Publications by authors named "Maximilian Kittel"

10 Publications

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Specificity testing by point prevalence as a simple assessment strategy using the Roche Elecsys® Anti-SARS-CoV-2 immunoassay.

Int J Infect Dis 2021 Feb 9. Epub 2021 Feb 9.

Department of Clinical Chemistry, University Medicine Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.

Background: The detection of antibodies against the novel coronavirus SARS-CoV-2 is mandatory for the diagnosis, retrospective assessment of disease progression, and correct evaluation of the current infection situation in the population. Many of these assays have been launched by various manufacturers. Unfortunately, the new FDA emergency use regulations have resulted in a situation where laboratories have to perform their own validation studies. Numerous of these labs do not have the biobank needed to carry the studies out.

Methods: In this paper, we introduce a method that allows institutions to quickly perform a verifiation study in a low-prevalence infection situation. As proof of concept, we used the Roche Elecsys Anti-SARS-CoV-2 ECLIA assay and an SAP-based hospital information system. The Shenzhen YHLO Biotech IgM and IgG assay targetting other surface patterns, was used as confirmatory test.

Results: The Roche assay demonstrated a limit of detection of 0.069 COI (cutoff index) and successfully passed the performance validation according to CLSI EP15-A3. The study population of 627 in-patients exhibited an age median of 64 years and approximately 13% of the group were under intensive care at the respective time point. All included patients were tested negative for SARS-CoV-2 infection by qRT-PCR (cobas 6800®, Roche, Mannheim, Germany). Only one false positive result was obtained, resulting in a specificity for the Roche Elecsys Anti-SARS-CoV-2 test of 99.84% and a negative predictive value of 99.98%.

Conclusions: The anonymized use of residual material enables quick evaluation of anti-SARS-CoV-2 immunoassays, as shown in this work with the Roche Elecsys assay. Comparison of the control population with economic data makes it possible to validate the sampling set and therefore to determine diagnostic specificity. Using the chosen approach, it was shown that the Roche test achieved very good results in terms of diagnostic specificity, reproducibility and limit of detection.
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http://dx.doi.org/10.1016/j.ijid.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872847PMC
February 2021

Copeptin reliably reflects longitudinal right ventricular function.

Ann Clin Biochem 2021 Feb 11:4563221989364. Epub 2021 Feb 11.

First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Data is limited evaluating novel biomarkers in right ventricular dysfunction. Normal right heart function improves the prognosis of patients with heart failure. Therefore, this study investigates the association between the novel biomarker copeptin and right heart function compared to NT-proBNP.

Methods: Patients undergoing routine echocardiography were enrolled prospectively. Right ventricular function was assessed by tricuspid annular plane systolic excursion (TAPSE) and further right ventricular and atrial parameters. Exclusion criteria were age under 18 years, left ventricular ejection fraction < 50% and moderate to severe valvular heart disease. Blood samples were taken for biomarker measurements within 72 h of echocardiography.

Results: Ninety-one patients were included. Median values of copeptin increased significantly according to decreasing values of TAPSE ( = 0.001; right heart function grade I: tricuspid annular plane systolic excursion; TAPSE > 24 mm: 5.20 pmol/L; grade II: TAPSE 18-24 mm: 8.10 pmol/L; grade III: TAPSE < 18 mm: 26.50 pmol/L). Copeptin concentrations were able to discriminate patients with decreased right heart function defined as TAPSE < 18 mm (area under the curves [AUC]: copeptin: 0.793;  = 0.001; NT-proBNP: 0.805;  = 0.0001). Within a multivariable linear regression model, copeptin was independently associated with TAPSE (copeptin: T: -4.43;  = 0.0001; NT-proBNP: T: -1.21;  = 0.23). Finally, copeptin concentrations were significantly associated with severely reduced right heart function (TAPSE < 18 mm) within a multivariate logistic regression model (copeptin: odds ratio: 0.94; 95% confidence interval: 0.911-0.975;  = 0.001).

Conclusions: This study demonstrates that the novel biomarker copeptin reflects longitudinal right heart function assessed by standardized transthoracic echocardiography compared with NT-proBNP.
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http://dx.doi.org/10.1177/0004563221989364DOI Listing
February 2021

Clinical evaluation of commercial automated SARS-CoV-2 immunoassays.

Int J Infect Dis 2021 Feb 9;103:590-596. Epub 2020 Dec 9.

MVZ Laboratory Dr. Limbach & Colleagues, Heidelberg, Germany.

Objective: Numerous immunoassays for detecting antibodies directed against SARS-CoV-2 have been rapidly developed and released. Validations of these have been performed with a limited number of samples. The lack of standardisation might lead to significantly different results. This study compared ten automated assays from six vendors in terms of sensitivity, specificity and reproducibility.

Methods: This study compared ten fully automated immunoassays from the following vendors: Diasorin, Epitope Diagnostics, Euroimmun, Roche, YHLO, and Snibe. The retrospective part of the study included patients with a laboratory-confirmed COVID-19 infection, and controls comprised patients with a suspected infection, in whom the disease was excluded. Furthermore, biobanked sera were taken as negative controls (n = 97). The retrospective part involved four groups: (1) laboratory-confirmed COVID-19 infection (n = 183); (1B) suspected COVID-19 infection (n = 167) without a qRT-PCR result but positive serological results from at least two different assays, and suspected COVID-19 infection due to a positive serological result from the Roche assay (n = 295); (2) biobanked sera obtained from patients before the emergence of SARS-CoV-2 (n = 97) as negative controls; and (2A) probably COVID-19-negative sera with negative serological results from at least two different assays (n = 152).

Results: Overall diagnostic sensitivities were: Euroimmun (IgA) 87%; Epitope Diagnostics (IgG) 83%; YHLO (IgG) 77%; Roche (IgM/IgG) 77%; Euroimmun (IgG) 75%; Diasorin (IgG) 53%; Epitope Diagnostics (IgM) 52%; Snibe (IgG) 47%; YHLO (IgM) 35%; and Snibe (IgM) 26%. Diagnostic specificities were: YHLO (IgG) 100%; Roche, 100%; Snibe (IgM/IgG) 100%; Diasorin (IgG) 97%; Euroimmun (IgG) 94%; YHLO (IgM) 94%; Euroimmun (IgA) 83%.

Conclusion: Assays from different vendors substantially varied in terms of their performance. These findings might facilitate selection of appropriate serological assays.
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http://dx.doi.org/10.1016/j.ijid.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725057PMC
February 2021

Deep Learning Frameworks for Rapid Gram Stain Image Data Interpretation: Protocol for a Retrospective Data Analysis.

JMIR Res Protoc 2020 Jul 13;9(7):e16843. Epub 2020 Jul 13.

Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: In recent years, remarkable progress has been made in deep learning technology and successful use cases have been introduced in the medical domain. However, not many studies have considered high-performance computing to fully appreciate the capability of deep learning technology.

Objective: This paper aims to design a solution to accelerate an automated Gram stain image interpretation by means of a deep learning framework without additional hardware resources.

Methods: We will apply and evaluate 3 methodologies, namely fine-tuning, an integer arithmetic-only framework, and hyperparameter tuning.

Results: The choice of pretrained models and the ideal setting for layer tuning and hyperparameter tuning will be determined. These results will provide an empirical yet reproducible guideline for those who consider a rapid deep learning solution for Gram stain image interpretation. The results are planned to be announced in the first quarter of 2021.

Conclusions: Making a balanced decision between modeling performance and computational performance is the key for a successful deep learning solution. Otherwise, highly accurate but slow deep learning solutions can add value to routine care.

International Registered Report Identifier (irrid): DERR1-10.2196/16843.
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http://dx.doi.org/10.2196/16843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385633PMC
July 2020

Comparison of test performance of commercial anti-SARS-CoV-2 immunoassays in serum and plasma samples.

Clin Chim Acta 2020 Nov 9;510:73-78. Epub 2020 Jul 9.

Department of Clinical Chemistry, University Medicine Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.

Background: For epidemiologic, social and economic reasons, assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prevalence and immunity are important to adapt decisions to current demands. Hence, immunoassays for detection of anti-SARS-CoV-2 antibodies are introduced rapidly without requiring FDA emergency use authorization approval. Thus, evaluation of test performance predominantly relies on laboratories. This study aimed to evaluate the test performance of recently launched commercial immunoassays in serum and plasma samples.

Methods: 51 serum samples from 26 patients with confirmed SARS-CoV-2 infection after end of quarantine and 25 control patients were analyzed using anti-SARS-CoV-2 IgG immunoassays from Roche, Euroimmun and Epitope to assess diagnostic sensitivity and specificity. 20 matching pairs of serum and plasma samples were included to analyze comparability between different specimens.

Results: Overall, a diagnostic sensitivity of 92.3%, 96.2-100% and 100% with a respective diagnostic specificity of 100%, 100% and 84-86% for the immunoassays from Roche, Euroimmun and Epitope were determined. In total, 84-96% of samples were correctly classified as negative and 92.3-95.2% as positive. The level of concordance between plasma- and serum-based testing diverged between the assays (Epitope r = 0.97; Euroimmun r = 0.91; Roche r = 0.76).

Conclusions: The immunoassays from Euroimmun and Roche revealed a higher specificity than the Epitope assay without a substantial drop of diagnostic sensitivity. Significant differences between plasma- and serum-based testing highlights the need for determination of appropriate cut-offs per specimen type. Hence, there is an urgent need for test harmonization and establishment of quality standards for an appropriate use of COVID-19 serological tests.
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http://dx.doi.org/10.1016/j.cca.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343640PMC
November 2020

Hypokalemia but not Hyperkalemia is Associated with Recurrences of Ventricular Tachyarrhythmias in ICD Recipients.

Clin Lab 2020 Mar;66(3)

Background: Only few data evaluating the prognostic impact of blood-derived potassium levels (K) on arrhythmic endpoints in patients with implantable cardioverter-defibrillators (ICD) is available. Therefore, this study evaluates the prognostic impact of potassium levels on recurrences of ventricular tachyarrhythmias in consecutive ICD recipients.

Methods: A large retrospective registry was used including all consecutive patients presenting with ventricular tachyarrhythmias on admission from 2002 to 2016 at one institution. Patients were divided into three subgroups: hypokalemia (i.e., K < 3.3 mmol/L), normokalemia (i.e., K 3.3 - 4.5 mmol/L), and hyperkalemia (i.e., K > 4.5 mmol/L). Kaplan-Meier and Cox regression analyses were applied for the evaluation of the primary endpoint of first recurrences of ventricular tachyarrhythmias at one year. Secondary endpoints comprised of first appropriate ICD therapy, first cardiac rehospitalization, and all-cause mortality at one year.

Results: Five hundred and thirty ICD recipients with a median potassium level of 4.23 mmol/L were included (67%: normokalemia, 27%: hyperkalemia, and 6%: hypokalemia). Whereas hyperkalemia was not associated with increasing risk of recurrent ventricular tachyarrhythmias, hypokalemia was associated with decreasing freedom from recurrent ventricular tachyarrhythmias (HR = 2.135; 95% CI 1.158 - 3.937; p = 0.015), even after mul-tivariable adjustment (HR = 2.577; 95% CI 1.236 - 5.372; p = 0.012). Higher risk of recurrences was especially attributed to higher rates of electrical storm in the presence of hypokalemia (15% vs. 3 - 4%). Negative impact of hypokalemia was mainly attributed to secondary preventive ICD (HR = 2.637; 95% CI 1.325 - 5.248; p = 0.006). Moreover, hypokalemia was associated with increasing risk of appropriate ICD therapies (HR = 1.920; 95% CI 0.912 - 4.042; statistical trend: p = 0.086), which was still demonstrated after multivariable adjustment. In contrast, risk of first cardiac rehospitalization and all-cause mortality were not affected by potassium levels.

Conclusions: In consecutive ICD recipients with ventricular tachyarrhythmias at index, hypokalemia - but not hyperkalemia - was associated with increasing risk of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190645DOI Listing
March 2020

Interaction between the heart and the brain in transient global amnesia.

J Neurol 2019 Dec 10;266(12):3048-3057. Epub 2019 Sep 10.

Department of Neurology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135, Mannheim, Germany.

Background: To analyse whether patients with transient global amnesia (TGA) have concomitant cardiac injury by assessing clinical symptoms, as well as blood and cardiologic test results.

Methods: In this retrospective observational study, we analysed 202 consecutive patients presenting with isolated TGA and treated at our institution between March 2010 and December 2018. We examined the incidence of high-sensitivity cardiac troponin I (hs-cTNI) level elevation, electrocardiogram (ECG) findings, and data on clinical management.

Results: Among the TGA patients, 17 (8.4%) exhibited elevated levels of hs-cTNI. Although none of the patients had ST elevation, 12 (6.7%) showed QTc prolongation and 11 (6.1%) an inverted T wave on ECG. No typical clinical symptoms suggestive of myocardial infarction were present in any of the cases, however, 17 (8.4%) patients complained of mild somatic symptoms. Patients with hs-cTNI level elevation had a significantly greater likelihood of a history of coronary heart disease (p = 0.03) and a significantly shorter TGA duration at presentation (p < 0.01). Of the 17 patients with hs-cTNI elevation, Takotsubo syndrome was diagnosed in 2, while in the remaining 15 hs-cTNI level elevation remained unresolved. A literature review indicated the female predominance for the occurrence of cardiac involvement in TGA.

Conclusions: Although the in-hospital outcomes appear favourable in all cases reported thus far, we believe that all patients with TGA should be carefully evaluated for potential underlying cardiac involvement and comorbidity. Further research on cardiac vulnerability in TGA should attempt to develop a diagnostic algorithm and assess the potential causes of cardiac injury in TGA.
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http://dx.doi.org/10.1007/s00415-019-09529-0DOI Listing
December 2019

Rapid susceptibility testing of multi-drug resistant Escherichia coli and Klebsiella by glucose metabolization monitoring.

Clin Chem Lab Med 2019 07;57(8):1271-1279

Institute for Clinical Chemistry, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany, Phone: +49 - 621 383 2222, Fax: +49 - 621 383 3819.

Background The increasing number of multi-drug resistant (MDR) bacteria provides enormous challenges for choosing an appropriate antibiotic therapy in the early phase of sepsis. While bacterial identification has been greatly accelerated by the introduction of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), the antibiotic susceptibility testing (AST) remains time-consuming. Here, we present a rapid susceptibility testing method for testing Gram-negative bacteria, exemplarily validated for Escherichia coli and Klebsiella spp. Methods Gram-negative isolates (E. coli and Klebsiella spp.) were either taken as single colonies from agar plates (n=136) or directly extracted and identified from positive blood cultures (n=42) using MALDI-TOF MS. Bacteria were incubated in glucose-supplemented Luria broths (LBs) each containing one antibiotic (ceftazidime, piperacillin, imipenem and ciprofloxacin), routinely used to classify Gram-negative bacteria in Germany. To determine susceptibility the dynamics of glucose utilization in bacterial suspensions were quantitatively measured in the presence or absence of antibiotics designated liquid-AST (L-AST). Results The L-AST can be run on clinical-chemistry analyzers and integrated into laboratory routines. It yields critical resistance information within 90-150 min downstream of a MS-based identification. The results showed a high concordance with routine susceptibility testing, with less than 1% very major errors (VME) and 3.51% major errors (ME) for 178 assessed isolates. Analysis of turnaround time (TAT) for 42 clinical samples indicated that L-AST results could be obtained 34 h earlier than the routine results. Conclusions As exemplified for E. coli and Klebsiella spp., L-AST provides substantial acceleration of susceptibility testing following MALDI-TOF MS identification. The assay is a simple and low-cost method that can be integrated into clinical laboratory to allow for 24/7 AST. This approach could improve antibiotic therapy.
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http://dx.doi.org/10.1515/cclm-2018-1178DOI Listing
July 2019

High Sensitivity Troponin I and T Reflect the Presence of Obstructive and Multi-Vessel Coronary Artery Disease Being Assessed by Coronary Computed Tomography Angiography.

Curr Pharm Biotechnol 2017 ;18(6):508-515

First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.

Background: This study evaluates the association between high sensitivity troponin I (hsTnI) and T (hsTnT) in patients with suspected stable Coronary Artery Disease (CAD) undergoing Coronary Computed Tomography Angiography (CCTA).

Methods: Patients undergoing CCTA were enrolled prospectively. CCTA was indicated in patients with angina and a low to intermediate pre-test probability for CAD during routine clinical care. Blood samples were taken at the time of CCTA to measure cardiac biomarkers.

Results: A total of 99 patients were enrolled with 43 % revealing no CAD, 30 % with non-obstructive and 26 % with obstructive CAD. Out of these, 61 % had single-vessel and 39 % had multi-vessel CAD. Both hsTnI and hsTnT levels increased significantly according to the presence and extent of CAD (p = 0.0001) and were able to discriminate the presence of both obstructive (AUC range: 0.775 - 0.785; p = 0.0001) and multi-vessel CAD (AUC range: 0.740 - 0.749; p = 0.01). In multivariate logistic regression models adjusted for cardiovascular risk factors and NT-proBNP, both hsTn were still associated significantly with obstructive CAD (range of odds ratios (OR): 8.3-32.3; p < 0.02).

Discussion: This study shows that high sensitivity troponin I and T reflect the presence and extent of CAD being diagnosed by CCTA in patients with a low to intermediate pretest probability for CAD.
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http://dx.doi.org/10.2174/1389201018666170601082145DOI Listing
January 2018