Elke Lainka

Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement.

The daily application of colchicine is the standard therapy for prophylaxis of attacks and amyloid deposition in familial Mediterranean fever. However, because of many issues (eg, dosage, time of introduction, etc), no standardized treatment recommendations have been established. In this work we review the available literature on colchicine use with respect to its indication, efficacy, mode of application, and safety in children and adolescents with familial Mediterranean fever. On the basis of this analysis, a consensus statement on the application of colchicine in children and adolescents with familial Mediterranean fever was developed by caregivers from Germany, Austria, and Turkey.

Disease severity in children and adolescents with Familial Mediterranean Fever: A comparative study to explore environmental effects on a monogenic disease

Background: Worldwide, familial Mediterranean fever (FMF) is the most common autoinflammatory disease. It has been suggested that environmental factors affect the phenotype as some patients do not develop the complication of secondary amyloidosis. Objective: To analyse whether disease severity in Turkish children with FMF, living in Turkey and Germany is different. Patients and methods: A total of 55 Turkish children living in Turkey were compared with 45 Turkish children born and raised in Germany. Mean age among the group from Turkey and Germany was 42.2 and 44.29 months, respectively. M694V was the leading mutation in both groups. The severity scores were compared with two scoring systems, modified according to published paediatric data for dosage. Results: There was no significant difference between the mean C-reactive protein and erythrocyte sedimentation rate levels of the two groups. According to the modified Sheba Center score, 78.2% of patients from the group living in Turkey had a severe course compared with 34.1% from the group living in Germany. The modified score of Pras et al also showed more severe disease in the patients from Turkey. The difference between the two groups for both scoring systems were significant (both p<0.05). Conclusions: We believe the modified scores that we introduce can be widely used for children. Our results suggest that the environment affects the phenotype of a monogenic disease of the innate inflammatory pathway.

Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients – A single-center experience

Hoerning A, Hegen B, Wingen A‐M, Cetiner M, Lainka E, Kathemann S, Fiedler M, Timm J, Wenzel JJ, Hoyer PF, Gerner P. Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients – A single‐center experience.

Translational research network and patient registry for auto-inflammatory diseases

OBJECTIVE Auto-inflammatory diseases (AIDs) are characterized by recurrent self-limiting systemic inflammation. In a multicentre effort, we set out to register genetic, epidemiological and clinical features as well as prognostic factors of these diseases by prospective longitudinal and long-term documentation, in order to define novel AIDs and to better understand treatment responses and outcome. METHODS In 2009, a federally funded clinical and research consortium (AID-Net) was established, including an online registry for AIDs (http://www.aid-register.uk-essen.de). Inclusion criteria are disease-associated mutations for hereditary periodic fever syndromes [FMF, hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), TNF receptor 1-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS)], or, alternatively, clinically confirmed AID, systemic-onset JIA (SoJIA) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome with unknown genetic background. Patients were recruited to the registry and patient material was deposited in biomaterial banks (DNA/serum). In addition, basic research projects were initiated that focus on molecular mechanisms of AID. RESULTS During the first 9 months, 117 patients (65 males, 52 females; age 1-21 years) have been recorded and classified as FMF (n=84), HIDS (n=1), TRAPS (n=3) and CAPS (n=1); clinically confirmed AID (n=5); SoJIA (n=22); and PFAPA (n=1). One hundred and fifty blood samples of 18 patients were included in biomaterial banks. CONCLUSION Recruitment and follow-up of patients with AID will enable us to comprehensively address the correlation between clinical and epidemiological data, genetics and biomarkers. The translational approach may help to identify genetic or inflammatory markers relevant for the course and outcome of diseases.

Polyethylene Glycol-Conjugated Adenosine Deaminase (ADA) Therapy Provides Temporary Immune Reconstitution to a Child with Delayed-Onset ADA Deficiency

ABSTRACT We describe the effects of polyethylene glycol-conjugated adenosine deaminase (ADA) replacement therapy on lymphocyte counts, activation, apoptosis, proliferation, and cytokine secretion in a 14-month-old girl with “delayed-onset” ADA deficiency and marked immunodysregulation. Pretreatment lymphopenia affected T cells (CD4, 150/μl; CD8, 459/μl), B cells (16/μl), and NK cells (55/μl). T cells were uniformly activated and largely apoptotic (CD4, 59%; CD8, 82%); and T-cell-dependent cytokine levels in plasma were elevated, including the levels of interleukin 2 (IL-2; 26 pg/ml), IL-4 (81 pg/ml), IL-5 (46 pg/ml), gamma interferon (1,430 pg/ml), tumor necrosis factor alpha (210 pg/ml), and IL-10 (168 pg/ml). Mitogen-stimulated peripheral blood mononuclear cells show reduced IL-2 secretion and proliferation. During the first 5 months of therapy there was clinical improvement and partial immune reconstitution, with nearly normal lymphocyte subset numbers, reduced T-cell activation and CD4-cell apoptosis, and decreased plasma cytokine levels. In parallel, IL-2 secretion and the lymphocyte mitogenic response improved. Between 4 and 7 months, immunoglobulin G antibodies to bovine ADA developed and resulted in the complete reversal of immune recovery.

Pulse Oximetry Is Insufficient for Timely Diagnosis of Hepatopulmonary Syndrome in Children with Liver Cirrhosis

OBJECTIVE To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation. STUDY DESIGN Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics. RESULTS Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level >98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient >15 mm Hg and PaO2 <70 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P < .04). Liver transplantation led to resolution of HPS in all patients. CONCLUSION IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged <2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.

Severe H1N1 infection in a pediatric liver transplant recipient treated with intravenous zanamivir: efficiency and complications.

The 2009 emerged pandemic influenza H1N1 is a leading cause for respiratory illness in children. Herein, we report about the first pediatric patient who developed severe bilateral pneumonia with acute respiratory distress syndrome caused by novel influenza H1N1 after liver transplantation. The 2-year-old child received a deceased whole organ liver transplantation because of end-stage Caroli’s disease. Early postoperative course was complicated by portal vein thrombosis, which was successfully treated by thrombectomy 12 hr after transplantation. Immunosuppression was started with cyclosporine A (CSA; 50 mg/m intravenously [IV]; trough blood level 180–230 ng/mL), prednisone (15 mg/ m), and two doses of basiliximab (10 mg on days 0 and 4). Respiratory deterioration occurred 4 days after transplantation. The patient required invasive ventilation and developed adult respiratory distress syndrome (bilateral infiltrates on chest x-ray, PaO2/FiO2 150). Other symptoms were leukopenia and fever. Liver enzymes and function remained stable. Extended bacterial, viral, and fungal diagnostic workup from tracheal secretions revealed positive pandemic H1N1 RNA detected by polymerase chain reaction (PCR). Treatment with oseltamivir (2 30 mg/day) was started immediately after reception of positive H1N1 results at day 3 after the onset of first respiratory symptoms. Because the respiratory situation further deteriorated (PaO2/FiO2 100) and the patient developed gastroparesis, absorption of oseltamivir became questionable. IV zanamivir (2 260 mg/day) was started as “compassionate use” for 5 days from days 10 to 15 after transplantation. Parents gave informed consent, but institutional review board approval could not be achieved because treatment decision was made 2 days before Christmas. The treatment course neither led to negative H1N1 PCR nor to respiratory improvement. CSA was discontinued, and prednisone was reduced to 10 mg/m at day 11 after transplantation. The H1N1 virus tested was susceptible to oseltamivir and zanamivir. Mutations known to be associated with an enhanced pathogenicity were not identified by sequencing analysis. During the treatment with zanamivir, the patient’s liver function worsened as indicated by the increase of serum aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) up to 628 U/L and 193 U/L, respectively. Ultrasound revealed an unexplained retrograde flow of the portal vein but no evidence of portal vein thrombosis. Rejection was ruled out by liver biopsy. Pandemic H1N1 RNA was not detectable in the liver biopsy. To improve the venous outflow of the liver, positive end-expiratory pressure (maximum 16 cm H2O) was gradually reduced without any effect. Portal vein flow normalized 10 days after stopping zanamivir. During zanamivir treatment, serum creatinine level increased from 0.36 mg/dL to a maximum of 0.68 mg/ dL. Kidney function normalized with termination of zanamivir. Oseltamivir was continued for another 10 days. The patient improved slowly and was weaned from mechanical ventilation after 25 days. Pandemic H1N1 RNA in tracheal aspirate became negative 22 days after first detection. Although the majority of cases of pandemic H1N1 infections in children are mild, severe courses have been described, especially in children with comorbidities (1). Until August 2009, 36 deaths had been occurred in children younger than 18 years in the United States (2). Usually treatment of the influenza A virus with the oral preparation oseltamivir is effective to shorten the illness when initiated within 48 hr after first symptoms (3). The neuraminidase inhibitor, zanamivir, developed for IV use is not currently commercially available. In patients with severe illness and a known resistance of pandemic H1N1 to oseltamivir or in patients not tolerating enteral nutrition, this therapy might be an important alternative. Recently, a first case report with successful administration of zanamivir in a child with acute lymphoblastic leukemia has been published (4). In the presented case, zanamivir treatment was initiated as “compassionate use” because of progressive worsening of respiratory symptoms and severe gastroparesis, leading to questionable oseltamivir absorption. However, we were unable to demonstrate any positive effect as neither the symptoms improved nor the PCR became negative. A possible explanation might be the late start of the medication. Conversely, it cannot be excluded that the otherwise unexplained retrograde portal vein flow and kidney injury were caused by the medication. We believe that the coincidence in time of worsening liver function and zanamivir treatment makes a causal relationship at least possible. Duration of treatment with neuraminidase inhibitors was totally 20 days. A prolonged period of treatment is consistent with current published guidelines (5), which recommend treatment in transplant patients until H1N1 PCR becomes negative. Recommendations are based on the fact that viral shedding is prolonged in immunocompromised patients. Conversely, these potential benefits have to outweigh the risk of resistance emergence. Probably, the most important actions for improvement of clinical course in our patient were aggressive ventilatory support and the reduction of immunosuppression, especially the discontinuation of CSA. The presented case also underlines the fact that immunization against pandemic H1N1 should be recommended strongly to the patients on waiting list for organ transplantation (6). Furthermore, vaccination programs for healthcare professionals are emphasized strongly, because our patient was probably infected by a doctor, nurse, or physiotherapist. In conclusion, in other cases, zanamivir has been proven to be effective to shorten pandemic H1N1 influenza illness. If given late in the disease course ( 48 hr after onset of symptoms), caregivers have to balance the reduced efficiency against possible toxic side effects.

Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

Disease severity in adult patients of Turkish ancestry with familial mediterranean fever living in Germany or Turkey. Does the country of residence affect the course of the disease

BackgroundThe environment may affect the course of familial Mediterranean fever (FMF). ObjectiveThe objective of this study was to compare disease severity between adult FMF patients in Turkey (TR) and Germany (G). MethodsAdult FMF patients of Turkish ancestry on colchicine living in Turkey (n = 40) or G (n = 35) were compared. Disease severity, C-reactive protein (CRP), and erythrocyte sedimentation rate were assessed. ResultsGroups differed significantly in the following aspects: age at onset of disease (TR: 15.6, G: 10.8 years; P = 0.02), delay between onset and initiation of colchicine treatment (TR: 6.8 years, G: 14.9 years; P < 0.001), female gender (TR: 80%, G: 57.1%; P = 0.04), and duration of disease (TR: 14.4 years, G: 23.4 years; P < 0.001). There was no significant difference in colchicine treatment concerning average dosing and duration of therapy. No significant difference could be found between the 2 groups in CRP and disease severity as assessed by the score of Pras et al. (Am J Med Genet. 1998;75:216–219) even after adjusting for potential confounding variables. Mean erythrocyte sedimentation rate was significantly higher among patients living in G (TR: 13.2 mm/first hour, G: 26.3 mm/first hour; P < 0.001). Among patients living in Germany, there was a significant difference in age at FMF onset depending on their country of birth (born in TR: 14.9 years, born in G: 6.9 years; P = 0.0001). ConclusionsIn adult FMF patients living in Turkey or Germany, no difference in disease activity or CRP could be found. German patients were younger at onset of disease and had a longer delay between onset and initiation of colchicine treatment.

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin‐encoding MEFV mutations. Patients present with recurrent but self‐limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil‐derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.