marrow examination is not required to establish the diagnosis, and autopsy findings ofmarrow hemophagocytosis are actually present in a minority ofchildren at the time ofdeath. 11 Classically, FHL manifests in the first few months of life, although rare cases have been reported with onset in adult years. 12 Three new diagnostic criteria have been added by the Histiocyte Society: (1) low or absent natural killer (NK) cell activity, (2) hyperferritinemia (ferritin X00 mg/l and () high plasma CD2 (IL-2 receptor) X2400 U/ml. Ifthere is a family history, diagnosis may be made on a molecular basis by detecting disease-related mutations in perforin or Munc Table 2 Systemic inflammatory syndromes in the peri-asct period Disorder Fever WBC Albumin Fibrinogen Ferritin Perforin Therapy Infection-associated hemophagocytic syndrome Familial lymphohistiocytosis Engraftment syndrome Yes Engraftment in progress Macrophage activation syndrome Yes Decreased NSD Decreased Increased Increased GCS Cyclosporine A Yes Decreased NSD Decreased Increased Decreased or normal, depending on the subtype Etoposide MTX BMT Same as infectionassociated hemophagocytic syndrome Normal or decreased NSD NSD NSD GCS Yes Decreased NSD Decreased Increased Normal or decreased GCS Cyclosporine A as alternative Abbreviations: BMT ¼ bone marrow transplantation; MTX ¼ methotrexate; NSD ¼ not sufficient data; GCS ¼ glucocorticosteroids.

4 4 1-4 genes. It appears that low numbers ofnk cells or NK cells that are not effective contribute to abnormal activation ofmacrophages in HLH. In MUNC 1-4 mutations, there is defective exocytosis of the cytotoxic granzymes. When there is either defective expression or release of perforin or defective delivery of granzymes, NK cells are not effective at eliminating target cells there is persistent antigenic stimulation. CD 8 þ T cells are also activated and secrete INF-g, which further activates macrophages. Cytokines are overproduced by activated macrophages including IL-1, IL-6 and TNF-a, contributing to the clinical findings in HLH. The details ofimmune dysregulation in HLH and the mechanisms ofmacrophage activation continue to be elucidated. Although decreased perforin levels are linked to at least six different mutations in the PRF-1 gene in a subset of HLH patients, not all patients with FHL have a defective perforin gene and genetic diagnostic criteria are not defined. 1 Infection-associated hemophagocytic syndrome, however, is clinically identical to FHL but is not familial. It occurs in association with infections and has been described following Epstein Barr virus, cytomegalovirus, parvovirus, herpes simplex, varicella-zoster and measles. Bacteria, fungi, rickettsia and parasites have also been implicated in IAHS. 14 Macrophage activation syndrome De Vere-Tyndall et al. 1 and Silverman et al. 16 initially described a consumptive coagulopathy in patients with sjra, which suggested a predilection for these patients to manifest signs and symptoms of cytokine-mediated dysfunction, and Scott et al. 17 emphasized that this phenomenon was observed in sjra but not polyarticular. These were the first descriptions ofthe condition subsequently called MAS by Prieur et al. Over the next decades, children with active systemic onset JRA and few adults with AOSD were reported, with non-remitting high fever, hepatosplenomegaly, lymphadenapathy, cytopenias and coagulopathy, evidence ofmacrophage activation and marrow hemophagocytosis. 1, Hemophagocytic lymphohistiocytosis- like episodes were also described in association with systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, mixed connective tissue disease and others. 18,19 These patients may be considered as having secondary or acquired HLH, commonly referred to as MAS in the rheumatologic literature. Macrophage activation syndrome shares many clinical/ laboratory features with HLH, and several authors classify MAS as secondary or acquired hemophagocytic syndrome. 20 Ravelli et al. have proposed diagnostic guidelines for MAS in patients with sjra, which attempt to distinguish a flare ofthe underlying disease from MAS. These guidelines share the criteria for HLH; however, they add as clinical criteria signs ofcentral nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures and coma) and signs ofcoagulopathy (purpura, bruising, mucosal bleeding). In addition, as ferritin levels may be elevated in a flare ofsjra, a threshold level of X has been suggested. 21,22 The first case ofmas/iahs following transplantation, reported by ten Cate et al., 2 was associated with persistent bacteremia and highly efficient T-cell depletion. Wulfratt et al. described two fatal cases of MAS/IAHS that occurred in sjia patients in the peri-transplant period. One appeared to be secondary to EBV activation 4 months after autologous transplantation, while the arthritis was dormant. The second occurred on day þ 18 while the patient s bone marrow was still completely aplastic. 24 De Kleer et al. reported an additional patient with disseminated toxoplasmosis and MAS/IAHS 10 days following autotransplantation. A % drug-free complete remission rate was reported in a recent meta-analysis ofautologous stem cell transplantation procedures performed for refractory juvenile idiopathic arthritis (n ¼ 4, mean follow-up months). At least one infection occurred in 71% of patients during the in-hospital transplant course, and the overall mortality rate was 1%. Two deaths occurred 1 16 months post transplantation. One patient died after a complete relapse ofsystemic JRA, requiring high-dose immunosuppressive therapy. The second patient died of hepatic failure of unclear etiology. Three fatal cases of IAHS were reported. 2 Although these patients seemed to have an infectious trigger for MAS, it was proposed that stringent T-cell depletion causes dysregulation of macrophage activation, with a subsequent inflammatory response. 2,24,26 It is noteworthy that aggressive T-cell depletion does not correlate with duration ofdisease remission, and potentially could be a risk factor for peritransplant complications, such as MAS. 2 Our patient received a significantly T-cell-depleted graft and also had two episodes ofmas during the decade before transplant. One might speculate that previous MAS is a risk factor for the future development of MAS. Hemophagocytosis, hyperferritinemia and NK cell abnormalities are components ofthe inflammatory process observed to variable degrees in patients with MAS. Emmenegger et al. defined reactive macrophage activation syndrome (rmas) as hemophagocytosis and ferritin ng/ml, with systemic inflammation. He retrospectively studied 20 patients who fit his criteria ofrmas and found that Still s disease was over-represented in this population (seven of20 patients). He reported 22 cases of rmas treated with IVIG in which ferritin levels closely reflected the course ofdisease. Seventeen ofthe 22 cases had a profound or partial benefit from IVIG. Ferritin levels in active Still s disease are many magnitudes higher than those seen in other inflammatory disorders. 27 Conversely, the glycosylated isoform of ferritin (ferritin attached to carbohydrate) appears to be constitutionally low in patients with Still s disease, compared to people with other inflammatory conditions. 28,29 Many authors have described hemophagocytosis in adult-onset Still s disease that is not related to FHL or IAHS, which suggests that a degree ofmacrophage activation occurs with active systemic JRA, and adultonset Still s disease that does not result in an acute life-threatening condition. 18,0,1 The hemophagocytosis reported in adult-onset Still s disease is identical to the MAS seen in patients with sjra patients, which makes sense because these conditions appear to be pathophysio-

5 logically identical. One could conclude that a variety of conditions can trigger active hemophagocytosis in patients with inflammatory conditions, such as sjra/ adult-onset Still s disease. Grom et al. compared the NK cell activity and perforin expression seen in patients with HLH and in seven sjra patients who developed MAS. Three ofthe seven JRA patients had a decrease in NK cell activity, a small decrease in NK cell numbers and a decrease in perforin expression in cytotoxic cells. This pattern was indistinguishable from carriers of the perforin-deficient form of HLH. 2 Four of the seven JRA patients had decreased NK activity and number, with mildly increased perforin levels. This pattern was also seen in IAHS. To further emphasize the role of perforin in sjra, Wulffratt et al. described four patients with sjra whose perforin expression normalized after an autologous stem cell transplant. These perforin and NK studies raise the question ofwhether HLH and MAS are identical. They are both characterized by extreme hyperferritinemia and by macrophage activation. 2, Some authors propose hemophagocytosis and the release of ferritin from erythrocytes as the primary cause. 0,4 The underlying cause for excessive macrophage activation is not known. Coffernils et al. 0 proposed that circulating immune complexes on bone marrow cells may stimulate macrophage activation and hemophagocytosis. Similarly, cytokine release from virus-infected T cells may activate macrophages in IAHS, resulting in hemophagocytosis and hyperferritinemia. Systemic inflammation and fever mediated by interleukin 1á may contribute. As an acutephase protein, ferritin plays a role in host defense as a scavenger for free radicals created by macrophages and neutrophils. 6 We suggest that our patient suffered from MAS, a type of secondary HLH. The differential diagnosis included a viral syndrome, bacterial or fungal infection with DIC, engraftment syndrome and serum sickness secondary to ATG and MAS. An infectious etiology was less likely as the Staphylococcus epidermidis was successfully treated, urine cultures were negative and no source of infection was found by chest CT or transthoracic echocardiogram. The fever and rash occurred 4 days after neutrophil recovery, which made engraftment syndrome less likely. Noncardiogenic pulmonary edema, one ofthe cardinal features ofengraftment syndrome, was absent. Furthermore, this patient does not meet the criteria for engraftment syndrome as described by Spitzer 8 or Maiolino. Viral, bacterial and fungal cultures were negative during the event (although the patient did have staph epi bacteremia 1 week before developing the fever) making IAHS less likely. Although EBV IgG anti-capsid and antinuclear Ab were present before transplantation, EBV PCR was negative during the systemic inflammatory illness. FHL is also unlikely, as the clinical features of this disease usually occur before the third decade of life, and no family history ofhemophagocytic episodes was reported. A flare of his underlying disease was also in the differential. However, leukocytosis and joint tenderness were not present, and this patient had leukopenia, decreasing ESR and no joint swelling. This made MAS more likely than a disease flare. We agree with Ramanan et al., that MAS should be considered a secondary hemophagocytic syndrome; however, the diagnosis ofthe specific subtype ofsecondary hemophagocytic syndrome is still extremely important because it will guide treatment. 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