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 DIC and is closely related or identical to infection-associated hemophagocytic syndrome. The diagnosis needs to be established in a timely fashion because early and appropriate treatment may improve outcome.
A variety of systemic 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, 2, 3, 4, 5 Treatment of these 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 of HCT.
The patient is a 29-year-old Caucasian male with JRA diagnosed at 16 years of age, 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 of autotransplant, 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 CD34+ cell selection resulted in a product with 3.8 × 106 CD34+ cells/kg and 0.7 × 104 CD3 cells/kg. Exacerbation of JRA was not observed during receipt of G-CSF. Following conditioning (using cyclophosphamide, ATG and 800 cGy of total body irradiation) and re-infusion of the cryopreserved CD34+ cells, his course was complicated by fever and coagulase negative staphylococcal bacteremia on day +5, treated with ceftazidime and vancomycin. Peripheral granulocyte recovery (>500/mm3) occurred on day +10 after transplant. He developed a cough; computerized chest tomography on day +10 revealed no infiltrates, and transthoracic echocardiogram did not reveal any vegetations. Meropenum was added. The patient spiked a fever of 39.0°C on day +12, and blood and urine cultures were negative. The patient developed a rash and vancomycin was switched to clindamycin on day +13. He then experienced daily fevers as high as 40.0°C on days +12 to +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+ edema, and musculoskeletal examination revealed no evidence of active synovitis. Within a few days, pancytopenia developed, white blood count of 1600/mm3, hemoglobin 7.9 g/dl and platelet count 10 000/mm3.
He was treated with broad-spectrum antibacterials, acyclovir, IVIG and prophylactic inhalational pentamadine. Intensive monitoring of liver 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 45 on day +15. Prothrombin time was 12.6 s, INR, 1.09; D-dimer was elevated and fibrinogen was decreased. Serum ferritin was 104 900 ng/ml (Table 1). Methylprednisolone, 0.5 mg/kg every 6 h (2 mg/kg/day), was given on day +15 to day +19. Cyclosporine A was begun on day +17 and on days +20 to 22, he received pulse glucocorticosteroids (GCS), 1000 mg q.d. Glucocorticosteroids were reduced to 1 mg/kg/day by day +30. Fever began to resolve, ferritin peaked at 162 400 ng/ml on day +17 and fibrinogen nadired at 79 mg/dl on day +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 of immunosuppressive medications continued uneventfully. He is currently 32 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.
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-α (TNF-α), and IL-1 are the primary cytokines involved in the widespread activation of the coagulation cascade and microvascular fibrin deposition.6 The resultant consumption of coagulation factors causes bleeding. Capillary leak syndrome is another cytokine-mediated entity that has been described in a wide variety of diseases and is most commonly seen in critically ill patients.
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, non-cardiogenic pulmonary edema and kidney and liver abnormalities. High levels of TNF and IL-1 are implicated as mediators. Spitzer et al. developed major and minor criteria based on clinical impressions of multiple anecdotes. Major criteria include temperature >38.3°C with no identifiable infectious etiology, erythroderma involving more than 25% of body surface area and non-cardiogenic pulmonary edema. Minor criteria include a total bilirubin ⩾2 mg/dl or transaminases ⩾two times normal, serum creatinine ⩾two times baseline, weight gain of ⩾2.5% 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 of patients 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 non-myeloabltive 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 of HLH, as defined by Henter et al., includes five major criteria: fever >38.5°C for 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 of marrow hemophagocytosis are actually present in a minority of children at the time of death.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 ⩾500 μg/l and (3) high plasma CD25 (IL-2 receptor) ⩾2400 U/ml. If there is a family history, diagnosis may be made on a molecular basis by detecting disease-related mutations in perforin or Munc 13-4 genes. It appears that low numbers of NK cells or NK cells that are not effective contribute to abnormal activation of macrophages in HLH. In MUNC 13-4 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+ T cells are also activated and secrete INF-γ, which further activates macrophages. Cytokines are overproduced by activated macrophages including IL-1, IL-6 and TNF-α, contributing to the clinical findings in HLH. The details of immune dysregulation in HLH and the mechanisms of macrophage 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.13 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.15 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 of the condition subsequently called MAS by Prieur et al.3 Over the next 3 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 of macrophage activation and marrow hemophagocytosis.1, 3 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 of the underlying disease from MAS. These guidelines share the criteria for HLH; however, they add as clinical criteria signs of central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures and coma) and signs of coagulopathy (purpura, bruising, mucosal bleeding). In addition, as ferritin levels may be elevated in a flare of sJRA, a threshold level of ⩾104 000 has been suggested.21, 22
The first case of MAS/IAHS following transplantation, reported by ten Cate et al.,23 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 +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 53% drug-free complete remission rate was reported in a recent meta-analysis of autologous stem cell transplantation procedures performed for refractory juvenile idiopathic arthritis (n=34, mean follow-up 12–60 months). At least one infection occurred in 71% of patients during the in-hospital transplant course, and the overall mortality rate was 15%. Two deaths occurred 13–16 months post transplantation. One patient died after a complete relapse of systemic JRA, requiring high-dose immunosuppressive therapy. The second patient died of hepatic failure of unclear etiology. Three fatal cases of IAHS were reported.25 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.23, 24, 26 It is noteworthy that aggressive T-cell depletion does not correlate with duration of disease remission, and potentially could be a risk factor for peri-transplant complications, such as MAS.25 Our patient received a significantly T-cell-depleted graft and also had two episodes of MAS 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 of the inflammatory process observed to variable degrees in patients with MAS. Emmenegger et al. defined ‘reactive macrophage activation syndrome’ (rMAS) as hemophagocytosis and ferritin >10 000 ng/ml, with systemic inflammation. He retrospectively studied 20 patients who fit his criteria of rMAS and found that Still's disease was over-represented in this population (seven of 20 patients). He reported 22 cases of rMAS treated with IVIG in which ferritin levels closely reflected the course of disease. Seventeen of the 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 of macrophage activation occurs with active systemic JRA, and adult-onset Still's disease that does not result in an acute life-threatening condition.18, 30, 31 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 pathophysiologically 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 of the 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.32 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.33 described four patients with sJRA whose perforin expression normalized after an autologous stem cell transplant. These perforin and NK studies raise the question of whether HLH and MAS are identical. They are both characterized by extreme hyperferritinemia and by macrophage activation.32, 33 Some authors propose hemophagocytosis and the release of ferritin from erythrocytes as the primary cause.30, 34 The underlying cause for excessive macrophage activation is not known. Coffernils et al.30 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.35 As an acute-phase protein, ferritin plays a role in host defense as a scavenger for free radicals created by macrophages and neutrophils.36
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 3–4 days after neutrophil recovery, which made engraftment syndrome less likely. Non-cardiogenic pulmonary edema, one of the cardinal features of engraftment syndrome, was absent. Furthermore, this patient does not meet the criteria for engraftment syndrome as described by Spitzer8 or Maiolino5.
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 anti-nuclear 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 of hemophagocytic 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 of the specific subtype of secondary hemophagocytic syndrome is still extremely important because it will guide treatment. The diagnosis of MAS and differentiation from sepsis and engraftment syndrome is critical in order to allow specific therapeutic interventions to begin as soon as possible in this potentially fatal group of diseases.
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