Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders

AIMS—To review the precipitating events, clinical features, treatment, and outcome of macrophage activation syndrome (MAS).
METHODS—Retrospective review of cases of MAS from a prospectively collected database of children with rheumatic diseases from 1980to 2000.
RESULTS—Nine patients (eight girls) were considered to have evidence of MAS. The primary diagnosis was systemic onset juvenile idiopathic arthritis in seven, enthesitis related arthritis in one, and chronic infantile neurological cutaneous articular syndrome in one. Mean age of onset was 5.7 years, and duration prior to MAS, 4.2 years. No medication was identified as a trigger. Eight had infections prior to MAS; specific infectious agents were identified in four. High grade fever, new onset hepatosplenomegaly, and lymphadenopathy were common clinical features. Platelet counts fell dramatically, from an average of 346 to 99 × 10⁹/l. Mean erythrocyte sedimentation rate (in three patients) fell from 115 to 28 mm/h. Eight had abnormal liver function during the disease course, and six had coagulopathy. Bone marrow examination supported the diagnosis with definite haemophagocytosis in four of seven. All received high dose steroids (eight intravenous, one oral), five cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two of three patients with significant renal impairment died.
CONCLUSION—MAS is a rare and potentially fatal complication of childhood rheumatic disorders. Most of our patients were female, and most cases were preceded by infection. Bone marrow studies support the diagnosis. Deranged renal function may be a poor prognostic sign. Aggressive early therapy is essential.
     

幼年特发性关节炎全身型并发巨噬细胞活化综合征24例临床分析

目的总结巨噬细胞活化综合征的临床特征、可能的诊断指标、治疗方法及转归,提高对本病的认识。方法回顾性分析2003年3月至2006年2月,我院收治的24例幼年特发性关节炎全身型（SOJIA）合并巨噬细胞活化综合征（MAS）患者的临床资料,分析其临床表现、早期特征、诊断标准、可能的诱因、治疗和转归。结果24例患者,男21例,女3例,平均年龄7岁。临床表现全部患者均有高热、肝脾或（和）淋巴结进行性增大、血液系统受累,12例有中枢神经系统功能障碍,9例有易出血现象,6例有呼吸系统受累（ARDS）,6例有消化系统表现,5例心脏受累。实验室检查均有血细胞减低、血清肝酶增高、乳酸脱氢酶增高、红细胞沉降率降低、高铁蛋白血症、钠离子减低、白蛋白减低及凝血功能异常,骨髓中发现吞噬血细胞,20例患者有甘油三酯增高。治疗应用甲泼尼龙加环孢素A可以达到较好的疗效。结论MAS是SOJIA的一个致死性并发症,可以造成全身各脏器的功能衰竭。提高认识、早期诊断并积极治疗是减少死亡率的关键。治疗给予甲泼尼龙冲击及环孢素A治疗往往能得到较好的疗效。     

儿童风湿性疾病合并巨噬细胞活化综合征六例临床分析

目的巨噬细胞活化综合征（MAS）的诊断和治疗尚未得到统一,总结分析我院6例MAS患儿的临床资料,为临床救治工作提供参考。方法回顾性分析我院1998-2004年风湿性疾病合并MAS患儿的临床资料。结果共有6例（女4例,男2例）患儿符合MAS的诊断条件。发生MAS前,4例诊断幼年特发性关节炎全身型（SOJIA）,2例诊断系统性红斑狼疮和狼疮性肾炎。所有病例确诊MAS时疾病状态处于低活动期,主要的临床特征是：峰形热（5／6）或中高热（1／6）,肝脾肿大（6／6）,淋巴结病（6／6）,外周血3系减少（6／6）,明显的肝损伤（6／6）,弥漫性血管内凝血象（2／6）和中枢神经系统功能障碍（3／6）。低纤维蛋白原血症、肝酶升高和高甘油三酯血症均持续存在。3例骨髓涂片可见吞噬血细胞现象和浆细胞岛,其他3例未行此检查。3例患儿被证实存在感染,2例单纯疱疹病毒（HSV）和1例甲型肝炎病毒（HAV）。未发现药物相关因素。分别进行个体化治疗,重点在早期发现和联合抗病毒治疗,适度地联合免疫化疗（HLH-94或环孢素A）可以获得及时的缓解。1例SOJIA患儿严重肝损伤经连续性血液滤过／肾脏替代治疗联合免疫化疗获得迅速缓解。2例SOJIA患儿死于严重的内脏出血。结论MAS不仅见于SOJIA,还可以发生在儿科其他风湿性疾病的任何阶段,其发生率可能要高于以往的认识。感染可能是主要的触发因素。适时的免疫净化联合免疫化疗有益于严重肝损伤的恢复。     

巨噬细胞活化综合征的临床和实验室特征分析

目的分析巨噬细胞活化综合征(MAS)患儿诊断初期的临床和实验室特征,探索早期识别MAS的方法。方法回顾性分析21例MAS患儿的临床、实验室特征,以及治疗和转归。结果 MAS患儿的原发病包括全身型幼年特发性关节炎(SJIA)14例、川崎病(KD)5例和结缔组织病(CTD)2例。发生MAS的中位时间为19 d,以KD-MAS发生最快,CTD-MAS发生最晚(P=0.009)。前10位的临床症状依次为发热(95%),皮疹(86%),淋巴结肿大(67%),骨髓吞噬现象(63%),肺部病变(62%),浆膜腔积液(62%),肝肿大(52%),脑脊液异常(50%),中枢神经系统损害(43%)和脾肿大(38%)。实验室特征方面,血红蛋白降低;超敏C反应蛋白、血沉升高、血清铁蛋白明显升高;谷丙转氨酶、谷草转氨酶、乳酸脱氢酶和甘油三酯升高;纤维蛋白原降低,D-二聚体明显升高;IL-6、IL-10和IFN-γ明显升高。21例患儿中20例好转出院。结论风湿性疾病患儿如出现持续发热,肝功能损害,凝血功能异常,甚至多脏器损害,以及IL-10、IFN-γ明显升高和血清铁蛋白持续升高,要高度警惕MAS发生。     

Macrophage activation syndrome in juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept. CONCLUSION: Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A.     

Macrophage activation syndrome in juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept.
Conclusion: Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A.     

Macrophage activation syndrome in 13 children with systemic-onset juvenile idiopathic arthritis

Background  Macrophage activation syndrome (MAS) is a severe, potentially life-threatening condition induced by chronic rheumatic diseases, especially systemic-onset juvenile idiopathic arthritis (SoJIA) in childhood. This study aimed to analyze the clinical and laboratory characteristics of systemic-onset juvenile idiopathic arthritis (SoJIA) with macrophage activation syndrome (MAS) in 13 patients. Methods  Clinical and laboratory data of 13 SoJIA patients with MAS treated in our hospital from January 2003 to October 2007 were analyzed. Results  In the 13 patients, 9 were boys and 4 girls aged from 5 months to 12 years. Clinical manifestations were of no typical characteristics including persistent fever, anemia, arthritis, hepatosplenomegaly, lymph-adenopathy, dysfunction of the liver, abnormal fat metabolism, and hemophagocytic cells in the bone marrow. Two patients experienced acute respiratory distress syndrome, two had mutiorgan failure, and three died. The perforin A91V (NCBI:SNP rs35947132) gene in 6 patients was normal. Glucocorticoid and immunoimpressive therapy were effective in all patients and plasmapheresis used in one severe patient was also effective. Conclusions  MAS is a serious complication of JIA, especially systemic-onset juvenile idiopathic arthritis. It is essentially important to recognize and treat MAS earlier in order to lower the mortality.     

幼年特发性关节炎全身型并发巨噬细胞活化综合征13例临床分析

目的对13例幼年特发性关节炎全身型（SOJIA）合并巨噬细胞活化综合征（MAS）患儿临床资料进行回顾性分析,以期提高临床认识。方法回顾性分析13例SOJIA合并MAS患儿可能触发因素、临床表现、实验室检查结果以及治疗和预后。结果90例SOJIA患儿并发MAS13例（14．4％）,男10例,女3例。全部患儿处于SOJIA活动状态;3例可能为药物触发;8例MAS发生前存在感染。全部患儿均持续高热;肝大12例（92．3％）;凝血功能障碍10例（76．9％）;神经精神系统功能障碍8例（61．5％）。MAS发生时全部患儿白细胞（WBC）、血小板（PLT）和红细胞沉降率（ESR）较发生前显著下降;5例（62．5％）血清铁蛋白（SF）≥10000μg／L;8例（72．7％）血纤维蛋白原（Fib）≤2．5g／L;9例（69．2％）甘油三酯（TG）≥2．5mmol／L。结论MAS是SOJIA严重而致命的并发症,原发SOJIA活动性、药物以及感染是MAS的重要触发因素。肝脏显著增大、出血倾向和神经精神系统功能障碍是MAS最具鉴别意义的临床指标。血WBC、PIJT和ESR较基础值急剧下降、SF急剧升高、Fib减少以及TG升高是MAS重要的临床实验室指标。早期有力的干预治疗决定MAS的预后。     

Inflammatory bowel disease associated with immune thrombocytopenic purpura in children.

OBJECTIVE: Previous reports suggest an association between inflammatory bowel disease (IBD) and immune thrombocytopenic purpura (ITP) in adults. To date, only five children with both diseases have been described. The aim of the study was to describe the characteristics of children with IBD and ITP. METHODS: Cases were obtained from the pediatric gastroenterology community by means of the pediatric gastroenterology internet bulletin board in June 1999. Eight cases were submitted from seven medical centers. Medical records were reviewed by two pediatric gastroenterologists and a pediatric hematologist. RESULTS: The age range of the patients was 2.1 to 16.5 years, with a mean age of 9.6 +/- 5.2 years. Four children had ulcerative colitis, three had Crohn disease, and one had indeterminate colitis. All had colonic involvement of IBD. Of eight patients, three had IBD first, three had ITP first, and two had both simultaneously. At ITP diagnosis, platelet count was less than 10,000/mL in five children, 17,000/mL in one child, and 50,000 to 60,000/mL in two children. Of the three children diagnosed with ITP first, two initially had rectal bleeding at the time of ITP diagnosis. Bone marrow evaluations, performed in six of eight children, were consistent with ITP. Six of the eight children had chronic ITP, including three children who were 5 years of age or younger. Therapy for ITP included steroids (n = 6), intravenous immunoglobulin (n = 6), Rh o (D) intravenous immunoglobulin (n = 2), and splenectomy (n = 1). CONCLUSIONS: The authors describe the largest pediatric case series of children with IBD and ITP. More than 50% of the children had the chronic form of ITP. Most patients responded to conventional therapy for ITP and IBD.     

Resection of foregut-derived duplications by minimal-access surgery

Eight children underwent minimal-access surgery (MAS) for duplications of foregut derivatives. The efficacy and safety of this approach are reviewed. The seven patients with mediastinal lesions had video-assisted thoracoscopic resection. One lesion presented as a subdiaphragmatic esophageal diverticulum, which was excised laparoscopically. Between March 1991 and October 1997, eight children were treated. Mean age was 27 months and mean weight was 11.4 kg. Mean operating time was 106 min, and mean postoperative hospital stay was 4.5 days (median = 2 days). Persistent air leaks occurred in two patients who had centrally-located bronchogenic cysts. One of these, who had undergone subtotal excision with laser photoablation of the remaining cyst mucosa, developed a recurrence that was excised at thoracotomy. We conclude that esophageal and bronchogenic cysts and duplications may be safely excised by MAS in children, with excellent cosmetic and functional outcome. Two technical points are noted: (1) a thoracostomy tube is required for central mediastinal lesions; and (2) complete excision is required to prevent recurrence. Accepted: 21 December 1998     

A retrospective study of juvenile chronic arthritis

During a 20 year period 214 patients had been admitted to a teaching hospital with a diagnosis of definite or possible juvenile chronic (rheumatoid) arthritis (JCA). Eighty-seven of these patients were reviewed clinically and were classified as having had JCA. Twelve of the 214 patients were later thought to have had rheumatic fever, while 12 had had an illness consistent with viral arthritis.
There was a poor functional outcome in three subgroups of JCA: (i) seropositive polyarticular onset, (ii) systemic onset, and (iii) pauciarticular onset, extending to polyarticular involvement.
The prevalence of inflammatory eye disease was very low with no significant visual handicap detected in patients in this study.     

A retrospective study of juvenile chronic arthritis

During a 20 year period 214 patients had been admitted to a teaching hospital with a diagnosis of definite or possible juvenile chronic (rheumatoid) arthritis (JCA). Eighty-seven of these patients were reviewed clinically and were classified as having had JCA. Twelve of the 214 patients were later thought to have had rheumatic fever, while 12 had had an illness consistent with viral arthritis. There was a poor functional outcome in three subgroups of JCA: (i) seropositive polyarticular onset (ii) systemic onset, and (iii) pauciarticular onset, extending to polyarticular involvement. The prevalence of inflammatory eye disease was very low with no significant visual handicap detected in patients in this study.     

Bone marrow findings in juvenile idiopathic arthritis

The diagnosis of juvenile idiopathic arthritis (JIA) is an exclusion one due to heterogeneous clinical presentation and lack of specific laboratory tests. The authors investigated bone marrow of 25 untreated children with JIA at the onset of the disease. Bone marrow smears were evaluated for cell populations as well as myelodysplastic features and compared to two control groups. The characteristic of bone marrow in JIA was myeloid hyperplasia and elevated plasmocyte count. There was no difference between JIA patients and control groups in terms of myelodysplastic features. These findings can be helpful in explaining hematological alterations in JIA.     

BONE MARROW FINDINGS IN JUVENILE IDIOPATHIC ARTHRITIS

The diagnosis of juvenile idiopathic arthritis (JIA) is an exclusion one due to heterogeneous clinical presentation and lack of specific laboratory tests. The authors investigated bone marrow of 25 untreated children with JIA at the onset of the disease. Bone marrow smears were evaluated for cell populations as well as myelodysplastic features and compared to two control groups. The characteristic of bone marrow in JIA was myeloid hyperplasia and elevated plasmocyte count. There was no difference between JIA patients and control groups in terms of myelodysplastic features. These findings can be helpful in explaining hematological alterations in JIA.     

Etanercept for therapy-resistant macrophage activation syndrome

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of childhood rheumatic diseases, especially systemic onset juvenile idiopathic arthritis (SoJIA). We report a 4-year-old girl with probable SoJIA who presented with MAS. She did not respond to pulse methyl prednisolone and Cyclosporine A (CsA). She also failed to respond to intravenous immunoglobulin (IVIG) therapy. Etanercept was started, based on the observation of increased serum levels of tumor necrosis factor-alpha (TNF-alpha) in patients with MAS. Her condition improved following etanercept, suggesting that etanercept might have a therapeutic role in resistant MAS.     

Macrophage activation syndrome as initial presentation of systemic lupus erythematosus

Macrophage activation syndrome (MAS) is known to be a severe and potentially life-threatening complication of rheumatic disorder, especially systemic juvenille rheumatoid arthritis. It is very rare for MAS to be an initial presentation of systemic lupus erythematosus (SLE). Here, we report a 14-year-old girl in whom MAS developed as an initial presentation of SLE. With early diagnosis and administration of cyclosporine A, she had a fair outcome. Further testing showed positive anti-dsDNA about 8 months later.     

Transient neutropenia of childhood

Patient characteristics and clinical course are described in 21 children with newly discovered neutropenia (absolute neutrophil count less than 1500/microliter). Only children over age 3 months are included; 19 of 21 were less than age 2 years. The majority had respiratory tract infections and 11 had been on various medications at the time neutropenia was discovered. Bacteria were isolated from the blood of three patients (S. pneumoniae in two, H. influenzae in one) and from urine in one (E. coli). Respiratory syncytial virus was cultured from the nasopharynx of two patients. Opportunistic, gram-negative and staphylococcal infections did not occur. Neutrophil counts in all but one child returned to normal within 6 weeks of onset; half recovered within 7 days. Bone marrow examination was performed in 13 patients: maturation arrest at various stages in the myeloid series was noted in six, and seven had normal myeloid maturation. Bone marrow findings did not correlate with degree or duration of neutropenia. These observations indicate that previously well infants with isolated neutropenia generally have a benign clinical course, although three patients were ultimately proven to have significant chronic illness. Recommendations are made as to management.     

Scintigraphic differentiation of bone infarction from osteomyelitis in children with sickle cell disease

Bone scans or bone marrow scans or both were obtained during 42 episodes of bone pain in 40 children with sickle cell disease, and the usefulness of these procedures was compared. On the basis of the subsequent clinical course, a diagnosis of bone infarction was made in 34 episodes, and osteomyelitis in eight. Among 22 patients with bone infarction, uptake on bone scan was increased in 14, decreased in three, and normal in five. Seven of eight patients with osteomyelitis had increased uptake on bone scan; one had normal uptake. In contrast, marrow scan uptake was markedly decreased in 15 of 16 patients with bone infarction, and was normal in five of five patients with osteomyelitis. Thus, decreased uptake on bone marrow scan in a patient with sickle cell disease and bone pain almost invariably indicates infarction, whereas normal uptake strongly suggests the diagnosis of osteomyelitis. We found marrow scans more useful than bone scans for this differential diagnosis.     

幼年特发性关节炎全身型合并巨噬细胞活化综合征4例报告并文献复习

目的 总结巨噬细胞活化综合征(macrophage activation syndrome,MAS)的临床特征及误诊原因,以提高对该病的认识.方法 回顾性分析54例幼年特发性关节炎全身型(systemic onset juvenile idiopathic arthritis,SO-JIA)合并MAS患儿的临床症状、体征、辅助检查及病情进展、诊断、治疗及预后.结果 54例SOJIA患儿中4例并发MAS(7.4%).临床特征有:持续高热、肝脾淋巴结增大、肝功能急剧恶化、皮肤黏膜易出血、外周血三系减少、中枢神经系统功能障碍、血沉进行性下降.结论 MAS是SOJIA的一个致死性并发症,起病突然,进展迅速,病死率高.在临床工作中需提高对其的认识,避免误诊.     

Haemophagocytic lymphohistiocytosis: a case series from Mumbai

A retrospective review of ten patients (8 girls, 2 boys) admitted over a 9-month period with haemophagocytic lymphohistiocytosis (HLH) is presented. Presenting features included fever and hepatosplenomegaly (10), bleeding manifestations (7), lymphadenopathy (4), skin rash (4), shock (4), jaundice (3), CNS disorder (3), renal failure (2) and arthritis (2). Three infants had familial HLH (FHL) while the other seven patients had acquired (secondary) HLH. Two patients with FHL had very low perforin levels (0 and 0.05%). There was secondary HLH owing to systemic onset juvenile idiopathic arthritis in two patients, and one each had anaplastic large cell lymphoma, measles with pneumonia, disseminated tuberculosis, dengue hemorrhagic fever and lymphoproliferative disorder. Cytopenia affecting two or three lineages in peripheral blood was present in all while haemophagocytosis in bone marrow was documented in nine patients .Other important laboratory parameters were raised ferritin (9), raised LDH (9), hypertriglyceridaemia (7) and hypofibrinogenaemia (5). The patients were treated according to the HLH2004 protocol. Diagnosis of HLH should be considered early in patients presenting with unremitting fever, hepatosplenomegaly and cytopenias as without appropriate treatment HLH is usually fatal.