Noninfectious febrile inflammatory syndromes in children: diagnosis and usefulness of diagnostic procedures]

OBJECTIVE: To determine the causes and to quantify the benefits obtained from further diagnostic investigations in children presenting with a non infectious inflammatory fever. METHODS: The records of 62 children aged from two-months to 15 years (median: four years) admitted to a paediatric department between 1990 and 2000 for the evaluation of a fever associated to an inflammatory syndrome, defined as temperature over 38 degrees C with an increase of the erythrocyte sedimentation rate (ESR) more than 20 mm/h and/or a serum C-reactive protein level (CRP) > 20 mg/L, and excluding overt infectious diseases, were retrospectively reviewed. RESULTS: Of these patients, 79% children (49 cases) had inflammatory systemic disease, 3.2% (two cases) had malignancy, and 17.8% (11 cases) had undiagnosed disorders. The most frequent disease was Kawasaki disease (22 children), especially in young children. Increase of ESR above 100 mm/h and of CRP above 100 mg/L was present in 59% of Kawasaki disease, 71% of idiopathic juvenile arthritis, 100% of malignancies and 7% of unknown diagnoses. Increase of ESR below 50 mm/h and of CRP below 50 mg/L was present in 75% of hemophagocytic syndromes and 46% of unknown diagnosis. The polymorphonuclear count, hepatic function evaluation, triglycerides levels, abdominal ultrasound, abdominal computed tomography, echocardiography, biopsies were useful diagnosis tools. Technetium scintigraphy was helpful only when abnormalities were found on physical examination. CONCLUSION: The diagnosis of Kawasaki disease must be quickly suspected in febrile young children with inflammatory syndrome without infection. ESR and CRP values, abdominal ultrasound and echocardiography are helpful tools for the diagnostic procedure.     

儿童EB病毒感染首发症状及相关疾病谱分析

目的 详细了解儿童EBV感染的首发症状及疾病诊断情况,以提高临床诊断水平,并探讨EBV感染临床多样性的机制。方法 对本院经酶联免疫吸附法(ELISA)测定EBV-VCA-IgM阳性的190例EBV感染患儿的首发症状、疾病诊断及预后进行前瞻回顾性分析。结果 EBV感染患儿起病症状不一,首发症状中以发热多见(66．8％),其他依次为咳嗽(14．2％)、皮疹(7．9％)、淋巴结肿大(5．3％)、眼睑浮肿(3．2％)、咽痛(1．6％)、惊厥(1．6％)、肉眼血尿(0．5％)等。可累及全身各个系统,引起疾病多样,但以呼吸道感染最多见(4|D．5％),其次为传染性单核细胞增多症(17．9％)、川崎病(6．3％)、特发性血小板减少性紫癜(11‘P)(5．8％)、病毒性心肌炎(2．6％)、病毒性脑炎(2．6％)、噬血细胞综合征(1．6％)、类风湿性关节炎(1．0％)、急性淋巴结炎(1．0％)、面神经炎(1．0％)、Evans综合征(0．5％)、系统性红斑狼疮(SLE)(0．5％),亚急性坏死性淋巴结炎(0．5％)等。EBV感染预后不一,1例病人因患噬血细胞综合征而死亡。结论 儿童EBV感染症状多样,累及系统多,临床医生应该综合分析,及早作相应的检查才能作出正确诊断及减少误诊率,并进行合理治疗。     

Kawasaki disease with a concomitant primary Epstein-Barr virus infection

A two year old boy exhibited not only clinical manifestations which suggested a recurrence of Kawasaki disease (KD) but also evidence of a primary infection by Epstein-Barr virus (EBV) including tonsillitis, splenomegaly and atypical lymphocytosis in the peripheral blood. An inverted CD4/CD8 ratio in lymphocyte subsets suggested the presence of infectious mononucleosis (IM). Epstein-Barr virus titers (viral capsid antigen-immunoglobulin G 1:20; Epstein-Barr virus-associated nuclear antigen < 1:10) showed an acute EBV infection and the presence of EBV genome in the blood was determined by the polymerase chain reaction technique. In Japan, the peak incidence of KD and IM is in children under 4 years of age. From the investigation of EBV titers, it has been reported that some patients with KD develop an associated, unusual primary EBV infection. Kawasaki disease concurrent with a primary EBV infection as in this case, suggests the possibility of an etiologic agent related to the KD rather than to the EBV infection itself.     

Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndrome

A patient with Wiskott-Aldrich syndrome who developed Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis (EBV-HLH) is described in this study. At 4 mo of age the patient developed fever associated with bicytopenia and splenomegaly. Analysis of a bone marrow specimen revealed extensive haemophagocytosis, and in situ hybridization for EBV of the bone marrow specimen using an EBV-encoded RNA probe was positive. Diagnosis of EBV-HLH was established and immunotherapy with HLH-94 protocol was started. HLH has been described in patients with other well-defined primary immunodeficiencies such as X-linked lymphoproliferative syndrome, Chediak-Higashi syndrome and Griscelli disease. Also, HLH was reported recently in severe combined immunodeficiency and DiGeorge syndrome.

Conclusion: The possibility of an underlying primary immunodeficiency should be considered in paediatric patients who present with HLH during infancy.     

Kawasaki disease in parents and children

Aim: To estimate the probability that the parents of patients with Kawasaki disease also had a history of the same disease. Methods: Self-reported parents' histories of Kawasaki disease were collected from data of the 16th nationwide survey of the disease conducted in Japan from January 1999 to December 2000. The incidence of Kawasaki disease was calculated by using data reported in all 16 nationwide surveys and live births in the Japanese vital statistics. The expected number of parents with a history of Kawasaki disease in the general population, which was calculated by using the assumed number of parents in the vital statistics and the incidence of this disease, was compared with the observed number. Results: Among 14 163 parent pairs of patients with Kawasaki disease, 33 parents (25 mothers and 8 fathers) had a history of the disease. The number of parents expected to have a history of Kawasaki disease was 16.1 (8.4 mothers and 7.7 fathers). From a Poisson distribution, the probability of the observed number was less than 0.001 among parents or mothers. The prevalence of a recurrence of Kawasaki disease and incidences involving siblings of patients whose parents had a history of the disease were five or six times higher than those of all patients who were reported in the 16th survey.

Conclusion: When compared with parents in the general population, the probability of a history of Kawasaki disease was significantly higher in those parents whose children suffered from the same disease. This suggests that, epidemiologically, a genetic predisposition to Kawasaki disease may be implicated in its occurrence.     

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目的探讨儿童非典型EB病毒(EBV)感染的临床特点。方法2000年3月至2005年4月,深圳市儿童医院在住院患儿中检测出EBVVCAIgM和(或)EBVDNA阳性共690例,其中传染性单核细胞增多症422例,另外268例为非典型EBV感染,对其临床特点进行回顾性分析。结果儿童非典型EBV感染以呼吸道感染最为多见(191/268,71.3%),其它为皮炎13例(4.9%)、腹泻病10例(3.7%)、血小板减少性紫癜10例(3.7%)、肾炎或肾病7例(2.6%)、肠系膜或颈淋巴结炎8例(3.0%)、结膜炎7例(2.6%),川崎病、嗜血细胞综合征、中枢神经系统感染各4例(1.5%),心肌炎、播散性脑脊髓炎各2例(0.7%),再生障碍性贫血、坏死性淋巴结炎、腮腺炎、高IgM血症、嗜酸细胞增多症各1例(0.4%),诊断不明1例(0.4%)。其中嗜血细胞综合征患儿有2例死亡。结论儿童非典型EBV感染症状多样,累及系统多,预后不一。EBVVCAIgM或EBVDNA检测有利于早期诊断,并进行合理治疗。     

Kawasaki Disease and Epstein-Barr Virus

We report the results of virological (serological and molecular biological) studies of Epstein-Barr virus (EBV) in patients with Kawasaki disease (KD). Forty-nine (86%) of 57 Kawasaki disease patients and 15 (68%) of 22 patients with recurrent Kawasaki disease had serological evidence of primary Epstein-Barr virus infection during the first month after the onset of their disease based on the results of a sensitive method of detecting antibody to viral capsid antigen (VCA). The serological response to EBV was significantly low and transient. EBV sequences were identified directly in peripheral blood mononuclear cell (PBMC) DNA samples from 23 (56%) of 41 KD patients within 2 weeks after onset by means of the polymerase chain reaction (PCR). EBV sequences were also detected in 10 (83%) of 12 repeatedly tested KD patients within 3 months after onset. In contrast, only 7 (18%) of 40 control DNA samples were PCR-positive. These virological studies indicate that an unusual EBV-cell interaction may occur in KD.     

Mortality among persons with a history of Kawasaki disease in Japan: Can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

Aim: To clarify the question of whether patients with Kawasaki disease suffer a higher mortality rate after the incidence of the disease in comparison with age-matched healthy individuals. Methods: Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new, definite diagnosis of Kawasaki disease. Patients were followed up until 31 December 2001 or their death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Results: Of 6576 patients enrolled, 29 (20 males and 9 females) died. The standardized mortality ratio (SMR: the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.15 (95% CI: 0.77-1.66). In spite of the high SMRs during the acute phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the SMR after the acute phase was 0.75 for those without cardiac sequelae, six males (but none of the females) with cardiac sequelae died during this period; and the SMR for the male group with cardiac sequelae was 1.95 (95% CI: 0.71-4.25). The mortality from congenital anomalies of the circulatory system was elevated, but no increase in cancer deaths was observed.

Conclusion: Although it was not statistically significant, the mortality rate among males with cardiac sequelae due to Kawasaki disease appeared to be higher than in the general population. On the other hand, the mortality rates for females with the sequelae and both males and females without sequelae were not elevated.     

Atypische Epstein-Barr-Virus(EBV)-Infektionen im Kindes- und Jugendalter

The clinical syndrome of acute infectious mononucleosis is predominantly a disease of older children and adolescents. Primary EBV infection in younger infants is often subclinical. Complications may affect any organ system and are usually mild. In the majority of cases acute infectious mononucleosis has an excellent prognosis. Severly immuncompromised children and adolescents (i. e. under immunosuppressive therapy, after stem cell transplantation) may develop EBV⁺ B-cell lymphoproliferative disorders and malignant B-cell lymphoma. In this review, mainly the following forms of atypical EBV infections are described in detail: Fulminant, mostly fatal acute infectious mononucleosis following primary EBV infection may occur 1) sporadically (approx. 1 per 3000 cases of acute infectious mononucleosis), 2) in aprox. 60% of boys with X-linked lymphoproliferative disease (XLP), and 3) in very rare cases of a fulminant EBV+ T-cell lymphoproliferative disorder. No efficient therapy exists so far. Early allogeneic stem cell transplantation in boys with XLP may prevent fatal acute infectious mononucleosis and other complications. Chronic active EBV (CAEBV) infection is characterized by recurrent clinical episodes of severe infectious mononucleosis over months or years and additional unusual clinical signs and complications such as coronary artery aneurisms, hypersensitivity to mosquito bites and hydroa vacciniforme, as well as an markedly increased risk for malignant lymphoma, mostly of a T-cell type. In general, prognosis of CAEBV infection is poor. Allogeneic stem cell transplantation may lead to clinical remission. EBV-associated hemophagocytic syndrome may occur as an independent disorder [EBV-related hemophagocytic lymphhistiocytosis (EBV-HLH)] or as a serious complication of fatal infectious mononucleosis or CAEBV infection. Early treatment with etoposide, cyclosporine A and corticosteroids may improve the otherwise poor prognosis. The pathogenesis of atypical EBV infections is not known in most cases. Further molecular and immunologic studies may help to characterize these severe disorders and to develop more specific and more efficient therapies.     

不明原因长期发热的临床分析

目的 探讨不明原因长期发热患儿的病因及诊断方法。方法 回顾性地总结分析符合ＦＵＯ诊断标准的患儿１１８例。结果 １１８例中晚期诊断有１０７例,确诊率为９０．７５,未能确诊１１例,确诊病例中,感染性疾病３３例,结缔组织病４４例,肿瘤及瘤样病１４例,其他疾病１３例,伪装热３例。最终确定诊断的方法分别为;血清学和细菌学检查７５例,占７０．０％;组织活检１３例,占１２．１％;骨髓检查９例,占８４％,影像学检     

Graves' disease in children and adolescents: response to long-term treatment

Background: Optimal treatment of Graves' disease in paediatric patients is still a matter of controversy. Antithyroid drugs, radioiodine and thyroidectomy are the three therapeutic options available. Aim: To report our experience of long-term medical treatment and outcome of paediatric Graves' disease. Methods: A 5-y-long medical protocol was implemented in 20 children and adolescents with Graves' disease. All patients received antithyroid drugs as the first therapeutic option; patients who did not enter long-term remission received I¹³¹ and/or surgery as the definitive treatment. Results: The mean age at diagnosis was 12.1±4 y. Only two patients were males, both presenting concomitant type 1 diabetes. Mean follow-up was 13.8±5.5 y. Forty per cent of patients achieved long-term remission with low antithyroid drugs doses (mean treatment time: 5.4±1.4 y). Six patients received I¹³¹ as definitive treatment and another six underwent surgery after completing medical treatment for 6.8±4.1 and 5.1±2 y, respectively. No patients requiring high antithyroid drugs doses to maintain euthyroidism reached long-term remission and needed I¹³¹ and/or surgery.

Conclusion: Implementation of a long-term antithyroid drug protocol achieved 40% long-term remissions in paediatric patients with Graves' disease. Need for maintained high doses of antithyroid drugs could be considered a predictive factor for no remission. When permanent remission was not obtained by medical treatment, I¹³¹and/or surgery allowed healing in all cases.     

传染性单核细胞增多综合征的诊断与治疗

目的探讨传染性单核细胞增多综合征(传单)的诊断与治疗。方法对39例具有传单临床表现患儿的病原学检查结果、临床特征和血异形淋巴细胞(异淋)变化规律进行回顾性总结。结果39例中EBV引起的传单14例,MP感染引起的12例,可能与MP感染有关2例,EBV和MP混合感染3例,CMV感染1例,病原不明7例。MP感染多为低中度发热,EBV感染以高热为主,EBV和MP混合感染发热持续时间长,与其他组比较差异显著(P<0.05)。MP感染异淋消失所需时间短,与EBV感染者比较差异显著(P<0.05)。结论MP引起的传单与EBV引起的传单十分类似,容易混淆,临床特征对鉴别诊断虽有参考价值,确诊必须靠病原学检查。MP感染需用大环内酯类抗生素治疗,EBV或CMV感染则用更昔洛韦。     

Rapid control of norovirus gastroenteritis outbreak in an acute paediatric ward

Aim: To provide a practical action plan for effective infection control of norovirus outbreak in acute paediatric wards.

Methods: We report the infection control measures that were implemented to terminate and to prevent nosocomial spread of norovirus gastroenteritis in an open-designed paediatric ward.

Results: Nine children, one visitor, and one medical student were affected in a norovirus gastroenteritis outbreak in an acute paediatric ward. Vomiting was the main presenting symptom. The outbreak was rapidly terminated three days after implementation of stringent infection control measures and there was no second wave of attack. These measures included strict contact precautions, prompt isolation and cohorting of symptomatic patients, vigorous environmental cleansing with concentrated disinfectant (hypochlorite solution 1000 ppm), meticulous handling of waste products, and efficient contact tracing of exposed patients, family members, and medical students.

Conclusion: Prompt implementation of stringent infection control measures and contact tracing can rapidly terminate the norovirus outbreak and prevent a second wave of infection. Children with unexplained vomiting and those with contact history of gastroenteritis should be properly triaged, isolated, and investigated for possible infective causes, including norovirus-induced gastroenteritis.     

317例儿童不明原因发热的临床分析

目的：探讨儿童不明原因发热(FUO)的病因,诊断方法和思维方式。方法：回顾性地总结分析1996年1月至2000年12月符合FUO诊断标准的住院患儿317例。结果：317例中明确诊断有298例,确诊率为94.0%。感染性疾病160例(53.7%),非感染性疾病138例(46.3%),两者之比为1.15∶1。最终确定诊断的方法分别为：临床综合诊断140例(47.0%);血清和骨髓细菌培养检查64例(21.5%);组织活检37例(12.4%);影像学检查35例(11.7%);尸体解剖11例(3.7%);骨髓形态学确诊6例(1.9%);回顾性诊断5例(1.7%)。结论：根据临床经过和必要的实验室检查大部分FUO病例可以明确病因诊断,病理学检查对疑难病例的诊断提供重要依据,极少数病人最终只能依赖尸检明确诊断。感染性疾病、结缔组织病和恶性肿瘤性疾病是该组FUO的主要原因。     

Children with chronic conditions in a paediatric emergency department

Aim: To describe the use of a paediatric emergency department by children with chronic conditions. Material and methods: We prospectively indexed all the children seen in our emergency department during 1 y to describe the population of children with chronic conditions, and to compare it with the general paediatric population. Results: There were 11 483 patient visits, of which 11% were by chronically ill children. Six subspeciality areas accounted for the vast majority of the chronic conditions seen: neurology (30%), cardiology (18%), pulmonology (18%), nephro-urology (16%), haemato-oncology (9%) and endocrinology (4%). Admission rate to the hospital was significantly higher for chronically ill patients (38% vs 23%). Among chief complaints, fever, respiratory distress, headache and seizures were overrepresented in chronically ill children. The chief complaint was related to the child's chronic condition in 51% of the visits. In both chronically and non-chronically ill patients, the majority of final diagnoses were related to infection (57% and 65%, respectively). Among diagnoses, bacterial infections, seizures, vasovagal syncopes and asthma were overrepresented in chronically ill children.

Conclusion: From the analysis of our data, we conclude that children with chronic conditions account for a tenth of all visits to a paediatric emergency department. The paediatric emergency physicians provide an important service to both the children with chronic conditions and the subspecialists who care for them.     

The X-Linked Lymphoproliferative Disease: From Autopsy Toward Cloning the Gene 1975-1990

Although X-linked lymphoproliferative disease (XLP) is rare (1-2 males per 1 × 10⁶), it serves as a model for discerning diverse diseases caused by Epstein-Barr virus (EBV) ranging from agammaglobulinemia to fatal infectious mononucleosis following infection with the virus. The study of patients with XLP has also paved the way to understanding how EBV induces diseases in children with primary immunodeficiency diseases, organ transplant recipients, and those with acquired immunodeficiency syndrome. This review is dedicated to the memory of Gordon Vawter, M.D., who generously provided insights into the causes of pathogenesis of immune deficiency and lymphoproliferative disorders.     

Visceral leishmaniasis in Malta--an 18 year paediatric, population based study.

BACKGROUND: Visceral leishmaniasis (VL) is a chronic parasitic infection that infects approximately 400,000 individuals annually, with a predilection towards early childhood. AIMS: To study the epidemiology of VL in childhood. METHODS: VL is endemic in Malta, a small archipelago of islands in the centre of the Mediterranean with a total population approaching half a million. Notification of human cases of leishmaniasis is compulsory. Case records of all 81 paediatric patients with VL between 1980 and 1998 were analysed. RESULTS: The annual incidence of VL declined for all cases of VL, and declined significantly for paediatric cases (p = 0.01). For 1994 to 1998, the overall incidence of VL was 0.9 per 100,000 total population and the paediatric incidence was 2.5 per 100,000 population. Median age at presentation was 34 months. Common features at presentation were splenomegaly, hepatomegaly, fever, and pancytopenia with high lymphocyte and monocyte counts. The diagnostic sensitivity of isolated immunofluorescent antibody testing was equivalent to bone marrow aspiration (95%). Blood transfusions for anaemia were required in 93% of patients. Eleven per cent had intercurrent infections. All patients were cured, and were initially treated with intravenous sodium stibogluconate. Defervescence occurred after a median of six days of treatment, and patients continued to be treated on a day case basis. Nine relapsers were retreated with sodium stibogluconate, achieving a cure rate of 94%, but five patients required additional drug therapy. There were no permanent sequelae associated with VL or its treatment. CONCLUSIONS: The decreased incidence is attributed to the eradication of stray dogs which are the disease reservoir.     

Low incidence of sepsis due to viridans streptococci in a ten-year retrospective study of pediatric acute myeloid leukemia

BACKGROUND: Infections remain an important cause of morbidity and mortality in children with acute myeloid leukemia (AML), and particularly viridans group streptococci (VGS) sepsis. The present study, conducted between 1993 and 2003 in children with AML, sought to assess the frequency and characteristics of infectious complications (ICs), the incidence of VGS sepsis, the interest of preventive decontamination, and a possible cytarabine dose-effect on the occurrence of ICs. METHODS: Medical charts of 78 children treated according to the EORTC 58921 clinical trial were analyzed retrospectively. Patients were isolated in laminar air flow rooms, received non-absorbable gut decontamination, gum decontamination with vancomycin mouthwash, and trimethoprim-sulfamethoxasole. ICs were categorized as microbiologically documented infections (MDI), clinically documented infections (CDI), or fever of unknown origin (FUO). RESULTS: Overall, 268 ICs occurred: 57.5% FUO, 8.5% CDI, and 34% MDI. Bloodstream infections occurred in 58 febrile episodes: Gram-positive bacteria represented 83% of the pathogens including 66.1% Staphylococcus species and 8.5% Streptococcus species (6.8% VGS), Gram-negative bacteria represented 13.5% of the pathogens and yeasts 3.5%. Five patients died of infection (6.4%). None died from bacterial infection and no case of VGS sepsis required intensive care. Invasive fungal infection was proven in four patients. Number of ICs was significantly different according to gum and gut decontamination status, and according to the cytarabine dose during the first intensification. No resistant strains were detected in spite of the use of local antibiotics. CONCLUSION: The low rate of VGS and enterobacteriaceae sepsis was probably due to the effective decontamination. Our supportive care strategy could potentially help enhance overall survival in children with AML.     

High prevalence of antibodies against Bartonella henselae with cervical lymphadenopathy in children

Background: Cat‐scratch disease is the most common form of Bartonella henselae infection. Although reports have shown that CSD is relatively common, they have not shown the prevalence of seropositivity for Bartonella henselae in cases of cervical lymphadenitis and Kawasaki disease, which are relatively common diseases in children. Methods: We evaluated the presence of immunoglobulin (Ig) G‐ and IgM‐class antibodies against Bartonella henselae in children with cervical lymphadenitis, Kawasaki disease, and infectious diseases without lymphadenopathy in a semi‐rural area in Japan. Results: We found that the positivity rate for the IgG antibody against Bartonella henselae in patients with cervical lymphadenitis who owned cats or dogs was significantly higher than that in patients with Kawasaki disease and infectious diseases without lymphadenopathy. However, the average age of children with cervical lymphadenitis did not significantly differ when compared to those with other infectious diseases. Conclusion: Our serological study showed that Bartonella henselae infection may contribute to the etiology of cervical lymphadenitis in children.     

Inflicted traumatic brain injury (ITBI) or shaken baby syndrome (SBS) in Estonia

Background: Inflicted traumatic brain injury (ITBI) or shaken baby syndrome (SBS) is recognized as a major cause of disability and death in the paediatric population. Aim: To find out the incidence of ITBI in Estonia. Methods: 26 cases of ITBI were recognized: four children died, 22 survived. Results: Of 26 children, 20 (77%) were boys and six (23%) were girls. Median age at admission to hospital was 3.9 mo, and the boys were younger than the girls. Conclusion: The overall incidence of ITBI was 28.7 per 100 000 infants. In the prospective group the incidence was 40.5 per 100 000, and in retrospective group 13.5 per 100 000. ITBI is not rare but not always a recognized form of child abuse. Healthcare professionals should be more aware of this condition.