Successful treatment of adult-onset still disease caused by pulmonary infection-associated hemophagocytic lymphohistiocytosis: A case report

BACKGROUND Adult-onset still disease(AOSD) and hemophagocytic syndrome(HPS) are two inflammatory diseases with very similar clinical manifestations. HPS is one of the most serious complications of AOSD and its risk of death is very high. It is difficult to identify HPS early in patients with AOSD, but early identification and proper treatment directly affects the prognosis.CASE SUMMARY A 39-year-old male showed a high spiking fever and myalgia. Laboratory data revealed elevated white blood cell, serum ferritin, and neutrophil percentage.However, his fever failed to relieve after a clear diagnosis of AOSD caused by pulmonary infection and treatment by antibiotics and corticosteroids;further laboratory data showed elevated serum ferritin, C-reactive protein, erythrocyte sedimentation rate and triglyceride, as well as liver abnormalities. Bone marrow smear showed hemophagocytosis. Secondary HPS was definitely diagnosed. The high fever disappeared and the laboratory findings returned to normal values after treatment by high-dose intravenous methylprednisolone and methotrexate.CONCLUSION For AOSD patients with high suspicion of HPS, active examination needs to be considered for early diagnosis, and timely using of adequate amount of corticosteroids is the key to reducing risk of HPS death.     

成人斯蒂尔病诊断与治疗

成人斯蒂尔病（AOSD）是一种自身免疫性风湿病，临床上以发热、关节痛、皮疹、白细胞增高为主要特征，实验室检查主要显示非特异性的炎症反应。非甾体抗炎药联合激素治疗AOSD取得了较好的疗效。本文就AOSD的诊断和治疗进行阐述。     

A case report of successful treatment with plasma exchange for adult‐onset Still's disease with autoimmune hepatitis

Adult onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology and pathogenesis. The disease is characterized by typical spiking fever with evanescent rash, sore throat, polyarthralgias or polyarthritis, and involvement of various organs. Most of the reported cases with liver involvement occurred during the period of treatment with hepatotoxic drugs, whereas AOSD associated autoimmune hepatitis (AIH) is extremely rare. AIH may be an indicator of the poor prognosis of AOSD. Herein we describe a case of successful treatment with plasma exchange for AOSD‐associated AIH. J. Clin. Apheresis 2010. © 2010 Wiley‐Liss, Inc.     

Atypical adult-onset Still’s disease with an initial and sole manifestation of liver injury: A case report and review of literature

BACKGROUNDAdult-onset Still''s disease (AOSD) typically presents with a high spiking fever, polyarthritis, transient maculopapular rash, neutrophilic leukocytosis, and hepatosplenomegaly. It has a wide spectrum of clinical symptoms ranging from mild to severe, with extensive involvement of almost every organ. Although liver involvement in the form of increased hepatic enzymes and bilirubin is common, no AOSD case with liver involvement as the initial manifestation of AOSD has been reported. CASE SUMMARYA 35-year-old woman presented to the hepatology department with progressively worsening jaundice for one week. Liver chemistry tests revealed a significantly increased liver enzymes and bilirubin level. Given that the clinical examination was unremarkable, liver biopsy was considered because the patient had a history of AOSD 6 years ago. Liver histopathology revealed that most hepatic lobules were still recognizable. Fusional necrosis was observed around most central veins. A few bridging necrotic zones were also found. Infiltration of multiple plasma cells were observed in the necrotic zone, and the reticular scaffold was still expanded. Additionally, no obvious fibrosis was observed in the portal area. Mild mixed inflammatory cell infiltration was noted in the interstitium of the portal area. Further examination was unremarkable except for a remarkably high level of ferritin. Collectively, a presumptive diagnosis of liver injury secondary to AOSD was made. The hepatic involvement responded well to glucocorticoid treatment.CONCLUSIONThis case highlights that hepatic involvement as an initial and sole manifestation could be a pattern of relapsed AOSD. The diagnosis of AOSD should be considered in the case of nonresolving liver injury after the exclusion of common etiologies for liver diseases. A liver biopsy can be useful for the differential diagnosis of liver injury associated with AOSD.     

Adult-onset Still's disease

Background: Adult‐onset Still's disease (AOSD) is a febrile disorder of unknown aetiology characterised by typical spiking fever, evanescent rash, arthralgia and leucocytosis. Methods: According to the diagnostic criteria of AOSD, we identified 84 patients between 1990 and 2003. The aim of this study was to analyse the characteristics of AOSD in Turkish patients who were followed‐up in a tertiary referral centre. Results: Of 84 patients of AOSD, 59 (70.2%) were female, 25 (29.8%) were male. Arthralgia (96.4%), fever (95.2%), arthritis (69%), sore throat (65.5%) and typical rheumatoid rash (59.5%) were the most common findings. The mean value of laboratory findings were as follows; C‐reactive protein level of 11.59 ± 6.81 mg/dl, erythrocyte sedimentation rate (ESR) of 89.05 ± 31 mm/h, leukocyte count of 16,234.51 ± 7785.2/μl. Leucocytosis was present in 69 patients (84.15%). Forty‐eight patients had a WBC count ≥ 15,000/μl. Hypoalbuminaemia was present in 35 patients. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were observed in 30 patients, whereas abnormal levels of alkaline phosphatase in 16 patients. Thirty‐seven patients had an ESR value of more than 100 mm/h. Thirty‐two patients had a ferritin value of more than 1000 ng/dl. Conclusion: High fever, sore throat, rheumatoid rash, polyarthritis, hyperferritinaemia (≥ 1000 ng/ml), leucocytosis with a neutrophilic predominance, anaemia and hypoalbuminaemia were remarkable observations in the initial examination.     

Adult-onset Still's disease—pathogenesis,clinical manifestations,and new treatment options

Abstract

Adult-onset Still's disease (AOSD), a systemic inflammatory disorder, is often considered a part of the spectrum of the better-known systemic-onset juvenile idiopathic arthritis, with later age onset. The diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders. AOSD is a heterogeneous entity, usually presenting with high fever, arthralgia, skin rash, lymphadenopathy, and hepatosplenomegaly accompanied by systemic manifestations. The diagnosis is clinical and empirical, where patients are required to meet inclusion and exclusion criteria with negative immunoserological results. There are no clear-cut diagnostic radiological or laboratory signs. Complications of AOSD include transient pulmonary hypertension, macrophage activation syndrome, diffuse alveolar hemorrhage, thrombotic thrombocytopenic purpura and amyloidosis. Common laboratory abnormalities include neutrophilic leukocytosis, abnormal liver function tests, and elevated acute-phase reactants (ESR, CRP, ferritin). Treatment consists of anti-inflammatory medications. Non-steroidal anti-inflammatory drugs have limited efficacy, and corticosteroid therapy and disease-modifying anti-rheumatic drugs are usually required.

Recent advances have revealed a pivotal role of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, and IL-18 in disease pathogenesis, giving rise to the development of novel targeted therapies aiming at optimal disease control.

The review aims to summarize recent advances in pathophysiology and potential therapeutic strategies in AOSD.     

Torsades de pointes episode in a woman with high-grade fever and inflammatory activation: A case report

BACKGROUNDQT interval prolongation can induce torsades de pointes (TdP), a potentially fatal ventricular arrhythmia. Recently, an increasing number of non-cardiac drugs have been found to cause QT prolongation and/or TdP onset. Moreover, recent findings have demonstrated the key roles of systemic inflammatory activation and fever in promoting long-QT syndrome (LQTS) and TdP development.CASE SUMMARYA 30-year-old woman was admitted with a moderate to high-grade episodic fever for two weeks. The patient was administered with multiple antibiotics after hospitalization but still had repeating fever and markedly elevated C-reactive protein. Once after a high fever, the patient suddenly lost consciousness, and electrocardiogram (ECG) showed transient TdP onset after frequent premature ventricular contraction. The patient recovered sinus rhythm and consciousness spontaneously, and post-TdP ECG revealed a prolonged QTc interval of 560 ms. The patient’s clinical manifestations and unresponsiveness to the antibiotics led to the final diagnosis of adult-onset Still’s disease (AOSD). There was no evidence of cardiac involvement. After the AOSD diagnosis, discontinuation of antibiotics and immediate initiation of intravenous dexamethasone administration resulted in the normal temperature and QTc interval. The genetic analysis identified that the patient and her father had heterozygous mutations in KCNH2 (c.1370C>T) and AKAP9 (c.7725A>C). During the 2-year follow-up period, the patient had no recurrence of any arrhythmia and maintained normal QTc interval.CONCLUSIONThis case study highlights the risk of systemic inflammatory activation and antibiotic-induced TdP/LQTS onset. Genetic analysis should be considered to identify individuals at high risk of developing TdP.     

NLRP3基因Q705K多态性与成人斯蒂尔病之间的相关性研究

目的 :检测成人斯蒂尔病(adult-onset Still′s disease,AOSD)患者g DNA内的NIRP3基因Q705K多态性,并探讨其基因多态性与AOSD发病间的相关性。方法:收集49例AOSD患者及94名正常人的g DNA,对目的 NLRP3片段进行扩增,检测其碱基序列,同时与PUBMED已解码的人源NLRP3进行比对。结果:本研究AOSD患者及正常人中未发现NLRP3基因Q705K突变位点,在比对中发现的A242A(rs3806268)和T219T(rs7525979)位点存在基因多态性,但与亚洲人群基因型频率进行比对后,发现其与AOSD的发病间无统计学相关性。结论:NLRP3基因Q705K多态性与AOSD的发生不相关。     

28例成人Still病患者的临床特点及护理

报道2000年1月-2005年12月收治的28例成人Still病患者的临床特点及护理。针对Still患者的临床特点及不同的护理问题,积极实施有效的护理对策：对28例突发性持续性高热患者在给予常规基础护理的同时选用消炎痛栓直肠给药,改变服用糖皮质激素的时间;对22例皮疹患者,指导其采取遮阳措施,避免阳光直射皮肤,注意及时修剪指甲,防止抓破皮肤,导致感染;对20例关节炎和肌肉痛者给予40℃温水热敷,配合肌肉按摩,红外线理疗;对9例未遵医嘱服药的患者加强用药护理,向患者说明药物的作用、用法及不良反应;对24例期待性焦虑患者讲解本病的特点及治疗方法,解除患者顾虑,同时教会患者及家属缓解焦虑的方法,如听音乐,放松训练等。所有患者经有针对性的护理后,症状缓解。     

The levels of macrophage migration inhibitory factor as an indicator of disease activity and severity in adult-onset Still's disease

Objectives:This study investigated the levels of macrophage migration inhibitory factor (MIF) in adult-onset Still's disease (AOSD) and explored the role of this pro-inflammatory cytokine in the systemic inflammation of AOSD.Design and methods:Serum MIF levels were measured by ELISA in patients with AOSD and controls. Intracellular MIF production by peripheral blood leukocytes was detected by three-color flow cytometry.Results:Serum MIF levels were significantly increased in patients with AOSD. Serum MIF levels were significantly higher in AOSD patients with sore throat, myalgias, splenomegaly, or pleuritis, and were closely correlated with clinical disease severity and activity. Examined by flow cytometry, the intracellular MIF levels in monocytes and T-lymphocytes from AOSD patients were significantly higher than those from healthy subjects.Conclusion:These data represent the first demonstration of increased MIF expression in AOSD, and suggest that MIF may be an important marker for disease evaluation and monitoring.     

Tocilizumab for the treatment of adult-onset Still’s disease

Introduction: Adult-onset Still´s disease (AOSD) is a systemic inflammatory condition that affects mainly young people. The clinical course consists of two distinctive patterns: one with a predominance of systemic symptoms and another manifested by progressive chronic polyarthritis. Glucocorticoids remain the mainstay in the treatment of AOSD. However, biologic therapies are often required to achieve clinical remission and allow glucocorticoid discontinuation.

Areas covered: The review summarizes the main retrospective and prospective studies, and case series on the use of the anti-interleukin (IL)-6 receptor tocilizumab in AOSD.

Expert opinion: Since IL-6 serum levels are highly increased in both active systemic and polyarticular phenotypes, IL-6 blockade was considered to be a plausible therapeutic option for the management of AOSD. Tocilizumab, the only anti-IL-6-receptor antagonist currently available for AOSD, has proved to be effective for the management of refractory AOSD patients, including those with life-threatening complications. Nevertheless, there are some reports describing patients who are refractory to any therapy. Future research should focus on the identification of prognostic biomarkers that help us to tailor an individualized treatment for each type of patient and in the search of new disease activity indices that help us to monitor the response to the therapy more closely.     

The role of damage-associated molecular pattern for pathogenesis and biomarkers in adult-onset Still’s disease

Introduction: Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease, which presents itself as an adult form of systemic juvenile idiopathic arthritis. Innate immune activation driven by a combination of genetic and environmental factors is the primary mechanism underlying disease pathogenesis in AOSD patients. Few biomarkers have been identified for AOSD diagnosis or for the assessment of disease activity or prediction of clinical outcomes. Damage-associated molecular patterns (DAMPs) can activate innate immunity, resulting in tissue damage. Changes in several DAMPs are associated with disease pathogenesis in AOSD patients.

Areas covered: This review describes the role of DAMPs in AOSD pathogenesis and discusses their potential for use as disease biomarkers. Together with overall pathogenesis of AOSD, high-mobility group box-1, advanced glycation end products, S100 proteins, and neutrophil extracellular traps are introduced and discussed in detail.

Expert opinion: The activation of macrophages and neutrophils is associated with several DAMPs, causing high concentrations of proinflammatory cytokines in AOSD patients. Involvement of certain DAMPs in AOSD patients is well documented due to the presence of sterile inflammation; however, direct evidence for some DAMPs is lacking. Further research into the role of DAMP molecules in AOSD patients may reveal new biomarkers and provide targets for disease intervention.     

Coexistence of thrombotic thrombocytopenic purpura and adult‐onset Still's disease

The association of Thrombotic thrombocytopenic purpura (TTP) and adult‐onset Still''s disease (AOSD) is very uncommon. Hereby, we present a case of TTP occurring in patient with a known AOSD and the successful outcome after plasma exchanges.     

Biologics for the treatment of adult-onset still’s disease

ABSTRACT

Introduction: Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60–70% of patients develop a chronic form. Up to 20–30% of patients who are refractory to conventional therapy need biologic agents. Recently, anti-cytokine biologic agents according to pathophysiology have resulted in significant progress in the treatment of AOSD.

Area Covered: Due to rarity and heterogeneous features of the disease, treatment of AOSD is not based on the controlled study but on case-based retrospective data. Here, we review the current status of the pathogenesis, limitations of therapeutic guidelines and outcome measures, utility of biologic agents, and future perspectives for treatment.

Expert opinion: IL-1 inhibitors are more effective for systemic manifestations and IL-6 inhibitors for both joint disease and systemic features. Anti-TNF agents would be useful for patients with the pure rheumatoid subgroup. Systemic manifestations respond rapidly, but arthritis shows rather slow response. Clinical response must be obtained within 2 to 3 months, and biologics with different mechanisms of action are required for non-responders. For patients in prolonged remission, we need to try tapering of biologics. Randomized controlled studies, new therapeutic agents, and composite biomarkers are required to improve the outcome of patients with AOSD.     

成人斯蒂尔病112例临床分析

目的:探讨成人斯蒂尔病(adult-onset Still's disease,AOSD)的临床特征、诊断、治疗与转归,以提高对该病的认识.方法:对112例AOSD的临床表现、实验室检查、治疗和预后等临床资料进行数理分析.结果:发热、关节痛、咽痛、皮疹和肌肉疼痛是AOSD患者最常见的5个症状.呼吸系统受累多见(33%),其中间质性肺疾病5例,其次为循环系统 (17%),消化系统 (7%),神经系统受累少见(4%).贫血72例(64%),白细胞增多92例(82%),中性粒细胞增多71例(63%),血小板增多53例(47%),ESR增快105例(94%),CRP升高92例(82%),ALT升高73例(65%),乳酸脱氢酶升高64例(57%),血清铁蛋白升高84%(59/70).仅7%的患者用非甾体抗炎药可控制病情,其余均需要加用肾上腺皮质激素(激素),需再加用1种免疫抑制药占44%,需要加用2种免疫抑制药占13%.随访62例患者,获长期缓解56%,病情呈慢性持续性16%,反复发作23%,死亡3例.结论:AOSD是一种以发热、皮疹、关节痛、白细胞增多为主要特征的自身免疫性疾病,预后良好,多数患者用激素治疗有效,但对以关节炎表现为主以及合并内脏损害的患者应尽早使用免疫抑制药,以控制病情.     

Ferritin,fever, and frequent visits: Hyperferritinemic syndromes in the emergency department

Fever of unknown origin (FUO) is defined as persistent fevers without an identifiable cause despite extensive medical workup. Emergency physicians caring for patients reporting a persistent, nonspecific, febrile illness should carefully consider potentially serious non-infectious causes of FUO. We present a case of a 35-year-old man who presented to the emergency department (ED) three times over a 10-day period for persistent febrile illness and was ultimately diagnosed with Adult-Onset Still's Disease (AOSD) after a serum ferritin level was found to be over 42,000 μg/L. AOSD, along with macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock comprise the four hyperferritinemic syndromes. These are potentially life-threatening febrile illnesses that characteristically present with elevated ferritin levels. In this article, we highlight the value of a serum ferritin level in the workup of a patient with prolonged febrile illness and its utility in facilitating early diagnosis and prompt treatment of hyperferritinemic syndromes in the ED.     

18F-FDG PET/CT在成人Still病中的表现及其评估疾病活动度的作用

目的 :探讨18F-FDG PET/CT在成人Still病(Adult-onset still disease,AOSD)中的表现及其评估疾病活动度的作用。方法:选取确诊为AOSD并进行18F-FDG PET/CT检查的患者46例,收集其临床资料和PET/CT特点,分析AOSD患者的骨髓、脾脏、淋巴结标准化摄取值(Standardized uptake values,SUV)强度与实验室指标、系统评分之间的相关性。结果:AOSD的18F-FDG摄取主要发生于骨髓(100%,SUV强度:2.00±0.66)、脾(96%,SUV强度:1.70±0.54)及淋巴结(98%,SUV强度:2.67±1.38),此外18F-FDG摄取还可发生于心包、胸膜、咽部、颌下腺、腮腺、甲状腺、皮肤、关节、食管、贲门部位。骨髓SUV强度与疾病系统评分、血沉、C-反应蛋白、白细胞计数和中性粒百分数显著相关(r=0.445、0.376、0.323、0.439、0.524,P<0.05)。脾脏SUV强度与疾病系统评分、乳酸脱氢酶显著相关(r=0.424、0.347,P<0.05)。淋巴结SUV强度与疾病系统评分显著相关(r=0.356,P<0.05)。结论:AOSD在18F-FDG PET/CT上主要表现为骨髓、脾脏及淋巴结的FDG高摄取,18F-FDG PET/CT有助于监测疾病活动性。     

Neoplastic fever: a neglected paraneoplastic syndrome

Neoplastic fever, a paraneoplastic syndrome caused by cancer itself, represents a diagnostic challenge for the clinician and is an important issue in supportive oncology. Timely recognition of this febrile condition by differentiating it from other cancer-associated fevers, such as infection and drug reaction, is essential for effective patient management. Although the pathophysiology of neoplastic fever is not well understood, it is suspected to be cytokine mediated. In clinical practice, when a patient with cancer presents with unexplained fever, extensive diagnostic studies are needed to differentiate neoplastic fever from nonneoplastic fever. Only after excluding identifiable etiologies of fever can the diagnosis of neoplastic fever be suspected. According to our experience, the naproxen test is a safe and useful test in differentiating neoplastic fever from infectious fever in patients with cancer. In addition, naproxen and other nonsteroidal anti-inflammatory drugs have been effective in the management of neoplastic fever and offer a significant palliative benefit for the patient.     

2019年1月全球传染病疫情概要

2019年1月全球共监测到传染病53种,涉及68个国家和地区,其中传染病数量位于前5位的为登革热（32个）、麻疹（24个）、霍乱（8个）、军团菌病（7个）和基孔肯雅热（6个）。 病死率位于前5位的传染病为埃博拉出血热（61.7%）、中东呼吸综合征（35.3%）、黄热病（28.5%）、拉沙热（19.7%）和汉坦病毒肺综合征（18.6%）。 死亡病例数位于前5位的传染病为埃博拉出血热、拉沙热、霍乱、登革热和汉坦病毒肺综合征。 非洲流行的传染病主要为霍乱、埃博拉出血热、黄热病、拉沙热和麻疹;亚洲流行的传染病主要为登革热、霍乱、中东呼吸综合征、流行性腮腺炎和肺结核;美洲流行的传染病主要为登革热、麻疹和基孔肯雅热;欧洲流行的传染病主要为麻疹和风疹。     

2020年11月全球传染病疫情概要

2020年11月全球共监测到传染病61种,涉及223个国家和地区。 除流感外,涉及国家和地区数量位于前5位分别为新型冠状病毒肺炎（COVID-19,223个）、登革热（30个）、麻疹（13个）、寨卡病毒病（11个）和脊髓灰质炎（11个）。 病死率位于前5位分别为埃博拉病毒病（42.3%）、黄热病（41.0%）、裂谷热（33.3%）、拉沙热（20.7%）和西尼罗热（11.1%）。 死亡病例数位于前5位分别为COVID-19、黄热病、登革热、霍乱和拉沙热。 亚洲主要流行COVID-19和登革热;非洲主要流行COVID-19、埃博拉病毒病、霍乱、黄热病、裂谷热和拉沙热;美洲主要流行COVID-19和登革热;欧洲主要流行COVID-19和西尼罗热。