Publications by authors named "Alexia Cusini"

31 Publications

Cohort profile: SARS-CoV-2/COVID-19 hospitalised patients in Switzerland.

Authors:
Amaury Thiabaud Anne Iten Carlo Balmelli Laurence Senn Nicolas Troillet Andreas Widmer Domenica Flury Peter W Schreiber Miriam Vázquez Lauro Damonti Michael Buettcher Danielle Vuichard-Gysin Christoph Kuhm Alexia Cusini Thomas Riedel Yvonne Nussbaumer-Ochsner Roman Gaudenz Ulrich Heininger Christoph Berger Franziska Zucol Sara Bernhard-Stirnemann Natascia Corti Petra Zimmermann Anita Uka Anita Niederer-Loher Céline Gardiol Maroussia Roelens Olivia Keiser

Swiss Med Wkly 2021 02 15;151:w20475. Epub 2021 Feb 15.

Institut de Santé Globale, Faculté de Médecine de l'Université de Genève, Geneva, Switzerland.

Background: SARS-CoV-2/COVID-19, which emerged in China in late 2019, rapidly spread across the world with several million victims in 213 countries. Switzerland was severely hit by the virus, with 43,000 confirmed cases as of 1 September 2020.

Aim: In cooperation with the Federal Office of Public Health, we set up a surveillance database in February 2020 to monitor hospitalised patients with COVID-19, in addition to their mandatory reporting system.

Methods: Patients hospitalised for more than 24 hours with a positive polymerase chain-reaction test, from 20 Swiss hospitals, are included. Data were collected in a customised case report form based on World Health Organisation recommendations and adapted to local needs. Nosocomial infections were defined as infections for which the onset of symptoms was more than 5 days after the patient’s admission date.

Results: As of 1 September 2020, 3645 patients were included. Most patients were male (2168, 59.5%), and aged between 50 and 89 years (2778, 76.2%), with a median age of 68 (interquartile range 54–79). Community infections dominated with 3249 (89.0%) reports. Comorbidities were frequently reported, with hypertension (1481, 61.7%), cardiovascular diseases (948, 39.5%) and diabetes (660, 27.5%) being the most frequent in adults; respiratory diseases and asthma (4, 21.1%), haematological and oncological diseases (3, 15.8%) were the most frequent in children. Complications occurred in 2679 (73.4%) episodes, mostly respiratory diseases (2470, 93.2% in adults; 16, 55.2% in children), and renal (681, 25.7%) and cardiac (631, 23.8%) complications for adults. The second and third most frequent complications in children affected the digestive system and the liver (7, 24.1%). A targeted treatment was given in 1299 (35.6%) episodes, mostly with hydroxychloroquine (989, 76.1%). Intensive care units stays were reported in 578 (15.8%) episodes. A total of 527 (14.5%) deaths were registered, all among adults.

Conclusion: The surveillance system has been successfully initiated and provides a robust set of data for Switzerland by including about 80% (compared with official statistics) of SARS-CoV-2/COVID-19 hospitalised patients, with similar age and comorbidity distributions. It adds detailed information on the epidemiology, risk factors and clinical course of these cases and, therefore, is a valuable addition to the existing mandatory reporting.
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http://dx.doi.org/10.4414/smw.2021.20475DOI Listing
February 2021

Characteristics of Three Different Chemiluminescence Assays for Testing for SARS-CoV-2 Antibodies.

Authors:
Myriam C Weber Martin Risch Sarah L Thiel Kirsten Grossmann Susanne Nigg Nadia Wohlwend Thomas Lung Dorothea Hillmann Michael Ritzler Francesca Ferrara Susanna Bigler Konrad Egli Thomas Bodmer Mauro Imperiali Yacir Salimi Felix Fleisch Alexia Cusini Sonja Heer Harald Renz Matthias Paprotny Philipp Kohler Pietro Vernazza Lorenz Risch Christian R Kahlert

Dis Markers 2021 6;2021:8810196. Epub 2021 Jan 6.

Department of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, Rohrschacherstrasse 95, 9007 St. Gallen, Switzerland.

Several tests based on chemiluminescence immunoassay techniques have become available to test for SARS-CoV-2 antibodies. There is currently insufficient data on serology assay performance beyond 35 days after symptoms onset. We aimed to evaluate SARS-CoV-2 antibody tests on three widely used platforms. A chemiluminescent microparticle immunoassay (CMIA; Abbott Diagnostics, USA), a luminescence immunoassay (LIA; Diasorin, Italy), and an electrochemiluminescence immunoassay (ECLIA; Roche Diagnostics, Switzerland) were investigated. In a multigroup study, sensitivity was assessed in a group of participants with confirmed SARS-CoV-2 ( = 145), whereas specificity was determined in two groups of participants without evidence of COVID-19 (i.e., healthy blood donors, = 191, and healthcare workers, = 1002). Receiver operating characteristic (ROC) curves, multilevel likelihood ratios (LR), and positive (PPV) and negative (NPV) predictive values were characterized. Finally, analytical specificity was characterized in samples with evidence of the Epstein-Barr virus (EBV) ( = 9), cytomegalovirus (CMV) ( = 7), and endemic common-cold coronavirus infections ( = 12) taken prior to the current SARS-CoV-2 pandemic. The diagnostic accuracy was comparable in all three assays (AUC 0.98). Using the manufacturers' cut-offs, the sensitivities were 90%, 95% confidence interval [84,94] (LIA), 93% [88,96] (CMIA), and 96% [91,98] (ECLIA). The specificities were 99.5% [98.9,99.8] (CMIA), 99.7% [99.3,99.9] (LIA), and 99.9% [99.5,99.98] (ECLIA). The LR at half of the manufacturers' cut-offs were 60 (CMIA), 82 (LIA), and 575 (ECLIA) for positive and 0.043 (CMIA) and 0.035 (LIA, ECLIA) for negative results. ECLIA had higher PPV at low pretest probabilities than CMIA and LIA. No interference with EBV or CMV infection was observed, whereas endemic coronavirus in some cases provided signals in LIA and/or CMIA. Although the diagnostic accuracy of the three investigated assays is comparable, their performance in low-prevalence settings is different. Introducing gray zones at half of the manufacturers' cut-offs is suggested, especially for orthogonal testing approaches that use a second assay for confirmation.
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http://dx.doi.org/10.1155/2021/8810196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834819PMC
February 2021

Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.

Authors:
Katarzyna Szajek Marie-Elisabeth Kajdi Valerie A Luyckx Thomas Hans Fehr Ariana Gaspert Alexia Cusini Karin Hohloch Philipp Grosse

BMC Nephrol 2021 01 8;22(1):19. Epub 2021 Jan 8.

Department of Internal Medicine, Division of Nephrology, Cantonal Hospital Graubuenden, Chur, Switzerland.

Background: Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive.

Case Presentation: The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis.

Conclusions: Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.
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http://dx.doi.org/10.1186/s12882-020-02213-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792557PMC
January 2021

Temporal Course of SARS-CoV-2 Antibody Positivity in Patients with COVID-19 following the First Clinical Presentation.

Authors:
Martin Risch Myriam Weber Sarah Thiel Kirsten Grossmann Nadia Wohlwend Thomas Lung Dorothea Hillmann Michael Ritzler Francesca Ferrara Susanna Bigler Konrad Egli Thomas Bodmer Mauro Imperiali Yacir Salimi Felix Fleisch Alexia Cusini Harald Renz Philipp Kohler Pietro Vernazza Christian R Kahlert Matthias Paprotny Lorenz Risch

Biomed Res Int 2020 16;2020:9878453. Epub 2020 Nov 16.

Labormedizinisches Zentrum Dr. Risch, Wuhrstrasse 14, 9490 Vaduz, Liechtenstein.

Knowledge of the sensitivities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests beyond 35 days after the clinical onset of COVID-19 is insufficient. We aimed to describe positivity rate of SARS-CoV-2 assays employing three different measurement principles over a prolonged period. Two hundred sixty-eight samples from 180 symptomatic patients with COVID-19 and a reverse transcription polymerase chain reaction (RT-PCR) test followed by serological investigation of SARS-CoV-2 antibodies were included. We conducted three chemiluminescence (including electrochemiluminescence assay (ECLIA)), four enzyme-linked immunosorbent assay (ELISA), and one lateral flow immunoassay (LFIA) test formats. Positivity rates, as well as positive (PPVs) and negative predictive values (NPVs), were calculated for each week after the first clinical presentation for COVID-19. Furthermore, combinations of tests were assessed within an orthogonal testing approach employing two independent assays and predictive values were calculated. Heat maps were constructed to graphically illustrate operational test characteristics. During a follow-up period of more than 9 weeks, chemiluminescence assays and one ELISA IgG test showed stable positivity rates after the third week. With the exception of ECLIA, the PPVs of the other chemiluminescence assays were ≥95% for COVID-19 only after the second week. ELISA and LFIA had somewhat lower PPVs. IgM exhibited insufficient predictive characteristics. An orthogonal testing approach provided PPVs ≥ 95% for patients with a moderate pretest probability (e.g., symptomatic patients), even for tests with a low single test performance. After the second week, NPVs of all but IgM assays were ≥95% for patients with low to moderate pretest probability. The confirmation of negative results using an orthogonal algorithm with another assay provided lower NPVs than the single assays. When interpreting results from SARS-CoV-2 tests, the pretest probability, time of blood draw, and assay characteristics must be carefully considered. An orthogonal testing approach increases the accuracy of positive, but not negative, predictions.
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http://dx.doi.org/10.1155/2020/9878453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673235PMC
December 2020

Flattening the curve in 52 days: characterisation of the COVID-19 pandemic in the Principality of Liechtenstein - an observational study.

Authors:
Sarah Lucia Thiel Myriam Carol Weber Lorenz Risch Nadia Wohlwend Thomas Lung Dorothea Hillmann Michael Ritzler Martin Risch Philipp Kohler Pietro Vernazza Christian R Kahlert Felix Fleisch Alexia Cusini Tomas V Karajan Sandra Copeland Matthias Paprotny

Swiss Med Wkly 2020 10 16;150:w20361. Epub 2020 Oct 16.

Department of General Internal Medicine, Landesspital Liechtenstein, Vaduz, Liechtenstein.

Background: The principality of Liechtenstein had its first COVID-19 case at the beginning of March 2020. After exponential growth, the pandemic’s first wave was contained, with the last case being diagnosed 52 days after the initial occurrence.

Aim: To characterise the COVID-19 pandemic in Liechtenstein.

Methods: All patients diagnosed in Liechtenstein were followed up until recovery and again 6–8 weeks after symptom onset. They were contacted every 2 days to record their clinical status until the resolution of their symptoms. The diagnosis of COVID-19 was based on clinical symptoms and molecular testing. Household and close workplace contacts were included in the follow-up, which also comprised antibody testing. In addition, public health measures installed during the pandemic in Liechtenstein are summarised.

Results: During the first wave, 5% of the population obtained a reverse transcriptase polymerase chain reaction test. A total of 95 patients (median age 39 years) were diagnosed with COVID-19 (82 who resided in Liechtenstein), resulting in an incidence in Liechtenstein of 0.211%. One patient, aged 94, died (mortality rate 1%). Only 62% of patients could retrospectively identify a potential source of infection. Testing the patients’ household and close workplace contacts (n = 170) with antibody tests revealed that 25% of those tested were additional COVID-19 cases, a quarter of whom were asymptomatic. Those households which adhered to strict isolation measures had a significantly lower rate of affected household members than those who didn’t follow such measures. The national public health measures never restricted free movement of residents. Masks were only mandatory in healthcare settings. The use of home working for the general workforce was promoted. Gatherings were prohibited. Schools, universities, certain public spaces (like sports facilities and playgrounds), childcare facilities, nonessential shops, restaurants and bars were closed. Social distancing, hygienic measures, solidarity and supporting individuals who were at risk were the main pillars of the public health campaigns.

Conclusion: The close collaboration of all relevant stakeholders allowed for the complete workup of all COVID-19 patients nationwide. A multitude of factors (e.g., young age of the patients, low-threshold access to testing, close monitoring of cases, high alertness and adherence to public health measures by the population) led to the early containment of the first wave of the pandemic, with a very low rate of serious outcomes. Antibody testing for SARS-CoV-2 revealed a substantial proportion of undiagnosed COVID-19 cases among close contacts of the patients.
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http://dx.doi.org/10.4414/smw.2020.20361DOI Listing
October 2020

Burden and Timeline of Infectious Diseases in the First Year After Solid Organ Transplantation in the Swiss Transplant Cohort Study.

Authors:
Christian van Delden Susanne Stampf Hans H Hirsch Oriol Manuel Pascal Meylan Alexia Cusini Cédric Hirzel Nina Khanna Maja Weisser Christian Garzoni Katja Boggian Christoph Berger David Nadal Michael Koller Ramon Saccilotto Nicolas J Mueller

Clin Infect Dis 2020 Oct;71(7):e159-e169

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zürich, Switzerland.

Background: The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis.

Methods: In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant-infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up.

Results: Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients.

Conclusions: In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.
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http://dx.doi.org/10.1093/cid/ciz1113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583409PMC
October 2020

Cross-Sectional and Cumulative Longitudinal Central Nervous System Penetration Effectiveness Scores Are Not Associated With Neurocognitive Impairment in a Well Treated Aging Human Immunodeficiency Virus-Positive Population in Switzerland.

Authors:
Galia M A Santos Isabella Locatelli Mélanie Métral Alexandra Calmy Thanh Doco Lecompte Isaure Nadin Christoph Hauser Alexia Cusini Barbara Hasse Helen Kovari Philip Tarr Marcel Stoeckle Christoph Fux Caroline Di Benedetto Patrick Schmid Katharine E A Darling Renaud Du Pasquier Matthias Cavassini

Open Forum Infect Dis 2019 Jul 8;6(7):ofz277. Epub 2019 Jul 8.

Infectious Diseases Service, Lausanne University Hospital, Switzerland.

Background: Neurocognitive impairment (NCI) in people with human immunodeficiency virus (PWH) remains a concern despite potent antiretroviral therapy (ART). Higher central nervous system (CNS) penetration effectiveness (CPE) scores have been associated with better CNS human immunodeficiency virus (HIV) replication control, but the association between CPE and NCI remains controversial.

Methods: The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is a subgroup of the Swiss HIV Cohort Study (SHCS) that invited patients aged ≥45 years enrolled in the SHCS and followed-up at NAMACO-affiliated centers in Switzerland to participate between May 2013 and November 2016. In total, 981 patients were enrolled, all of whom underwent standardized neurocognitive assessment. Neurocognitive impairment, if present, was characterized using Frascati criteria. The CPE scores of NAMACO study participants with undetectable plasma HIV-ribonucleic acid at enrollment (909 patients) were analyzed. Cross-sectional CPE scores (at neurocognitive assessment) were examined as potential predictors of NCI in multivariate logistic regression models. The analysis was then repeated taking CPE as a cumulative score (summarizing CPE scores from ART initiation to the time of neurocognitive assessment).

Results: Most patients were male (80%) and Caucasian (92%). Neurocognitive impairment was present in 40%: 27% with HIV-associated NCI (mostly asymptomatic neurocognitive impairment), and 13% with NCI related to other factors. None of the CPE scores, neither cross-sectional nor cumulative, was statistically significantly associated with NCI.

Conclusions: In this large cohort of aviremic PWH, we observed no association between NCI, whether HIV-associated or related to other factors, and CPE score, whether cross-sectional or cumulative.
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http://dx.doi.org/10.1093/ofid/ofz277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612860PMC
July 2019

Pneumocystis jirovecii pneumonia in solid organ transplant recipients: a descriptive analysis for the Swiss Transplant Cohort.

Authors:
Dionysios Neofytos Cedric Hirzel Elsa Boely Thanh Lecompte Nina Khanna Nicolas J Mueller Katia Boggian Alexia Cusini Oriol Manuel Christian van Delden

Transpl Infect Dis 2018 Dec 19;20(6):e12984. Epub 2018 Sep 19.

Transplant Infectious Diseases Unit, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.

Background: Descriptive data on Pneumocystis jirovecii pneumonia (PJP) in solid organ transplant recipients (SOTr) in the era of routine Pneumocystis-prophylaxis are lacking.

Methods: All adult SOTr between 2008 and 2016 were included. PJP was diagnosed based on consensus guidelines. Early-onset PJP was defined as PJP within the first-year-post-transplant.

Results: 41/2842 SOTr (1.4%) developed PJP (incidence rate: 0.01/1000 person-days) at a mean of 493-days post-transplant: 21 (51.2%) early vs 20 (48.8%) late-onset PJP. 2465 (86.7%) SOTr received Pneumocystis-prophylaxis for a mean 316 days. PJP incidence was 0.001% and 0.003% (log-rank < 0.001) in SOTr with and without Pneumocystis-prophylaxis, respectively. PJP was an early event in 10/12 (83.3%) SOTr who did not receive Pneumocystis-prophylaxis and developed PJP, compared to those patients who received prophylaxis (11/29, 37.9%; P-value: 0.008). Among late-onset PJP patients, most cases (13/20, 65%) were observed during the 2nd year post-transplant. Age ≥65 years (OR: 2.4, P-value: 0.03) and CMV infection during the first 6 months post-SOT (OR: 2.5, P-value: 0.006) were significant PJP predictors, while Pneumocystis-prophylaxis was protective for PJP (OR: 0.3, P-value: 0.006) in the overall population. Most patients (35, 85.4%) were treated with trimethoprim-sulfamethoxazole for a mean 20.6 days. 1-year mortality was 14.6%.

Conclusions: In the Pneumocystis-prophylaxis-era, PJP remains a rare post-transplant complication. Most cases occurred post-PJP-prophylaxis-discontinuation, particularly during the second-year-post-transplant. Additional research may help identify indications for Pneumocystis-prophylaxis prolongation.
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http://dx.doi.org/10.1111/tid.12984DOI Listing
December 2018

Intra-hospital differences in antibiotic use correlate with antimicrobial resistance rate in and : a retrospective observational study.

Authors:
Alexia Cusini David Herren Lukas Bütikofer Catherine Plüss-Suard Andreas Kronenberg Jonas Marschall

Antimicrob Resist Infect Control 2018 28;7:89. Epub 2018 Jul 28.

1Department of Infectious Diseases and Hospital Epidemiology, Bern University Hospital and University of Bern, Bern, Switzerland.

Background: Monitoring antimicrobial use and resistance in hospitals are important tools of antimicrobial stewardship programs. We aimed to determine the association between the use of frequently prescribed antibiotics and the corresponding resistance rates in and among the clinical departments of a tertiary care hospital.

Methods: We performed a retrospective observational study to analyse the use of nine frequently prescribed antibiotics and the corresponding antimicrobial resistance rates in hospital acquired and isolates from 18 departments of our institution over 9 years (2008-2016). The main cross-sectional analysis assessed the hypothetical influence of antibiotic consumption on resistance by mixed logistic regression models.

Results: We found an association between antibiotic use and resistance rates in for amoxicillin-clavulanic acid (OR per each step of 5 defined daily dose/100 bed-days 1.07, 95% CI 1.02-1.12;  = 0.004), piperacillin-tazobactam (OR 2.11, 95% CI 1.45-3.07;  < 0.001), quinolones (OR 1.52, 95% CI 1.25-1.86;  < 0.001) and trimethoprim-sulfamethoxazole (OR 1.59, 95% CI 1.19-2.13;  = 0.002). Additionally, we found a significant association when all nine antibiotics were combined in one analysis. The association between consumption and resistance rates was stronger for nosocomial than for community strains. In we found an association for amoxicillin-clavulanic acid (OR 1.07, 95% CI 1.01-1.14;  = 0.025) and for trimethoprim-sulfamethoxazole (OR 2.02, 95% CI 1.44-2.84;  < 0.001). The combined analysis did not show an association between consumption and resistance (OR 1.06, 95% CI 0.99-1.14;  = 0.07).

Conclusions: We documented an association between antibiotic use and resistance rate for amoxicillin-clavulanic acid, piperacillin-tazobactam, quinolones and trimethoprim-sulfamethoxazole in and for amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole in across different hospital departments. Our data will support stewardship interventions to optimize antibiotic prescribing at a department level.
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http://dx.doi.org/10.1186/s13756-018-0387-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064170PMC
September 2019

LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions.

Authors:
Kang Yu Chelsea L Davidson Agnieszka Wójtowicz Luiz Lisboa Ting Wang Adriana M Airo Jean Villard Jeremie Buratto Tatyana Sandalova Adnane Achour Atul Humar Katia Boggian Alexia Cusini Christian van Delden Adrian Egli Oriol Manuel Nicolas Mueller Pierre-Yves Bochud Deborah N Burshtyn

J Clin Invest 2018 04 12;128(4):1523-1537. Epub 2018 Mar 12.

Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance.
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http://dx.doi.org/10.1172/JCI96174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873860PMC
April 2018

Clinical Course, Radiological Manifestations, and Outcome of Pneumocystis jirovecii Pneumonia in HIV Patients and Renal Transplant Recipients.

Authors:
Lukas Ebner Laura N Walti Andri Rauch Hansjakob Furrer Alexia Cusini Andreas M J Meyer Stefan Weiler Uyen Huynh-Do Johannes Heverhagen Spyridon Arampatzis Andreas Christe

PLoS One 2016 8;11(11):e0164320. Epub 2016 Nov 8.

Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Pneumocystis jirovecii pneumonia (PCP) is a frequent opportunistic infection in immunocompromised patients. In literature, presentation and outcome of PCP differs between patients with human immunodeficiency virus (HIV) infection and renal transplant recipients (RTRs).

Methods: We conducted a cross-sectional study of patients with PCP based on the HIV and renal transplant registries at our institution. Radiological and clinical data from all confirmed PCP cases between 2005 and 2012 were compared.

Results: Forty patients were included: 16 with HIV and 24 RTRs. Radiologically, HIV patients had significantly more areas of diffuse lung affection (81% HIV vs. 25% RTR; p = 0.02), more ground glass nodules 5-10 mm (69% vs. 4%; p = <0.001) and enlarged hilar lymph nodes were found only in HIV patients (44%). Cough and dyspnea were the most common clinical signs (>80%) in both groups. Duration from illness onset to hospital presentation was longer in the HIV patients (median of 18 vs. 10 days (p = 0.02)), implying a less fulminant clinical course. Sixty percent of PCP cases in RTRs occurred >12 months after transplantation. Lengths of hospitalization, admission rates to the intensive care unit, and requirements for mechanical ventilation were similar. Outcome in both groups was favourable.

Conclusions: While important differences in radiological presentation of PCP between HIV patients and RTRs were found, clinical presentation was similar. PCP only rarely presented with fulminant respiratory symptoms requiring ICU admission, with similar results and outcomes for HIV patients and RTRs. Early diagnosis and treatment is mandatory for clinical success.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100884PMC
June 2017

Ventricular assist devices as bridge to heart transplantation: impact on post-transplant infections.

Authors:
Delphine Héquet Georg Kralidis Thierry Carrel Alexia Cusini Christian Garzoni Roger Hullin Pascal R Meylan Paul Mohacsi Nicolas J Mueller Frank Ruschitzka Piergiorgio Tozzi Christian van Delden Maja Weisser Markus J Wilhelm Manuel Pascual Oriol Manuel

BMC Infect Dis 2016 07 8;16:321. Epub 2016 Jul 8.

Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.

Background: Ventricular assist devices (VAD) are valuable options for patients with heart failure awaiting cardiac transplantation. We assessed the impact of pre-transplant VAD implantation on the incidence of post-transplant infections in a nationwide cohort of heart transplant recipients.

Methods: Heart transplant recipients included in the Swiss Transplant Cohort Study between May 2008 and December 2012 were analyzed. Cumulative incidence curves were used to calculate the incidence of bacterial or Candida infections (primary endpoint) and of other infections (secondary endpoint) after transplant. Cox regression models treating death as a competing risk were used to identify risk factors for the development of infection after transplant.

Results: Overall, 119 patients were included in the study, 35 with a VAD and 84 without VAD. Cumulative incidences of post-transplant bacterial or Candida infections were 37.7 % in VAD patients and 40.4 % in non-VAD patients. In multivariate analysis, the use of cotrimoxazole prophylaxis was the only variable associated with bacterial/Candida infections after transplant (HR 0.29 [95 % CI 0.15-0.57], p < 0.001), but presence of a VAD was not (HR 0.94, [95 % CI 0.38-2.32], p = 0.89, for continuous-flow devices, and HR 0.45 [0.15 - 1.34], p = 0.15, for other devices). Risk for post-transplant viral and all fungal infections was not increased in patients with VAD. One-year survival was 82.9 % (29/35) in the VAD group and 82.1 % (69/84) in the non-VAD group. All 6 patients in the VAD group that died after transplant had a history of pre-transplant VAD infection.

Conclusion: In this nationwide cohort of heart transplant recipients, the presence of VAD at the time of transplant had no influence on the development of post-transplant infections.
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http://dx.doi.org/10.1186/s12879-016-1658-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938972PMC
July 2016

Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus.

Authors:
Laurent Parmentier Alexia Cusini Norbert Müller Haroun Zangger Mary-Anne Hartley Chantal Desponds Patrik Castiglioni Patrick Dubach Catherine Ronet Stephen M Beverley Nicolas Fasel

Am J Trop Med Hyg 2016 Apr 1;94(4):840-843. Epub 2016 Feb 1.

Leishmania parasites cause a broad range of disease, with cutaneous afflictions being, by far, the most prevalent. Variations in disease severity and symptomatic spectrum are mostly associated to parasite species. One risk factor for the severity and emergence of leishmaniasis is immunosuppression, usually arising by coinfection of the patient with human immunodeficiency virus (HIV). Interestingly, several species of Leishmania have been shown to bear an endogenous cytoplasmic dsRNA virus (LRV) of the Totiviridae family, and recently we correlated the presence of LRV1 within Leishmania parasites to an exacerbation murine leishmaniasis and with an elevated frequency of drug treatment failures in humans. This raises the possibility of further exacerbation of leishmaniasis in the presence of both viruses, and here we report a case of cutaneous leishmaniasis caused by Leishmania braziliensis bearing LRV1 with aggressive pathogenesis in an HIV patient. LRV1 was isolated and partially sequenced from skin and nasal lesions. Genetic identity of both sequences reinforced the assumption that nasal parasites originate from primary skin lesions. Surprisingly, combined antiretroviral therapy did not impact the devolution of Leishmania infection. The Leishmania infection was successfully treated through administration of liposomal amphotericin B.
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http://dx.doi.org/10.4269/ajtmh.15-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824227PMC
April 2016

Reply to Cunha et al.

Authors:
Agnieszka Wójtowicz Thanh Doco Lecompte Stéphanie Bibert Oriol Manuel Sina Rüeger Christoph Berger Katia Boggian Alexia Cusini Christian Garzoni Nina Khanna Nicolas J Mueller Pascal R Meylan Manuel Pascual Christian van Delden Pierre-Yves Bochud

Clin Infect Dis 2015 Dec 10;61(12):1894-5. Epub 2015 Aug 10.

Infectious Diseases Service, University Hospital and University of Lausanne.

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http://dx.doi.org/10.1093/cid/civ681DOI Listing
December 2015

Improved hand hygiene compliance after eliminating mandatory glove use from contact precautions-Is less more?

Authors:
Alexia Cusini Doris Nydegger Tanja Kaspar Alexander Schweiger Rolf Kuhn Jonas Marschall

Am J Infect Control 2015 09 27;43(9):922-7. Epub 2015 Jun 27.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital of Bern, Bern, Switzerland.

Background: Guidelines recommend that health care personnel (HCP) wear gloves for all interactions with patients on contact precautions. We aimed to assess hand hygiene (HH) compliance during contact precautions before and after eliminating mandatory glove use.

Methods: We assessed HH compliance of HCP in the care of patients on contact precautions in 50 series before (2009) and 6 months after (2012) eliminating mandatory glove use and compared these results with the hospital-wide HH compliance.

Results: We assessed 426 HH indications before and 492 indications after the policy change. Compared with 2009, we observed a significantly higher HH compliance in patients on contact precautions in 2012 (52%; 95% confidence interval [95% CI], 47-57) vs 85%; 95% CI, 82-88; P < .001). During the same period, hospital-wide HH compliance also increased from 63% (95% CI, 61-65) to 81% (95% CI 80-83) (P < .001). However, the relative improvement (RI) of HH compliance during contact precautions was significantly higher than the hospital-wide relative improvement (RI, 1.6; 95% CI, 1.49-1.81 vs 1.29; 95% CI, 1.25-1.34), with a relative improvement ratio of 1.27 (95% CI, 1.15-1.41).

Conclusion: Eliminating mandatory glove use in the care of patients on contact precautions increased HH compliance in our institution, particularly before invasive procedures and before patient contacts. Further studies on the effect on pathogen transmission are needed before revisiting the current official guidelines on the topic.
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http://dx.doi.org/10.1016/j.ajic.2015.05.019DOI Listing
September 2015

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant.

Authors:
Agnieszka Wójtowicz T Doco Lecompte Stephanie Bibert Oriol Manuel Sina Rüeger Christoph Berger Katia Boggian Alexia Cusini Christian Garzoni Hans Hirsch Nina Khanna Nicolas J Mueller Pascal R Meylan Manuel Pascual Christian van Delden Pierre-Yves Bochud

Clin Infect Dis 2015 Aug 14;61(4):619-22. Epub 2015 May 14.

Infectious Diseases Service, University Hospital and University of Lausanne.

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratification.
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http://dx.doi.org/10.1093/cid/civ386DOI Listing
August 2015

Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study.

Authors:
Jim Young Yongling Xiao Erica E M Moodie Michal Abrahamowicz Marina B Klein Enos Bernasconi Patrick Schmid Alexandra Calmy Matthias Cavassini Alexia Cusini Rainer Weber Heiner C Bucher

J Acquir Immune Defic Syndr 2015 Aug;69(4):413-21

*Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland; †Analysis Group Inc, Montreal, QC, Canada; ‡Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada; §Department of Medicine, Royal Victoria Hospital, McGill University Health Centre, Montreal, QC, Canada; ‖Division of Infectious Diseases, Regional Hospital of Lugano, Lugano, Switzerland; ¶Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; #Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland; **Division of Infectious Diseases, University Hospital Lausanne, Lausanne, Switzerland; ††Department of Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland; ‡‡Division of Infectious Diseases and Hospital Epidemiology, University Hospital and University of Zürich, Zürich, Switzerland; and §§Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.

Background: Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates.

Methods: We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD.

Results: A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk.

Conclusions: Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.
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http://dx.doi.org/10.1097/QAI.0000000000000662DOI Listing
August 2015

The swiss transplant cohort study: lessons from the first 6 years.

Authors:
Christoph Berger Pierre-Yves Bochud Katja Boggian Alexia Cusini Adrian Egli Christian Garzoni Hans H Hirsch Matthias Hoffmann Nina Khanna Oriol Manuel Pascal Meylan David Nadal Christian van Delden Maja Weisser Nicolas J Mueller

Curr Infect Dis Rep 2015 Jun;17(6):486

Division of Infectious Diseases and Hospital Epidemiology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland.

Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.
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http://dx.doi.org/10.1007/s11908-015-0486-5DOI Listing
June 2015

Increased mortality after a first myocardial infarction in human immunodeficiency virus-infected patients; a nested cohort study.

Authors:
David Carballo Cécile Delhumeau Sebastian Carballo Caroline Bähler Dragona Radovanovic Bernard Hirschel Olivier Clerc Enos Bernasconi Dominique Fasel Patrick Schmid Alexia Cusini Jan Fehr Paul Erne Pierre-Fréderic Keller Bruno Ledergerber Alexandra Calmy

AIDS Res Ther 2015 22;12. Epub 2015 Feb 22.

HIV Metabolic Clinic, University Hospital, Geneva, Switzerland.

Aims: HIV infection may be associated with an increased recurrence rate of myocardial infarction. Our aim was to determine whether HIV infection is a risk factor for worse outcomes in patients with coronaray artery disease.

Methods: We compared data aggregated from two ongoing cohorts: (i) the Acute Myocardial Infarction in Switzerland (AMIS) registry, which includes patients with acute myocardial infarction (AMI), and (ii) the Swiss HIV Cohort Study (SHCS), a prospective registry of HIV-positive (HIV+) patients. We included all patients who survived an incident AMI occurring on or after 1st January 2005. Our primary outcome measure was all-cause mortality at one year; secondary outcomes included AMI recurrence and cardiovascular-related hospitalisations. Comparisons used Cox and logistic regression analyses, respectively.

Results: There were 133 HIV+, (SHCS) and 5,328 HIV-negative [HIV-] (AMIS) individuals with incident AMI. In the SHCS and AMIS registries, patients were predominantly male (72% and 85% male, respectively), with a median age of 51 years (interquartile range [IQR] 46-57) and 64 years (IQR 55-74), respectively. Nearly all (90%) of HIV+ individuals were on successful antiretroviral therapy. During the first year of follow-up, 5 (3.6%) HIV+ and 135 (2.5%) HIV- individuals died. At one year, HIV+ status after adjustment for age, sex, calendar year of AMI, smoking status, hypertension and diabetes was associated with a higher risk of death (HR 4.42, 95% CI 1.73-11.27). There were no significant differences in recurrent AMIs (4 [3.0%] HIV+ and 146 [3.0%] HIV- individuals, OR 1.16, 95% CI 0.41-3.27) or in hospitalization rates (OR 0.68 [95% CI 0.42-1.11]).

Conclusions: HIV infection was associated with a significantly increased risk of all-cause mortality one year after incident AMI.
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http://dx.doi.org/10.1186/s12981-015-0045-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336509PMC
February 2015

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.

Authors:
Agnieszka Wójtowicz Mark S Gresnigt Thanh Lecompte Stephanie Bibert Oriol Manuel Leo A B Joosten Sina Rüeger Christoph Berger Katia Boggian Alexia Cusini Christian Garzoni Hans H Hirsch Maja Weisser Nicolas J Mueller Pascal R Meylan Jürg Steiger Zoltan Kutalik Manuel Pascual Christian van Delden Frank L van de Veerdonk Pierre-Yves Bochud

J Infect Dis 2015 May 14;211(10):1646-57. Epub 2014 Nov 14.

Infectious Diseases Service.

Background: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients.

Methods: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes.

Results: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs.

Conclusions: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.
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http://dx.doi.org/10.1093/infdis/jiu636DOI Listing
May 2015

Viral escape in the CNS with multidrug-resistant HIV-1.

Authors:
Charles Béguelin Miriam Vázquez Manuel Bertschi Sabine Yerly Denise de Jong Andri Rauch Alexia Cusini

J Int AIDS Soc 2014 2;17(4 Suppl 3):19745. Epub 2014 Nov 2.

Department of Infectious Diseases, University Hospital and University of Bern, Bern, Switzerland.

Introduction: HIV-1 viral escape in the cerebrospinal fluid (CSF) despite viral suppression in plasma is rare [1,2]. We describe the case of a 50-year-old HIV-1 infected patient who was diagnosed with HIV-1 in 1995. Antiretroviral therapy (ART) was started in 1998 with a CD4 T cell count of 71 cells/ìL and HIV-viremia of 46,000 copies/mL. ART with zidovudine (AZT), lamivudine (3TC) and efavirenz achieved full viral suppression. After the patient had interrupted ART for two years, treatment was re-introduced with tenofovir (TDF), emtricitabin (FTC) and ritonavir boosted atazanavir (ATVr). This regimen suppressed HIV-1 in plasma for nine years and CD4 cells stabilized around 600 cells/ìL. Since July 2013, the patient complained about severe gait ataxia and decreased concentration.

Materials And Methods: Additionally to a neurological examination, two lumbar punctures, a cerebral MRI and a neuropsycological test were performed. HIV-1 viral load in plasma and in CSF was quantified using Cobas TaqMan HIV-1 version 2.0 (Cobas Ampliprep, Roche diagnostic, Basel, Switzerland) with a detection limit of 20 copies/mL. Drug resistance mutations in HIV-1 reverse transcriptase and protease were evaluated using bulk sequencing.

Results: The CSF in January 2014 showed a pleocytosis with 75 cells/ìL (100% mononuclear) and 1,184 HIV-1 RNA copies/mL, while HIV-1 in plasma was below 20 copies/mL. The resistance testing of the CSF-HIV-1 RNA showed two NRTI resistance-associated mutations (M184V and K65R) and one NNRTI resistance-associated mutation (K103N). The cerebral MRI showed increased signal on T2-weighted images in the subcortical and periventricular white matter, in the basal ganglia and thalamus. Four months after ART intensification with AZT, 3TC, boosted darunavir and raltegravir, the pleocytosis in CSF cell count normalized to 1 cell/ìL and HIV viral load was suppressed. The neurological symptoms improved; however, equilibrium disturbances and impaired memory persisted. The neuro-psychological evaluation confirmed neurocognitive impairments in executive functions, attention, working and nonverbal memory, speed of information processing, visuospatial abilities and motor skills.

Conclusions: HIV-1 infected patients with neurological complaints prompt further investigations of the CSF including measurement of HIV viral load and genotypic resistance testing since isolated replication of HIV with drug resistant variants can rarely occur despite viral suppression in plasma. Optimizing ART by using drugs with improved CNS penetration may achieve viral suppression in CSF with improvement of neurological symptoms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225423PMC
http://dx.doi.org/10.7448/IAS.17.4.19745DOI Listing
January 2016

Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation.

Authors:
Oriol Manuel Agnieszka Wójtowicz Stéphanie Bibert Nicolas J Mueller Christian van Delden Hans H Hirsch Juerg Steiger Martin Stern Adrian Egli Christian Garzoni Isabelle Binet Maja Weisser Christoph Berger Alexia Cusini Pascal Meylan Manuel Pascual Pierre-Yves Bochud

J Infect Dis 2015 Mar 9;211(6):906-14. Epub 2014 Oct 9.

Infectious Diseases Service, Department of Medicine.

Background: Polymorphisms in IFNL3 and IFNL4, the genes encoding interferon λ3 and interferon λ4, respectively, have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid-organ transplant recipients.

Methods: White patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated.

Results: A total of 840 solid-organ transplant recipients at risk for CMV infection were included, among whom 373 (44%) received antiviral prophylaxis. The 12-month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR], 1.30 [95% confidence interval {CI}, .97-1.74]; P = .07), compared with other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR, 1.46 [95% CI, 1.01-2.12]; P = .047), especially in patients receiving an organ from a seropositive donor (SHR, 1.92 [95% CI, 1.30-2.85]; P = .001), but not among those who received antiviral prophylaxis (SHR, 1.13 [95% CI, .70-1.83]; P = .6). These associations remained significant in multivariate competing risk regression models.

Conclusions: Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis.
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http://dx.doi.org/10.1093/infdis/jiu557DOI Listing
March 2015

Cytomegalovirus serology and replication remain associated with solid organ graft rejection and graft loss in the era of prophylactic treatment.

Authors:
Martin Stern Hans Hirsch Alexia Cusini Christian van Delden Oriol Manuel Pascal Meylan Katia Boggian Nicolas J Mueller Michael Dickenmann

Transplantation 2014 Nov;98(9):1013-8

1 Immunotherapy Laboratory, Department of Biomedicine, University Hospital Basel, Switzerland. 2 Infectious Diseases and Hospital Epidemiology, University Hospital, Basel, Switzerland. 3 Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland. 4 Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland. 5 Service of Infectious Diseases, University Hospital, Geneva, Switzerland. 6 Infectious Diseases Service and Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland. 7 Institute of Microbiology and Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland. 8 Division of Infectious Diseases and Hospital Hygiene, Kantonsspital, St. Gallen, Switzerland. 9 Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Switzerland. 10 Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Switzerland. 11 Address correspondence to: Martin Stern, M.D., Immunotherapy Laboratory, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20 4031, Basel, Switzerland.

Background: Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV.

Methods: We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study.

Results: Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants.

Conclusion: Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.
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http://dx.doi.org/10.1097/TP.0000000000000160DOI Listing
November 2014

Response to Calcagno comment on "Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid".

Authors:
Alexia Cusini Bruno Ledergerber Nicolas Widmer Huldrych F Günthard

J Acquir Immune Defic Syndr 2013 Oct;64(2):e14-5

*Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland †Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland ‡Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.

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http://dx.doi.org/10.1097/QAI.0b013e3182a82281DOI Listing
October 2013

Microbial communities in the respiratory tract of patients with interstitial lung disease.

Authors:
Christian Garzoni Silvio D Brugger Weihong Qi Sarah Wasmer Alexia Cusini Philippe Dumont Meri Gorgievski-Hrisoho Kathrin Mühlemann Christophe von Garnier Markus Hilty

Thorax 2013 Dec 14;68(12):1150-6. Epub 2013 Aug 14.

Institute for Infectious Diseases, University of Bern, , Bern, Switzerland.

Background: Molecular methods based on phylogenetic differences in the 16S rRNA gene are able to characterise the microbiota of the respiratory tract in health and disease.

Objectives: Our goals were (1) to characterise bacterial communities in lower and upper airways of patients with interstitial lung disease (ILD) and (2) to compare the results with the microbiota of patients with Pneumocystis pneumonia (PCP) and normal controls.

Methods: We examined the upper and lower respiratory tract of 18 patients with ILD of whom 5, 6, and 7 had idiopathic interstitial pneumonia (IIP), non-IIP and sarcoidosis, respectively. In addition, six immune-compromised patients with PCP and nine healthy subjects were included as controls. Exclusion criteria were recent bacterial/viral respiratory tract infection, HIV-positivity and subjects receiving antibiotic therapy. Bronchoalveolar lavage fluid and oropharyngeal swabs were simultaneously collected, and microbiota was characterised by ultra-deep 16S rRNA gene sequencing.

Results: The microbiota in lower airways of the majority of patients (30; 90%) primarily consisted of Prevotellaceae, Streptococcaceae and Acidaminococcaceae. α and β diversity measurements revealed no significant differences in airway microbiota composition between the five different groups of patients. Comparison of bacterial populations in upper and lower respiratory tract showed significant topographical discontinuities for 7 (23%) individuals.

Conclusions: IIP, non-IIP and sarcoidosis are not associated with disordered airway microbiota and a pathogenic role of commensals in the disease process is therefore unlikely. Nevertheless, molecular analysis of the topographical microbiota continuity along the respiratory tract may provide additional information to assist management of individual patients.
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http://dx.doi.org/10.1136/thoraxjnl-2012-202917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841796PMC
December 2013

Relevance of cohort studies for the study of transplant infectious diseases.

Authors:
Christoph Berger Katia Boggian Alexia Cusini Christian van Delden Christian Garzoni Hans H Hirsch Nina Khanna Michael Koller Oriol Manuel Pascal Meylan David Nadal Maja Weisser Nicolas J Mueller

Curr Opin Organ Transplant 2012 Dec;17(6):581-5

Division of Infectious Diseases and Hospital Epidemiology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland.

Purpose Of Review: The debate on the merits of observational studies as compared with randomized trials is ongoing. We will briefly touch on this subject, and demonstrate the role of cohort studies for the description of infectious disease patterns after transplantation. The potential benefits of cohort studies for the clinical management of patients outside of the expected gain in epidemiological knowledge are reviewed. The newly established Swiss Transplantation Cohort Study and in particular the part focusing on infectious diseases will serve as an illustration.

Recent Findings: A neglected area of research is the indirect value of large, multicenter cohort studies. These benefits can range from a deepened collaboration to the development of common definitions and guidelines. Unfortunately, very few data exist on the role of such indirect effects on improving quality of patient management.

Summary: This review postulates an important role for cohort studies, which should not be viewed as inferior but complementary to established research tools, in particular randomized trials. Randomized trials remain the least bias-prone method to establish knowledge regarding the significance of diagnostic or therapeutic measures. Cohort studies have the power to reflect a real-world situation and to pinpoint areas of knowledge as well as of uncertainty. Prerequisite is a prospective design requiring a set of inclusive data coupled with the meticulous insistence on data retrieval and quality.
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http://dx.doi.org/10.1097/MOT.0b013e328359263aDOI Listing
December 2012

Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy.

Authors:
Renaud A Du Pasquier Samantha Jilek Malela Kalubi Sabine Yerly Christoph A Fux Christine Gutmann Alexia Cusini Huldrych F Günthard Matthias Cavassini Pietro L Vernazza

AIDS 2013 Jan;27(2):203-10

Unit of Neuroimmunology, Division of Neurology and Division of Immunology, Department of Clinical Neurosciences and Department of Medicine, University Hospital of Lausanne, University of Lausanne, Lausanne 1011, Switzerland.

Objective: To determine changes of cerebrospinal fluid (CSF) biomarkers of patients on monotherapy with lopinavir/ritonavir.

Design: The Monotherapy Switzerland/Thailand study (MOST) trial compared monotherapy with ritonavir-boosted lopinavir with continued therapy. The trial was prematurely stopped due to virological failure in six patients on monotherapy. It, thus, offers a unique opportunity to assess brain markers in the early stage of HIV virological escape.

Methods: : Sixty-five CSF samples (34 on continued therapy and 31 on monotherapy) from 49 HIV-positive patients enrolled in MOST. Using enzyme-linked immunosorbent assay, we determined the CSF concentration of S100B (astrocytosis), neopterin (inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-β 1-42 (Aβ), the latter three indicating neuronal damage. Controls were CSF samples of 29 HIV-negative patients with Alzheimer dementia.

Results: In the CSF of monotherapy, concentrations of S100B and neopterin were significantly higher than in continued therapy (P = 0.006 and P = 0.013, respectively) and Alzheimer dementia patients (P < 0.0001 and P = 0.0005, respectively). In Alzheimer dementia, concentration of Aβ was lower than in monotherapy (P = 0.005) and continued therapy (P = 0.016) and concentrations of tTau were higher than in monotherapy (P = 0.019) and continued therapy (P = 0.001). There was no difference in pTau among the three groups. After removal of the 16 CSF with detectable viral load in the blood and/or CSF, only S100B remained significantly higher in monotherapy than in the two other groups.

Conclusion: Despite full viral load-suppression in blood and CSF, antiretroviral monotherapy with lopinavir/ritonavir can raise CSF levels of S100B, suggesting astrocytic damage.
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http://dx.doi.org/10.1097/QAD.0b013e32835a9a4aDOI Listing
January 2013

Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid.

Authors:
Alexia Cusini Pietro L Vernazza Sabine Yerly Laurent A Decosterd Bruno Ledergerber Christoph A Fux Janine Rohrbach Nicolas Widmer Bernhard Hirschel Roman Gaudenz Matthias Cavassini Thomas Klimkait Franziska Zenger Chistine Gutmann Milos Opravil Huldyrich F Günthard

J Acquir Immune Defic Syndr 2013 Jan;62(1):28-35

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objectives: To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression.

Methods: Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods.

Results: The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43-82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0-1.5) versus 2.3 (range, 1.0-3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6-8) versus 8 (range, 5-12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA.

Conclusions: This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.
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http://dx.doi.org/10.1097/QAI.0b013e318274e2b0DOI Listing
January 2013

Different patterns of inappropriate antimicrobial use in surgical and medical units at a tertiary care hospital in Switzerland: a prevalence survey.

Authors:
Alexia Cusini Silvana K Rampini Vineeta Bansal Bruno Ledergerber Stefan P Kuster Christian Ruef Rainer Weber

PLoS One 2010 Nov 16;5(11):e14011. Epub 2010 Nov 16.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.

Background: Unnecessary or inappropriate use of antimicrobials is associated with the emergence of antimicrobial resistance, drug toxicity, increased morbidity and health care costs. Antimicrobial use has been reported to be incorrect or not indicated in 9-64% of inpatients. We studied the quality of antimicrobial therapy and prophylaxis in hospitalized patients at a tertiary care hospital to plan interventions to improve the quality of antimicrobial prescription.

Methodology/principal Findings: Experienced infectious diseases (ID) fellows performed audits of antimicrobial use at regular intervals among all patients--with or without antimicrobials--hospitalized in predefined surgical, medical, haemato-oncological, or intensive care units. Data were collected from medical and nursing patient charts with a standardized questionnaire. Appropriateness of antimicrobial use was evaluated using a modified algorithm developed by Gyssens et al.; the assessment was double-checked by a senior ID specialist. We evaluated 1577 patients of whom 700 (44.4%) had antimicrobials, receiving a total of 1270 prescriptions. 958 (75.4%) prescriptions were for therapy and 312 (24.6%) for prophylaxis. 37.0% of therapeutic and 16.6% of prophylactic prescriptions were found to be inappropriate. Most frequent characteristics of inappropriate treatments included: No indication (17.5%); incorrect choice of antimicrobials (7.6%); incorrect application of drugs (9.3%); and divergence from institutional guidelines (8%). Characteristics of inappropriate prophylaxes were: No indication (9%); incorrect choice of antimicrobials (1%); duration too long or other inappropriate use (6.7%). Patterns of inappropriate antimicrobial varied widely in the different hospital units; empirical prescriptions were more frequently incorrect than prescriptions based on available microbiological results.

Conclusions/significance: Audits of individual patient care provide important data to identify local problems in antimicrobial prescription practice. In our study, antimicrobial prescriptions without indication, and divergence from institutional guidelines were frequent errors. Based on these results, we will tailor education, amend institutional guidelines and further develop the infectious diseases consultation service.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014011PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982822PMC
November 2010

Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir.

Authors:
Christine Gutmann Alexia Cusini Huldrych F Günthard Christoph Fux Bernard Hirschel Laurent-Arthur Decosterd Matthias Cavassini Sabine Yerly Pietro L Vernazza

AIDS 2010 Sep;24(15):2347-54

Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Background: Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown.

Methods: Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml.

Results: The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02).

Conclusion: Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.
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http://dx.doi.org/10.1097/QAD.0b013e32833db9a1DOI Listing
September 2010