Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital

Abstract

Background. Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by fever, hepatosplenomegaly, cytopenia, and progressive multiple-organ failure. HLH in adults is often secondary to autoimmune diseases, cancer, or infections in contrast to familial HLH. Treatment of secondary HLH is directed against the triggering disease in addition to immunosuppressive therapy, the latter commonly according to the HLH-2004 protocol.

Methods. We conducted a retrospective study to identify triggering diseases, disease-specific and immunosuppressive therapy administered, and prognosis in adult patients with secondary HLH. Patient data were collected from October 2010 to January 2015.

Results. Ten adult patients with secondary HLH were identified. Seven were men, and the median age at diagnosis was 62 years. Five cases were triggered by malignant disease and five by infection. The median patient fulfilled five of the eight HLH-2004 diagnostic criteria. All patients fulfilled the criteria fever, cytopenia, and ferritin >500 µg/L. Median time from hospital admission to HLH diagnosis was 20 days. Four patients received immunosuppressive therapy according to the HLH-2004 protocol. The prognosis was dismal, especially for the patients with malignancy-associated HLH, of whom all died.

Conclusion.HLH should be suspected in patients who present with fever, cytopenia, and ferritin >500 µg/L. Secondary HLH has a dismal prognosis. None of the patients with HLH triggered by malignancy survived. Achieving remission of the triggering disease seems to be important for a favourable outcome as, in all surviving patients, the haemophagocytic syndrome resolved after remission of the underlying infection.     

A study of haematological and bone marrow changes in symptomatic patients with human immune deficiency virus infection with special mention of functional iron deficiency,anaemia of critically ill and haemophagocytic lymphohistiocytosis

Background

Haematological abnormalities are among the most common complications of HIV. These involve all lineages of blood cells. Bone marrow studies form integral part of complete workup of the HIV positive patients specially when they present as case of pyrexia of unknown origin (PUO), refractory anaemia and pancytopenia.

Method

55 HIV infected symptomatic patient requiring bone marrow examination were included in the study. Relevant clinical history, baseline haematological investigations including full blood count, CD4 cell counts using flow cytometry were recorded.

Results

Median ANC values in males were found to be significantly lower than females (p = 0.046). CD4 cell count statistically significantly correlated with age, TLC, ANC & platelet count. Anaemia was present in 45 patients and out of which 66.66% patients had normocytic normochromic anaemia. Iron deficiency anaemia was present in (37.77%) patients and anaemia of chronic disease in (62.22%) patients. 2 patients had anaemia of the critically ill.Two patients had non-Hodgkin's lymphoma (NHL) and showed lymphoma deposit in the bone marrow. Gelatinous degeneration was seen in 3 patients. Ill formed epithelioid cell granulomas were seen in 7 cases, and 2 cases were positive for acid fast bacilli (AFB). Haemophagocytosis was seen in 8 cases; two cases later diagnosed as a case of infection induced HLH. Leishmania donovani (LD) bodies seen in 2 cases.

Conclusions

Bone marrow study is an important investigation in HIV infected symptomatic patients with peripheral haematological abnormalities.     

Mutations in the perform gene in children with hemophagocytic lymphohistiocytosis

Background Recent studies have reported germline mutations in the perforin gene (PRF1) in some types of hemophagocytic lymphohistiocytosis (HLH). However, the prevalence of PRF1 mutations in HLH in Chinese pediatric patients has not been extensively studied. The aim of this study was to investigate the prevalence of mutations and sequence variations in the PRF1 gene in Chinese pediatric patients with HLH.Methods Polymerase chain reaction (PCR) was performed with five pairs of primers for the coding exons and the flanking intron sequences of PRF1. Sequencing of PCR products was subsequently applied in 30 pediatric patients with HLH and in 50 controls.Results Three heterozygous mutations in a coding region were found, which resulted in amino acid changes (C102F, S108N and T450M) in three patients. These mutations were not detected in control subjects. One patient had compound heterozygous mutations (S108N and T450M) in PRF1 as the background defect, and documented familial HLH type 2 (FHL2). One synonymous sequence variant (Q540Q) was observed in one patient but not in the controls. Two SNPs (A274A, H300H) in the coding region were detected in HLH patients and controls, but without differences in the heterozygosity rate between the two groups (P＞0.05 for all comparisons).Conclusions We have identified three patients with three heterozygous missense mutations in PRF1; two of those three mutations (C102F and S108N) have so far been found only from Chinese patients. These findings are useful in evaluating the prevalence of PRF1 mutations in Chinese pediatric patients with HLH, and to correlate their genotype with phenotype. Some patients without familial history probably have primary HLH, which should be suspected even beyond the usual age range.     

Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis

Background Recent studies have reported germline mutations in the perforin gene （PRF1） in some types of hemophagocytic lymphohistiocytosis （HLH）. However, the prevalence of PRF1 mutations in HLH in Chinese pediatric patients has not been extensively studied. The aim of this study was to investigate the prevalence of mutations and sequence variations in the PRF1 gene in Chinese pediatric patients with HLH. Methods Polymerase chain reaction （PCR） was performed with five pairs of primers for the coding exons and the flanking intron sequences of PRF1. Sequencing of PCR products was subsequently applied in 30 pediatric patients with HLH and in 50 controls. Results Three heterozygous mutations in a coding region were found, which resulted in amino acid changes （C102F, S108N and T450M） in three patients. These mutations were not detected in control subjects. One patient had compound heterozygous mutations （S108N and T450M） in PRF1 as the background defect, and documented familial HLH type 2 （FHL2）. One synonymous sequence variant （Q540Q） was observed in one patient but not in the controls. Two SNPs （A274A, H300H） in the coding region were detected in HLH patients and controls, but without differences in the heterozygosity rate between the two groups （P 〉0.05 for all comparisons）. Conclusions We have identified three patients with three heterozygous missense mutations in PRF1; two of those three mutations （C102F and S108N） have so far been found only from Chinese patients. These findings are useful in evaluating the prevalence of PRF1 mutations in Chinese pediatric patients with HLH, and to correlate their genotype with phenotype. Some patients without familial history probably have primary HLH, which should be suspected even beyond the usual age range.     

噬血细胞性淋巴组织细胞增多症治疗的临床研究新进展

噬血细胞性淋巴组织细胞增多症(HLH)是一种由遗传性或获得性免疫功能异常导致的、以病理性炎症反应为主要特征的高病死率疾病。由国际组织细胞协会制定的HLH-94治疗方案将这一致命性疾病的临床缓解率由过去的不足10%提高到50%~70%,成为目前推荐的一线治疗方案。但是,HLH依然是一种难治性疾病,关于HLH治疗的临床试验在近10年蓬勃开展。这些新的治疗手段包括改进的化学免疫治疗方案,以及新的细胞因子生物靶向治疗等。综述了目前全球范围内关于HLH治疗新方法的临床研究进展,为噬血细胞综合征治疗提供新观点和新思路。     

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: a retrospective study of 78 pediatric cases in mainland of China

Background The clinical characteristics of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis （EBV-HLH） are largely unreported in the pediatric patients in mainland of China. The main aim of this study was to recognize the clinical features of EBV-HLH in children and to explore its prognosis and risk factors. Methods A retrospective study was performed on 78 pediatric patients with EBV-HLH who were admitted to Beijing Children＇s Hospital between 2003 and 2008. All patients＇ medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory and outcome information was collected. Statistical analysis was conducted via multivariate and univariate analysis. Results The age of onset peaked between 1-2 years and boys were more likely developed EBV-HLH. EBV-HLH occurred mainly in the serological pattern with EBV nuclear antigen （EBNA） positive （70.5%）. The overall fatality of the disease was 56.7%. Twelve of the 39 fatalities （30.8%） died rapidly within 2 months after diagnosis. Multivariate analysis revealed that not receiving chemotherapy （P=0.002）, 〉4 weeks of illness prior to diagnosis （P=0.004）, and albumin levels 〈20 g/L （P=-0.045） significantly predicted an increased fatality risk. Conclusions EBV-HLH is a severe disease with a high fatality rate that occurs mainly in the serological pattern with EBNA positive. Early initiation of chemotherapy and timely diagnosis significantly improves survival rate. Practical strategies should focus on reducing the likelihood of early death.     

血源播散性肺结核继发噬血细胞综合征1例

<正>1病例资料患者男性,28岁,主因“发热2个月,鼻衄及双下肢出血性皮疹10天”入院。2个月前,患者无明显诱因出现发热,体温39℃,弛张热型,伴乏力,不伴咳嗽、咳痰、腹痛、腹泻、尿急、尿频、尿痛等不适。自行口服退热药(具体不详)后可短暂退热,但效果不佳,遂于当地医院就诊,予“头孢菌素”及“地塞米松”静脉输液(具体剂量不详) 6 d,体温恢复正常,但停药后再次出现发热,体温波动于38.5～40℃,未再诊治。1个月余前就诊于外院,查血常规未见异常,胸片示“双肺纹理增多”,予莫西沙星口服2 d(具体剂量不详),患者体温波动于38.5～40℃。     

Fulminant hemophagocytic lymphohistiocytosis secondary to a reactivated EBV infection: A case report

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive inflammatory syndrome that results from inappropriate activation of the immune system. HLH has a high mortality if not treated. We describe a case of a fulminant HLH, associated with a reactivation of an EBV infection. The patient responded well to steroid treatment.     

二级综合医院检验科质量管理的体会

保证检验质量是检验科工作的重中之重，是临床实验室科学管理的重要组成部分，也是医院医疗安全和可持续发展的重要要求，更是为患者提供优质、高效服务之必须，笔者就如何强化检验质量管理，提高检验质量，谈几点体会。     

Hemophagocytic lymphohistiocytosis in a child with chronic granulomatous disease: A rare complication of a rare disorder

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder (PID) of phagocytic cells resulting in failure to eradicate catalase positive microorganisms like Staphylococci and fungal infections; due to deficiency or malfunction of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits in phagocytic leucocytes. We illustrate here one such case; a six year old girl who was admitted in our hospital with history of prolonged fever, non resolving bilateral otitis media and recurrent pneumonia. She was evaluated for an underlying PID and was found to have CGD based on Nitro blue Tetrazolium (NBT) Slide Test and flow cytometric Dihydrorhodamine (DHR) assay. The child was symptomatic despite initial treatment with first-line followed by second-line antibiotics. During the course of current systemic infection, she also developed infection-associated secondary Hemophagocytic Lympho Histiocytosis (HLH) as suggested by her clinical and laboratory parameters. Despite a thorough search, no microorganism could be isolated and so she was treated with empircal antibiotic therapy comprising of meropenem, linezolid and an antifungal. Fever resolved with gradual improvement of laboratory parameters and finally spontaneous resolution of HLH. We conclude that a high index of suspicion for PID is required in a child with recurrent infections. Identification of underlying infectious agent should be attempted to start targeted antimicrobial therapy; both to prevent as well as cure infection associated secondary HLH.     

山西医科大学第二医院对口支援社区卫生服务工作的实践与思考

目的 回顾社区卫生服务工作现状,调查社区卫生服务工作需求,分析社区卫生服务工作实践和效果,提出社区卫生服务工作中存在的问题及解决办法.方法 采用问卷调查、文献研究方法 调查社区卫生服务机构对公立医院支援项目的 需求,并结合山西医科大学第二医院及其下属的社区卫生服务机构的实际情况进行分析.结果 社区卫生服务机构最需要公立医院支援的项目是:技术指导、人才培养、双向转诊、健康教育、慢性病管理指导和信息化建设.2005年以来迎泽区社区卫生服务机构门诊量、社区居民满意度、社区技术人员培训率呈逐年上升趋势,通过社区转诊渠道实现转诊患者的数量也在逐年上升.结论 公立医院支援社区卫生服务是现阶段提高社区卫生服务机构医疗水平、综合服务能力及缓解社区居民看病难、看病贵的重要举措.     

Myelodysplastic syndrome: a review from University Hospital, Kuala Lumpur

Twenty patients with Myelodysplastic Syndrome (MDS) were diagnosed in University Hospital, Kuala Lumpur over a 5 year period. They were subclassified using the French American British (FAB) criteria. 90% of the patients were above 40 years old and the sex ratio was about equal. The predominant presenting symptom was anaemia and there was paucity of physical signs at presentation. Patients with 'aggressive' subtypes of MDS i.e. refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB(-)+) and chronic myelomonocytic leukaemia (CMML) had more frequent thrombocytopenia and neutropenia and their marrow pictures frequently had dysmegakaryopoiesis and dysgranulopoiesis as compared to more the "benign" subtypes i.e. refractory anaemia (RA) and refractory leukaemic anaemia with ringed sideroblasts (RARS). Four patients had leukaemic transformation and all of them came from the 'aggressive' subtypes. The current views on treatment of MDS are discussed.     

浅谈我院危机公关管理中的启示

随着医患纠纷及突发事件时有发生,一定程度上对医院的应对能力造成了冲击,应对得当不但能度过危机,还能提升医院的知名度;应对不当就会给医院带来负面影响。危机无处不在,危害难以预测,小事件可以演化为大风险的导火索,而成熟、高效的危机公关管理,不仅能使医院度过危机难关,也可赢得患者和公众的理解和支持。     

A Norm Utilisation for Scarce Hospital Resources: Evidence from Operating Rooms in a Dutch University Hospital

Background  

Utilisation of operating rooms is high on the agenda of hospital managers and researchers. Many efforts in the area of maximising the utilisation have been focussed on finding the holy grail of 100% utilisation. The utilisation that can be realised, however, depends on the patient mix and the willingness to accept the risk of working in overtime.     

Retinoblastoma--a 20 year review from the University Hospital Kuala Lumpur.

Retinoblastoma was clinically diagnosed in 38 patients in the University Hospital between 1968 to 1988. White pupil or cat's eye reflex, found in 25 patients, was the most common symptom. Four patients refused any form of treatment. Of the 27 histopathologically confirmed cases, 16 were males and 11 were females. There was no ethnic group predominance, although a male preponderance was observed among Malay patients (M:F 3:1, p less than 0.05). Treatment in cases with unilateral disease, without extra ocular extension consisted of enucleation of the involved eye, with close examination of the contralateral eye in follow-up. In cases presenting with bilateral tumour the worse eye was removed. Of 20 cases of histopathologically proven unilateral retinoblastoma treated surgically, 12 patients survived for a mean period of 4.5 years (Range: 1-19 years). The defaulter rate for this group of patients was 55%. None of the 7 cases of bilateral retinoblastoma survived beyond 5 years (Mean survival 2.5 years).     

基层医院新生儿导尿方法的应用与体会

目的探讨在基层医院利用不同材料行新生儿导尿时的优点与缺点。方法 2008年3月—2011年5月我院儿科需导尿的新生儿60例,随机分为改良头皮针软管组(A组),小号吸痰管组(B组),6 F一次性硅胶胃管组(C组)和6号导尿管对照组(D组),每组15例。观察各组一次导尿成功率、漏尿发生率和扭曲脱落率。结果 A、B、C、D组一次导尿成功率、漏尿发生率和扭曲脱落率比较,差异均无统计学意义(P>0.05)。结论当遇到无合适导尿管时,基层医院可以利用改良头皮针软管、小号吸痰管或6 F一次性硅胶胃管行新生儿导尿术。     

Mortality in acute upper gastrointestinal haemorrhage: a six-year survey from the University Hospital of Wales

In a retrospective survey of normal hospital practice, 583 patients were admitted between March 1972 and 1978 because of haematemesis or melaena. Sixty (10·3%) of these patients died; most deaths occurred in elderly patients (mean age 75 years) 75% of whom had a serious medical problem which complicated the situation. Malignancy, cardiovascular disease and respiratory problems were the most commonly associated factors. The attitude towards both emergency investigation and surgical intervention was very conservative and any reduction in mortality would require a concerted effort to deal with the special problems in elderly patients who are at particular risk.