Large European Multicenter Study Research Articles

Human Immunodeficiency Virus-Infected Boy With Stevens-Johnson Syndrome Caused by Nevirapine

To the Editors: We read with interest the recent case report by Oberdorfer et al1 published in the June edition of the journal, entitled “Human immunodeficiency virus-infected boy with Stevens-Johnson syndrome caused by nevirapine.” However, we believe that certain aspects of the report require further clarification for readers. Following an initial report by Warren et al2 in 1998, nevirapine-induced Stevens-Johnson syndrome (SJS) is now a well-recognized and -documented phenomenon. Although data in children are relatively limited, to our knowledge the first description of this particular complication in children was in a report by Pollard et al in 1998.3 That report summarized the early experience with nevirapine in adults, as well as children (pediatric investigational trials BI 892, ACTG 180, and ACTG 245), focusing primarily on adverse events. Interestingly, the authors described 2 cases of SJS in the pediatric population and estimated the overall incidence of this complication to be approximately 0.3%. Further pediatric cases of SJS related to nevirapine therapy have since been described.4,5 Oberdorfer et al's case adds to these previous reports. Human immunodeficiency virus (HIV) infection alone is a significant risk factor for SJS and toxic epidermal necrolysis (TEN). In a recent, large European multicenter study (EuroSCAR study) on SJS/TEN, HIV-infected individuals had an estimated 12-fold increased risk of developing SJS/TEN compared with healthy controls.6 The mechanisms involved are not fully understood, although it has been postulated that immune dysregulation resulting from HIV infection plays a contributory role. Notably, the EuroSCAR study also reported a strong association between the administration of nevirapine and the development of SJS/TEN (relative risk: greater than 22), with the majority of cases occurring within the first 28 days of therapy. We would like to remind readers of the most commonly used terminology in relation to SJS/TEN originally proposed by Bastuji-Garin et al.7 In brief, SJS is defined as involvement of 2 or more mucosal areas and less than 10% of the body surface area. Epidermal necrolysis of greater than 30% of the body surface area is classified as TEN; cases with 10–30% involvement are referred to as overlap syndrome SJS/TEN. A patient with 60% body surface area involvement is therefore better described as TEN, although arguably the distinction between syndromes is somewhat arbitrary. Nevirapine is the only non-nucleoside reverse transcription inhibitor (NNRTI) recommended for use in children younger than 3 years, and is therefore an integral component of first-line NNRTI-based antiretroviral regimens in infants and young children. Liquid preparations of protease-inhibitors are generally unpalatable and thus used less commonly in this age group. Consequently, nevirapine remains invaluable in the treatment of HIV in children, despite the association with potentially serious side effects, which in addition to SJS/TEN include fulminant hepatitis and other variants of hypersensitivity reactions.8 Marc Tebruegge Nicole Ritz Tom Connell Nigel Curtis Department of Paediatrics The University of Melbourne Infectious Diseases Unit/ Department of Medicine Murdoch Children's Research Institute Royal Children's Hospital Melbourne Parkville, Victoria, Australia

Interleukin-10 (-819 C/T) and TNF-A (-308 G/A) as Risk Factors for H. pylori-Associated Gastric MALT-Lymphoma

With great interest we read the article by Achyut et al. about the influence of genetic variants in the promoter region of the Interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-A) gene on gastritis and lymphoid follicle development in patients with H. pylori infection [1]. The authors genotyped 130 patients with non-ulcer dyspepsia (NUD) and 200 healthy age-matched controls for IL-10 (-819) and TNF-A (-308). They found that carriers of the TNF-A (-308) A allele had a more than twofold increased risk of lymphoid follicle formation. It is generally accepted that the presence of lymphoid follicles and mucosa associated lymphatic tissue (MALT) is solely a sequelae of H. pylori infection [2,3]. Pro-inflammatory genetic polymorphisms may influence the histological degree of mucosal inflammation [4] which may vary according to the localization of the biopsy. To identify a robust association of germline polymorphisms with the outcome of H. pylori infection, unambiguous phenotypes such as ulcer disease, gastric carcinoma, or primary gastric B-cell lymphoma are needed. Immediately, the question arises if these two polymorphisms constitute risk factors for the development of H. pylori-associated gastric MALT-lymphoma. In a previous study we investigated the association of four TNF-A promoter polymorphisms with gastric lymphoma [5]. Carriers of the rare allele T of TNF-A (-857) had a significantly increased risk to develop primary lowand high-grade lymphoma. TNF-A (-308) did not show any association signal. To our knowledge IL-10 (-819) has never been tested for association with gastric MALT lymphoma. Thus, we genotyped IL-10 (-819) in a sample of 363 healthy blood donors, 88 patients with primary gastric low-grade lymphoma (MALT) from a large European multicenter study [6] and 342 H. pylori-infected patients without MALTlymphoma (Table 1). There was no difference in allele and genotype distribution between the three groups. In a preceding study we could show that IL-10 promoter haplotypes do not confer a risk factor for gastric ulcer in H. pylori infection as well [7]. When comparing the results of genetic association studies, the ethnic background of the study population has to be taken into consideration. Prevalence of the rare allele A of TNF-A (-308) was 16.0% in our healthy blood donors and 10.7% in the Indian control group. The prevalence of the rare allele T of IL-10 (-819) was 22.5% in our healthy blood donors and 35.7% in the Indian control group, respectively. In conclusion, there is no evidence that IL-10 (-819) and TNF-A (-308) confer genetic risk factors for H. pylori-associated gastric MALT lymphoma, at least in Caucasian individuals. Table 1 shows genotype frequencies of IL-10 (-819 C/T) and TNF-A (-308) in healthy blood donors, H. pyloriinfected individuals, and gastric MALT-lymphoma patients. Susceptibility to infection was tested by comparing genotype frequencies of blood donors and H. pylori-infected individuals and susceptibility to MALT-lymphoma was S. Hellmig (&) T. Bartscht U. R. Folsch Department of General Internal Medicine, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany e-mail: shellmig@1med.uni-kiel.de

A positive fluid balance is associated with a worse outcome in patients with acute renal failure.

IntroductionDespite significant improvements in intensive care medicine, the prognosis of acute renal failure (ARF) remains poor, with mortality ranging from 40% to 65%. The aim of the present observational study was to analyze the influence of patient characteristics and fluid balance on the outcome of ARF in intensive care unit (ICU) patients.MethodsThe data were extracted from the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter observational cohort study to which 198 ICUs from 24 European countries contributed. All adult patients admitted to a participating ICU between 1 and 15 May 2002, except those admitted for uncomplicated postoperative surveillance, were eligible for the study. For the purposes of this substudy, patients were divided into two groups according to whether they had ARF. The groups were compared with respect to patient characteristics, fluid balance, and outcome.ResultsOf the 3,147 patients included in the SOAP study, 1,120 (36%) had ARF at some point during their ICU stay. Sixty-day mortality rates were 36% in patients with ARF and 16% in patients without ARF (P < 0.01). Oliguric patients and patients treated with renal replacement therapy (RRT) had higher 60-day mortality rates than patients without oliguria or the need for RRT (41% versus 33% and 52% versus 32%, respectively; P < 0.01). Independent risk factors for 60-day mortality in the patients with ARF were age, Simplified Acute Physiology Score II (SAPS II), heart failure, liver cirrhosis, medical admission, mean fluid balance, and need for mechanical ventilation. Among patients treated with RRT, length of stay and mortality were lower when RRT was started early in the course of the ICU stay.ConclusionIn this large European multicenter study, a positive fluid balance was an important factor associated with increased 60-day mortality. Outcome among patients treated with RRT was better when RRT was started early in the course of the ICU stay.

EARLY- VERSUS LATE-ONSET SHOCK IN EUROPEAN INTENSIVE CARE UNITS

We investigated the possible differences in epidemiology, clinical course, management, and outcome between early and late occurrence of shock using data from the Sepsis Occurrence in Acutely Ill Patients Study, a large European multicenter study, which prospectively collected data from all adult intensive care unit (ICU) patients admitted to a participating center within a 2-week period in 2002. Shock was defined as hemodynamic compromise necessitating the administration of vasopressor agents. Early and late shock were defined as onset of shock within the first 2 days in the ICU or later, respectively. Of 3,147 patients, 1,058 (33.6%) had shock at any time, of whom 462 (43.7%) had septic shock. Patients with late shock had a higher incidence of respiratory (87.4 vs. 69.7%, P < 0.001) and hepatic (15.5 vs. 8.7%, P < 0.05) failure, and more often received dopamine (44.7% vs. 34.5%, P < 0.05) and albumin (31.1% vs. 20.3%, P < 0.001) than patients who developed shock early. Intensive care unit and hospital mortality rates were greater in patients who developed shock late, rather than early (52.4% vs. 36.8% and 55.3% vs. 43%, respectively, P < 0.02). In a multivariable analysis, late shock was associated with an independent risk of higher ICU mortality in shock patients (odds ratio, 2.6; 95% confidence interval, 1.6-4.3, P < 0.001). These observations have important implications in establishing individual prognosis as well as in the design and interpretation of clinical trials.

HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study

HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study

Hepatitis C and Risk of Lymphoma: Results of the European Multicenter Case-Control Study EPILYMPH

Increasing evidence points toward a role of hepatitis C virus (HCV) infection in the etiology of malignant lymphomas. However, previous epidemiologic studies were limited in size to establish an association between HCV infection and specific lymphoma subtypes. We performed a large, multicenter, case-control study to address this question. The study comprised 5 European countries and included newly diagnosed cases of any lymphoid malignancy recruited between 1998 and 2004. Controls were matched to cases by 5-year age group, sex, and study center. In-person interviews were conducted to collect data on demographic, medical, and family history as well as environmental exposures. Serum samples of 1807 cases and 1788 controls (excluding human immunodeficiency virus-positive and organ-transplantation subjects) were screened for HCV infection using an enzyme immunoassay. Positive as well as randomly selected negative samples were subjected to HCV RNA detection and HCV genotyping. HCV infection was detected in 53 (2.9%) lymphoma cases and in 41 (2.3%) control subjects (odds ratio [OR], 1.42; 95% confidence interval [CI]: 0.93-2.15). Restricted to individuals who tested positive for HCV-RNA (indicating persistent infection and active viral replication), the OR was 1.82 (95% CI: 1.13-2.91). In subtype-specific analyses, HCV prevalence was associated with diffuse large B-cell lymphoma (OR, 2.19; 95% CI: 1.23-3.91) but not with chronic lymphocytic leukemia or follicular, Hodgkin's, or T-cell lymphoma. The sample size was not sufficient to derive any conclusions for rare lymphoma entities such as splenic marginal zone lymphoma. These results support a model that chronic HCV replication contributes to lymphomagenesis and establish a specific role of HCV infection in the pathogenesis of diffuse large B-cell lymphoma.

P.1.05 HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter genetic association study

P.1.05 HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter genetic association study

Vasopressin in shock states

There is growing evidence that in end-stage shock or during cardiac arrest, inappropriately low endogenous vasopressin plasma levels may be responsible for pathologic vasodilatation, inadequate organ perfusion, and poor outcome. The purpose of this article is to review recent publications featuring arginine vasopressin as a potent vasoconstrictor in various shock states such as systemic vasodilatation, severe hypovolemia, or cardiac arrest. Several retrospective investigations give evidence that vasopressin at a dosage of 2-6 U/h is effective in reversing catecholamine-resistant vasodilatory shock due to sepsis or after cardiopulmonary bypass, but prospective randomized controlled trials are warranted. In experimental hypovolemic cardiac arrest or therapy-resistant (irreversible) hypovolemic shock, vasopressin may be an intriguing therapy, although human evidence is not available. Animal data gives strong evidence that vasopressin given during cardiopulmonary resuscitation improves both return of spontaneous circulation and neurological outcome. Clinical experience on the use of vasopressin for in-hospital cardiopulmonary resuscitation with short response time showed equipotency with epinephrine; in patients with out-of-hospital ventricular fibrillation, vasopressin showed improved 24 h survival in comparison with epinephrine. After the large European multicenter study completed in summer 2002, we will hopefully be able to better determine the role of vasopressin versus epinephrine in the management of adult cardiac arrest. Vasopressin administration is emerging as a rational and promising therapy in the management of various shock states and cardiac arrest.

Effective Compliance during the First 3 Months of Continuous Positive Airway Pressure

Effective compliance (time spent at the effective pressure) with nasal CPAP in obstructive sleep apnea has been reported to be poor. The aim of our study was to evaluate effective compliance in a large European multicenter study. One hundred twenty-one consecutive newly treated patients (initial apnea-hypopnea index [AHI] = 62.0 +/- 29. 5/h, AHI under CPAP = 6.4 +/- 8.1/h, CPAP pressure = 8.7 +/- 2.6 cm H(2)O, BMI = 33.1 +/- 6.8 kg/m(2)) were randomly allocated to a group with (MC(+)) (n = 58) or without (MC(-)) (n = 63) a control unit measuring effective compliance at 1, 2, and 3 mo, which was compared with the built-in time counter data. MC(+) data were 94 +/- 10, 98 +/- 5, and 96 +/- 9% of counter data at 1, 2, and 3 mo, respectively. Using criteria of regular use already reported in the literature (at least 4 h of nCPAP per day of use and nCPAP administered more than 70% of the days) we found 77, 82, and 79% compliant patients at 1, 2, and 3 mo, respectively, 79% of the patients meeting these criteria each month. Although there were no pulmonary functions or polysomnographic differences between the two subgroups, the compliant patients did report a greater improvement in minor symptoms. We found a close correlation between effective use of CPAP and the machine run time. The main result of our study was a higher effective compliance than previously reported, approximately 80% of the patients being regular users versus 46% in a previously published study. This may result from different technical and medical follow-up.

Structure of the standardized computerized 24-h diet recall interview used as reference method in the 22 centers participating in the EPIC project

A computerized 24-h diet recall interview program (EPIC-SOFT) was developed for use in a large European multi-center study, namely the European Prospective Investigation into Cancer and Nutrition (EPIC). This program, which was adapted for each participating country and translated into nine languages, was developed to standardize interviews between the 22 EPIC centers. Common rules were pre-entered into the system to describe, quantify and probe approximately 1500-2200 foods and 150-350 recipes. Common methods used to classify and export the EPIC-SOFT dietary data facilitate their exchange, comparison and analysis. So far, EPIC-SOFT is the only available computerized 24-h diet recall system developed to provide comparable food consumption data between several European countries.