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Bone and joint infection (BJI) epidemiology and outcomes in solid organ transplant recipients (SOTr) remain largely unknown. We aim to describe BJI in a multi-center cohort of SOTr (Swiss Transplant Cohort Study). All consecutive SOTr with BJI (01.05.2008-31.12.2019) were included. A nested case-control study to identify risk factors for BJI was performed. Among 4482 patients, 61 SOTr with 82 BJI were included, at an incidence of 1.4% (95% CI 1.1-1.7), higher in heart and kidney-pancreas SOTr (Gray's test p .01). Although BJI were predominately late events (median of 18.5 months post-SOT), most infections occurred during the first year post-transplant in thoracic SOTr. Diabetic foot osteomyelitis was the most frequent infection (38/82, 46.3%), followed by non-vertebral osteomyelitis (26/82, 31.7%). Pathogens included Gram-positive cocci (70/131, 53.4%), Gram-negative bacilli (34/131, 26.0%), and fungi (9/131, 6.9%). BJI predictors included male gender (OR 2.94, 95% CI 1.26-6.89) and diabetes (OR 2.97, 95% CI 1.34-6.56). Treatment failure was observed in 25.9% (21/81) patients and 1-year mortality post-BJI diagnosis was 14.8% (9/61). BJI remain a rare event in SOTr, associated with subtle clinical presentations, high morbidity and relapses, requiring additional studies in the future.

There is a paucity of data on posaconazole (PCZ) dosing and therapeutic-drug-monitoring (TDM) in allogeneic hematopoietic cell transplant recipients (allogeneic-HCTr). This was a 3-year retrospective multicenter study (January 1, 2016 to December 31, 2018) in adult allogeneic-HCTr who received PCZ (intravenously, IV and/or as delayed-release tablet, DRT) as prophylaxis or treatment for ≥7 consecutive days (D) with at least 1-PCZ-level available using data of the Swiss Transplant Cohort Study. The primary objective was to describe the distribution of PCZ-level and identify predictors of therapeutic PCZ-level and associations between PCZ-dosing and PCZ-level. A total of 288 patients were included: 194 (67.4%) and 94 (32.6%) received PCZ as prophylaxis and treatment, respectively, for a median of 90 days (interquartile range, IQR: 42–188.5). There were 1944 PCZ-level measurements performed, with a median PCZ level of 1.3 mg/L (IQR: 0.8-1.96). PCZ-level was

Outbreaks of viral infections, such as measles, are regularly observed and pose a serious threat to recipients of allogeneic hematopoietic cell transplantation (HCT). The questions of how long cellular and humoral protective host immunity persists, and whether donor immunity can be transferred has not been clarified. Here we present a retrospective analysis of humoral immunity—serial antibody titers against measles, mumps, and rubella—in 331 patients who underwent allogeneic HCT at our single center between 2002 and 2015. Associations between the loss of protective antibody levels and clinical patient characteristics and transplantation parameters were examined. In general, antibody protection against measles persisted longer, with 72% of patients maintaining sufficient titers at 5 years post-HCT even without revaccination, while at that time only 65% and 50% of patients had protective immunity against rubella and mumps, respectively. The great majority of donors were seropositive for all 3 viruses; however, it appeared that donor humoral immunity could not be transferred and had no impact on post-HCT serostatus. Rather, the most relevant factor for persistent protective antibody titers against measles and rubella was whether patients were born before the introduction of the respective vaccine and thus were immunized by the wild-type disease-inducing virus instead of the vaccine. Moreover, the presence of moderate and severe chronic graft-versus-host disease (GVHD) was associated with more rapid loss of immune protection. In contrast, underlying disease, intensity of the conditioning regimen, use of antithymocyte globulin, age, and graft source had no influence on antibody titers. Overall, our findings suggest that the majority of antibodies against measles, mumps, and rubella originate from residual host cells, whereas donor immune status appears to have no influence on antibody protection post-HCT.

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., Data on burden and timeline of infections following solid organ transplantation are currently lacking. This Swiss nationwide cohort study found a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.

OBJECTIVES To describe the epidemiology and clinical presentation of central nervous system (CNS) infections in solid organ transplant (SOT) recipients in the current era of transplantation. METHODS Patients from the Swiss Transplant Cohort Study (STCS) transplanted between 2008 and 2018 were included with a median follow-up of 3.8 years. Epidemiological, microbiological, and clinical data were extracted from the STCS database and patients' medical records. We calculated incidence rates and 90-day survival of transplant recipients with CNS infection. RESULTS Among 4762 patients, 42 episodes of CNS infection in 41 (0.8%) SOT recipients were identified, with an overall incidence rate of 2.06 per 1000 patient-years. Incidence of CNS infections was similar across all types of transplantations. Time to CNS infection onset ranged from 0.6 to 97 months after transplant. There were 22/42 (52.4%) cases of viral infections, 11/42 (26.2%) of fungal infections, 5/42 (11.9%) of bacterial infections and 4/42 (9.5%) of probable viral/bacterial etiology. Clinical presentation was meningitis/encephalitis in 25 cases (59.5%) and brain-space occupying lesions in 17 cases (40.5%). Twenty-three cases (60.5%) were considered opportunistic infections. Diagnosis were achieved mainly by brain biopsy/necropsy (15/42, 36%) or by cerebrospinal fluid analysis (20/42, 48%). Up to 40% of cases (17/42) had concurrent extra-neurological disease localizations. Overall, 90-day mortality rate was 29.0% (73.0% for fungal, 14.0% for viral and 11.0% for bacterial and probable infections, p

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/μl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.

Background BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna are the most commonly used vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Head-to-head comparison of the efficacy of these vaccines in immunocompromised patients is lacking. Methods Parallel, 2-arm (allocation 1:1), open-label, noninferiority randomized clinical trial nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. People living with human immunodeficiency virus (PLWH) or solid organ transplant recipients (SOTR; ie, lung and kidney) from these cohorts were randomized to mRNA-1273 or BNT162b2. The primary endpoint was antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain (Elecsys Anti-SARS-CoV-2 immunoassay, Roche; cutoff ≥0.8 units/mL) 12 weeks after first vaccination (ie, 8 weeks after second vaccination). In addition, antibody response was measured with the Antibody Coronavirus Assay 2 (ABCORA 2). Results A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 PLWH and 71 SOTR). The percentage of patients showing an immune response was 92.1% (95% confidence interval [CI]: 88.4–95.8; 186/202) for mRNA-1273 and 94.3% (95% CI: 91.2–97.4; 198/210) for BNT162b2 (difference: -2.2%; 95% CI: -7.1 to 2.7), fulfilling noninferiority of mRNA-1273. With the ABCORA 2 test, 89.1% had an immune response to mRNA-1273 (95% CI: 84.8–93.4; 180/202) and 89.5% to BNT162b2 (95% CI: 85.4–93.7; 188/210). Based on the Elecsys test, all PLWH had an antibody response (100.0%; 341/341), whereas for SOTR, only 60.6% (95% CI: 49.2–71.9; 43/71) had titers above the cutoff level. Conclusions In immunocompromised patients, the antibody response of mRNA-1273 was noninferior to BNT162b2. PLWH had in general an antibody response, whereas a high proportion of SOTR had no antibody response.

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.

Food-safety measures are recommended to solid organ transplant (SOT) recipients. However, the burden of foodborne infections in SOT recipients has not been established. We describe the epidemiology and outcomes of bacterial foodborne infections in a nationwide cohort including 4405 SOT recipients in Switzerland between 2008 and 2018. Participants were prospectively followed for a median of 4.2 years with systematic collection of data on infections, and patient and graft-related outcomes. We identified 151 episodes of microbiologically confirmed bacterial foodborne infections occurring in median 1.6 years (IQR 0.58-3.40) after transplantation (131 [88%] Campylobacter spp. and 15 [10%] non-typhoidal Salmonella). The cumulative incidence of bacterial foodborne infections was 4% (95% CI 3.4-4.8). Standardized incidence rates were 7.4 (95% CI 6.2-8.7) and 4.6 (95% CI 2.6-7.5) for Campylobacter and Salmonella infections, respectively. Invasive infection was more common with Salmonella (33.3% [5/15]) compared to Campylobacter (3.2% [4/125]; p = .001). Hospital and ICU admission rates were 47.7% (69/145) and 4.1% (6/145), respectively. A composite endpoint of acute rejection, graft loss, or death occurred within 30 days in 3.3% (5/151) of cases. In conclusion, in our cohort bacterial foodborne infections were late post-transplant infections and were associated with significant morbidity, supporting the need for implementation of food-safety recommendations.

INTRODUCTION The use of normothermic liver machine perfusion to repair injured grafts ex situ is an emerging topic of clinical importance. However, a major concern is the possibility of microbial contamination in the absence of a fully functional immune system. Here, we report a standardized approach to maintain sterility during normothermic liver machine perfusion of porcine livers for one week. METHODS Porcine livers (n = 42) were procured and perfused with blood at 34°C following aseptic technique and standard operating procedures. The antimicrobial prophylaxis was adapted and improved in a step-wise manner taking into account the pathogens that were detected during the development phase. Piperacillin-Tazobactam was applied as a single dose initially and modified to continuous application in the final protocol. In addition, the perfusion machine was improved to recapitulate partially the host's defense system. The final protocol was tested for infection prevention during one week of perfusion. RESULTS During the development phase, microbial contamination occurred in 27 out of 39 (69%) livers with a mean occurrence of growth on 4 ± 1.6 perfusion days. The recovered microorganisms suggested an exogenous source of microbial contamination. The antimicrobial agents (piperacillin/tazobactam) could be maintained above the targeted minimal inhibitory concentration (8-16 mg/L) only with continuous application. In addition to continuous application of piperacillin/tazobactam, partial recapitulation of the host immune system ex situ accompanied by strict preventive measures for contact and air contamination maintained sterility during one week of perfusion. CONCLUSION The work demonstrates feasibility of sterility maintenance for one week during ex situ normothermic liver perfusion.

BACKGROUND Little is known regarding the optimal management of nocardiosis among solid organ transplant (SOT) recipients. It is often suggested to avoid trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy in heavily immunocompromised patients (such as SOT recipients) and/or in case of severe or disseminated nocardiosis. Our aim was to report our experience with TMP-SMX monotherapy in SOT recipients with nocardiosis. METHODS Using data from a previously published European study, we assessed the incidence of adverse events in SOT recipients receiving TMP-SMX monotherapy and assessed its effectiveness. RESULTS Thirty-one SOT recipients with nocardiosis were included, mostly kidney transplant recipients (20/31, 65%). Eleven (36%) had disseminated infection, and four (13%) had brain nocardiosis. Most patients had lung and/or pleural involvement (26/31, 84%). Daily dose of trimethoprim at initiation was 10 [6.4-14.8]��mg/kg. The median estimated glomerular filtration rate at time of diagnosis of nocardiosis was 44 [30-62] ml/min/1.73��m��. TMP-SMX was discontinued prematurely in one third of the patients (10/31, 32%, mostly for hematological toxicity [n��=��3] or increased serum creatinine [n��=��3]). Focusing on the 24 (77%) patients who completed at least 30��days of TMP-SMX monotherapy, 4 had late (>30��days) drug discontinuation, 1 experienced treatment failure, and 19 completed planned TMP-SMX monotherapy. Clinical outcome was favorable in these 19 patients, despite the fact that 8 (42%) had disseminated infection and 2 (11%) brain nocardiosis. Overall, all-cause 1-year mortality was 10% (3/31). CONCLUSIONS TMP-SMX monotherapy appears to be effective for the treatment of most nocardiosis among SOT recipients. Interventional studies are needed to compare its safety and effectiveness with those of other regimens used to treat posttransplant nocardiosis.

Solid organ transplant (SOT) recipients are exposed to respiratory viral infection (RVI) during seasonal epidemics; however, the associated burden of disease has not been fully characterized. We describe the epidemiology and outcomes of RVI in a cohort enrolling 3294 consecutive patients undergoing SOT from May 2008 to December 2015 in Switzerland. Patient and allograft outcomes, and RVI diagnosed during routine clinical practice were prospectively collected. Median follow-up was 3.4 years (interquartile range 1.61-5.56). Six hundred ninety-six RVIs were diagnosed in 151/334 (45%) lung and 265/2960 (9%) non-lung transplant recipients. Cumulative incidence was 60% (95% confidence interval [CI] 53%-69%) in lung and 12% (95% CI 11%-14%) in non-lung transplant recipients. RVI led to 17.9 (95% CI 15.7-20.5) hospital admissions per 1000 patient-years. Intensive care unit admission was required in 4% (27/691) of cases. Thirty-day all-cause case fatality rate was 0.9% (6/696). Using proportional hazard models we found that RVI (adjusted hazard ratio [aHR] 2.45; 95% CI 1.62-3.73), lower respiratory tract RVI (aHR 3.45; 95% CI 2.15-5.52), and influenza (aHR 3.57; 95% CI 1.75-7.26) were associated with graft failure or death. In this cohort of SOT recipients, RVI caused important morbidity and may affect long-term outcomes, underlying the need for improved preventive strategies.

Objectives: During the COVID-19 pandemic, few scientific congresses have been held on-site. We prospectively evaluated the safety concept of the congress of the Swiss Societies of Infectious Diseases and Hospital Hygiene.Methods: The congress was held in Geneva (Switzerland) while local COVID-19 incidence (with SARS-CoV-2 wild type circulating) was 65/100,000 population (September 2020). A rigorous safety concept was implemented. Congress attendees filled out a questionnaire to assess risk perception, exposures, symptoms and diagnoses of SARS-CoV-2 before, during and after the congress. Dried blood spots were taken on-site and 4 weeks later to detect SARS-CoV-2 seroconversions.Results: Of 365 congress attendees, 196 (54%) either answered the questionnaire (N = 150) or provided baseline and follow-up blood samples (N = 168). None of the participants reported a positive PCR in the 2 weeks after the congress. Five of 168 (3%) participants were seropositive at follow-up, all of which had already been positive at baseline.Conclusion: Findings indicate that congresses with a rigorous safety concept may take place, even in areas with moderately-high COVID-19 activity. Whether this holds true in vaccinated populations and with more transmissible viral variants circulating remains unclear.

Background Worldwide, scientific congresses are cancelled because of the COVID-19 pandemic. Yet, scientific exchange is more important than ever, especially for infectious diseases and infection prevention specialists. Within a prospective cohort of congress attendees, we evaluated the safety concept of the 2020 congress of the Swiss Societies of Infectious Diseases and Hospital Hygiene. Methods The congress was held between September 2nd and 4th 2020 in Geneva (Switzerland), where COVID-19 incidence in the week during the congress was 65 cases /100 000 population within 7 days. A rigorous safety concept was implemented including universal face masking, physical distancing during sessions, and maximal reduction of social events. We invited congress attendees to participate in this prospective cohort and used an anonymized online questionnaire to assess risk perception, risk exposures, symptoms and diagnosis of SARS-CoV-2 of attendees before, during and after the congress. Dried blood spots were taken from attendees on-site and four weeks later to detect specific antibodies against SARS-CoV-2 and to document seroconversions. Results A total of 365 people attended the congress, thereof 271 healthcare professionals. Of these, 196 (54%) either answered the questionnaire (N = 150) or provided baseline and follow-up blood samples (N = 168). None of the study participants reported a positive PCR result in the 2 weeks after the congress. Five of 168 (3%) participants were seropositive at follow-up, all of which had already been positive at baseline. The safety concept was deemed appropriate by 92% of the study participants and hygiene measures were performed correctly by the vast majority. Conclusion In this prospective cohort of congress attendees, no PCR positive cases or seroconversions could be documented after attending an on-site medical congress. These findings indicate that congresses with a rigorous safety concept may take place, even in areas with moderately-high COVID-19 activity.

Primary varicella zoster virus [VZV] infection results in varicella [chickenpox] and its reactivation results in herpes zoster [HZ; shingles]. Patients with inflammatory bowel disease [IBD] are susceptible to complications of primary VZV infection and have an increased risk of HZ. Concerns of VZV and HZ infection in the IBD population have been highlighted by the emergence of JAK inhibitors and their safety profile in this patient population, as with tofacitinib for the treatment of ulcerative colitis [UC]. The current pipeline of emerging therapies includes novel molecules targeting multiple pathways, including JAK/signal transducer and cytokine signalling pathways, such as JAK/STAT. Hence VZV and HZ will be increasingly relevant for gastroenterologists treating IBD patients in light of these emerging therapies. This review will focus on the epidemiology, disease course, prevention, and management of these two distinct infections in patients with IBD.

Background Before kidney transplantation, donors and recipients are routinely screened for viral pathogens using specific tests. Little is known about unrecognized viruses of the urinary tract that potentially result in transmission. Using an open metagenomic approach, we aimed to comprehensively assess virus transmission in living-donor kidney transplantation. Methods Living kidney donors and their corresponding recipients were enrolled at the time of transplantation. Follow-up study visits for recipients were scheduled 4–6 weeks and 1 year thereafter. At each visit, plasma and urine samples were collected and transplant recipients were evaluated for signs of infection or other transplant-related complications. For metagenomic analysis, samples were enriched for viruses, amplified by anchored random polymerase chain reaction (PCR), and sequenced using high-throughput metagenomic sequencing. Viruses detected by sequencing were confirmed using real-time PCR. Results We analyzed a total of 30 living kidney donor and recipient pairs, with a follow-up of at least 1 year. In addition to viruses commonly detected during routine post-transplant virus monitoring, metagenomic sequencing detected JC polyomavirus (JCPyV) in the urine of 7 donors and their corresponding recipients. Phylogenetic analysis confirmed infection with the donor strain in 6 cases, suggesting transmission from the transplant donor to the recipient, despite recipient seropositivity for JCPyV at the time of transplantation. Conclusions Metagenomic sequencing identified frequent transmission of JCPyV from kidney transplant donors to recipients. Considering the high incidence rate, future studies within larger cohorts are needed to define the relevance of JCPyV infection and the donor’s virome for transplant outcomes., Kidney transplantation is inevitably associated with the transmission of viral and microbial pathogens. Using metagenomic virome sequencing, we revealed JC polyomavirus (JCPyV) transmission in 20% of cases, despite seropositivity. The relevance of JCPyV infection in kidney transplantation demands further attention.

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.

Zusammenfassung. Das Varizella-Zoster-Virus (VZV) ist die zweithäufigste virale Ursache einer Meningoenzephalitis, welche sowohl bei der Primärinfektion als auch bei Reaktivierung als Komplikation auftreten kann. Wir beschreiben eine auffällige Akkumulation von sechs Fällen mit einer Herpes-Zoster-Meningoenzephalitis im Jahr 2014 im Kantonsspital Graubünden, welche wir retrospektiv bezüglich Klinik, Diagnostik, Therapie und Outcome ausgewertet haben. Fünf von sechs Patienten zeigten die typische Monozytose und positive PCR für VZV im Liquor. Das Zoster-Exanthem erschien entweder vor, während oder nach Beginn der neurologischen Symptomatik, oder es fehlte gänzlich. Epidemiologische Vergleiche mit dem Universitätsspital Zürich und dem Kantonsspital St. Gallen zeigten keine vergleichbare Häufung von Fällen. Die Gründe für die erhöhte Inzidenz im Jahr 2014 im Kantonsspital Graubünden sind unklar, sie könnten demografisch beeinflusst sein.

Background: Vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved rapidly. However, pivotal studies have been conducted in healthy volunteers, while recipients of allogeneic hematopoietic cell transplantations (allo-HCT) may have different dynamics and patterns of response to the vaccine and data in this cohort is lacking. Methods: Here, we examined longitudinal antibody (AB) titers to SARS-CoV-2 vaccination with BNT162b (Comirnaty ®) or mRNA-1273 (Moderna Covid-19 Vaccine ®) in allo-HCT recipients who had undergone allo-HCT >3months (m) ago and in healthy controls (hospital employers). Serial AB titers (prior to (T0); 1m after 1 st dose (T1); 1m (T2), 3m (T3), 6m (T4) post 2 nd dose) were measured with an in-house developed multiplex Antibody CORonavirus Assay (ABCORA) that measures SARS-CoV-2 IgG, IgA, and IgM reactivities against RBD (receptor binding domain), S1 (subunit 1 of the spike protein), S2 (subunit 2 of the spike protein) and N (nucleoprotein), thereby allowing to differentiate immunity after vaccination versus immunity after infection. As neutralization activity correlates well with S1 AB binding, the potency of the AB response was defined as the sum of S1 IgG, IgA and IgM reactivities (cumulative S1 (cS1)). Based on computational methods high neutralization potency was predicted above a cS1 threshold of 17. Results: We enrolled 114 allo-HCT patients (median age 57y (range 18y-74y)) between March 9th 2021 and May 31st 2021 at the University Hospital Zurich, Switzerland. Currently, AB responses at T1, T2, and T3 are available for 99, 95 and 89 patients, respectively. Patients were grouped into those (A) 3-6m post-HCT (T1: n=25 at, T2: n=23, T3: n=20); (B) 6-12m post-HCT (T1: n=13, T2: n=13, T3: n=12); and (C) >12m post-HCT (T1: n=61, T2: n=59, T3: n=57). In addition, AB responses are available for healthy controls (median age 35y (range 23y-64y)) (T1: n=75, T2: n=69, T3: n=48). There were 10 patients and 5 healthy subjects with a reported or detected SARS-CoV-2 infection. There was a statistically significant difference of cS1 AB levels between the 4 groups at T1, T2, and T3 (ANOVA p-values (p) 12m post-HCT with generally higher AB levels. Consistent with other reports age >65y was also associated with lower cS1 responses (p=0.03). Conclusion: Allo-HCT recipients early post-transplant, those of older age, and those given IST displayed insufficient AB titers to the vaccine. Such knowledge is of critical importance to transplant recipients and their physicians to guide treatment decisions regarding re-vaccination, and social behavior during this pandemic. Monitoring AB development in all allo-HCT recipients and vulnerable patients with other immunocompromising conditions may be crucial to determine those at increased risk for infection and for the timing of booster vaccines. Figure 1 Figure 1. Disclosures Manz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company; University of Zurich: Patents & Royalties: CD117xCD3 TEA.

BACKGROUND Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals. METHODS We conducted a multicenter retrospective study of heart and lung transplantation in HIV-infected patients and describe key transplant- and HIV-related outcomes. RESULTS We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184–3,745) days for heart and 1,540 (range, 116–3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/µl for HTRs and 638 to 280 cells/µl for LTRs. Acquired immunodeficiency syndrome–related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants . CONCLUSIONS HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols.

Metagenomic next-generation sequencing (mNGS) can capture the full spectrum of viral pathogens in a specimen and has the potential to become an all-in-one solution for virus diagnostics. To date, clinical application is still in an early phase and limitations remain. Here, we evaluated the impact of viral mNGS for cases analyzed over two years in a tertiary diagnostics unit. High throughput mNGS was performed upon request by the treating clinician in cases where the etiology of infection remained unknown or the initial differential diagnosis was very broad. The results were compared to conventional routine testing regarding outcome and workload. In total, 163 specimens from 105 patients were sequenced. The main sample types were cerebrospinal fluid (34%), blood (33%) and throat swabs (10%). In the majority of the cases, viral encephalitis/meningitis or respiratory infection was suspected. In parallel, conventional virus diagnostic tests were performed (mean 18.5 individually probed targets/patients). mNGS detected viruses in 34 cases (32%). While often confirmatory, in multiple cases, the identified viruses were not included in the selected routine diagnostic tests. Two years of mNGS in a tertiary diagnostics unit demonstrated the advantages of a single, untargeted approach for comprehensive, rapid and efficient virus diagnostics, confirming the utility of mNGS in complementing current routine tests.

The risk for infection after solid organ transplantation is determined by interactions between the net state of immunosuppression, the organ transplanted, the preventive measures implemented, and the epidemiology of pre-existing infections in both the donor and recipient and any environmental exposure to endemic and epidemic community infections. Clinical experience and observational studies have revealed some common patterns of posttransplant infections that may be considered in developing a differential diagnosis for infectious syndromes. However, any proposed timeline must be interpreted in the context of the clinical course of the specific recipient and the local epidemiology. This chapter provides an overview of common patterns of infectious risk in transplantation. Detailed considerations of the equation of infectious risk, including pretransplant assessments, donor-derived infections, and early and late posttransplant infections, are presented in subsequent chapters.

These guidelines from the AST Infectious Diseases Community of Practice review the diagnosis and management of pneumonia in the post‐transplant period. Clinical presentations and differential diagnosis for pneumonia in the solid organ transplant recipient are reviewed. A two‐tier approach is proposed based on the net state of immunosuppression and the severity of presentation. With a lower risk of opportunistic, hospital‐acquired, or exposure‐specific pathogens and a non‐severe presentation, empirical therapy may be initiated under close clinical observation. In all other patients, or those not responding to the initial therapy, a more aggressive diagnostic approach including sampling of tissue for microbiological and pathological testing is warranted. Given the broad range of potential pathogens, a microbiological diagnosis is often key for optimal care. Given the limited literature comparatively evaluating diagnostic approaches to pneumonia in the solid organ transplant recipient, much of the proposed diagnostic algorithm reflects clinical experience rather than evidence‐based data. It should serve as a template which may be modified according to local needs. The same holds true for the suggested empiric therapies, which need to be adapted to the local resistance patterns. Further study is needed to comparatively evaluate diagnostic and empiric treatment strategies in SOT recipients.

Selective digestive decontamination (SDD) with the oral, non-absorbable antimicrobial substances gentamicin, vancomycin and amphotericin B was optionally used at our institution to reduce the risk of gastrointestinal tract derived infections in multiple myeloma (MM) patients undergoing high-dose chemotherapy with subsequent autologous stem cell transplantation (HDCT/ASCT). The majority of patients received sulfamethoxazole-trimethoprim as pneumocystis pneumonia prophylaxis. From 203 patients receiving their first HDCT/ASCT between 2009 and 2015, we compared retrospectively 90 patients receiving SDD to 113 patients not receiving SDD. The administration of SDD was associated with a reduction of bacterial infections after HDCT/ASCT (overall: 8% versus 24%, p = .002; gram-negative pathogens: 1% versus 11%, p = .006) and less use of systemic antibiotics (62% versus 77%, p = .022). Omission of SDD was an independent risk factor for developing neutropenic fever and bloodstream infections. SDD could be an option to reduce bacterial infections in patients undergoing HDCT/ASCT that needs to be tested in prospective trials.

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

In this retrospective, single-center data analysis, we audited our clinical practice to treat Stenotrophomonas maltophilia in asymptomatic lung transplant recipients (LTRs). Eighteen LTRs with confirmed isolation of S. maltophilia were identified. Twelve of these LTRs have been treated with antibiotics, while 6 were managed without treatment. Treatment was based on antibiograms (trimethoprim/sulfamethoxazole [TMP/SMX] (8/12), levofloxacin (1/12), or both (3/12). Clearance (12/12 vs 6/6), eradication (10/12 vs 3/6, P=.27), and freedom from S. maltophilia recurrence (83%±11% vs 40%±22% after one year, log-rank P=.09) were not found to differ significantly between treated and untreated patients. None of the patient groups showed significant changes in lung function or biochemical variables. Creatinine levels at the end of the study period were found to be higher in treated patients compared to the untreated group (P=.049). De novo acquired TMP/SMX resistance in S. maltophilia strains was not observed. These results indicate no evidence that antibiotic treatment for S. maltophilia in asymptomatic LTRs alters lung function or the clinical outcome.

Purpose Nontuberculous mycobacteria (NTM) are challenging pathogens in cystic fibrosis (CF). The best approach is unknown, in particular, in patients in need of a lung transplant (LTX). Methods NTM sputum-positive patients were identified from all CF patients treated at the University Hospital of Zurich Adult CF Center. Course of disease and resistance to macrolide therapy was recorded. Of 6 patients who received a LTX, NTM patients were compared with patients without NTM for survival and development of chronic lung allograft dysfunction (CLAD). Results Of 111 CF patients, 43 (38.7%) patients grew at least one NTM culture of which 28 (25.2%) reached the stringent criteria for NTM positivity defined by three NTM positive cultures. With 32 (74.4%) isolates, M. abcessus spp. (MABSC) were the most frequent and acquired at an earlier age as compared to other NTM species (20 y [17-8] vs. 27 y [24-33]). NTM patients tended to be male and homozygous for PheF508del mutation, in particular, patients with MABSC, and more likely to require a LTX than patients without NTM (14.3% vs. 2.4%, p = 0.035). Of 28 MABSC patients with susceptibility testing, only three out of 16 (18.8%.) patients receiving treatment achieved long-term culture negativity. Treated patients were more likely to develop clarithromycin resistance than patients without treatment (68.8% vs. 16.7%, p = 0.019) with no difference in developing advanced lung disease (ALD), receiving a LTPL or death. 2 of the 6 patients undergoing LTX suffered from infection with MABSC, both of them being NTM positive before LTX. No difference in long-term survival nor in developing CLAD was observed. Two patients developed pulmonary and one extra-pulmonary infection. Conclusion NTM patients are at greater risk of ALD and requiring LTX, with MABSC infection acquired at an earlier age and being more common in patients with PheF508del homozygous genotype. It is unclear whether this reflects a more rapid underlying course of CF. In MABSC patients, response to chemotherapy was poor and development of resistance common. NTM infection after LTX did not result in increased mortality or development of CLAD and BOS, but was associated with infection. Our experience supports that NTM infection should not generally be regarded as an absolute contraindication for LTX, but NTM eradication prior to LTX should be attempted.

Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was

Background: In immunocompromised patients, human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality. Suppressor of cytokine signaling (SOCS) proteins are very potent negative regulators of the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. We hypothesized that HCMV exploits SOCS1 and/or SOCS3 to its advantage. Methods: All experiments were carried out with primary human lung-derived microvascular endothelial cells (HMVEC). SOCS1 and SOCS3 were silenced by transfecting the cells with siRNA. HCMV was propagated and titered on human lung-derived fibroblasts MRC5. Real-time PCR and Western blot were used to detect mRNA and protein levels, respectively. Results: The data presented show that an efficient replication of HCMV in HMVEC is dependent on SOCS3 protein. Time course analysis revealed an increase in SOCS3 protein levels in infected cells. Silencing of SOCS3 (siSOCS3) resulted in inhibition of viral immediate early, early, and late antigen production. Consistently, HCMV titers produced by siSOCS3 cultures were significantly decreased when compared to control transfected cultures (siCNTRs). STAT1 and STAT2 phosphorylation was increased in siSOCS3-infected cells when compared to siCNTR-treated cells. Conclusion: These findings indicate the implication of SOCS3 in the mechanism of HCMV-mediated control of cellular immune responses.

Transplantation activity is increasing, leading to a growing number of patients at risk for toxoplasmosis. We reviewed toxoplasmosis prevention practices, prevalence, and outcomes for hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT; heart, kidney, or liver) patients in Europe. We collected electronic data on the transplant population and prevention guidelines/regulations and clinical data on toxoplasmosis cases diagnosed during 2010-2014. Serologic pretransplant screening of allo-hematopoietic stem cell donors was performed in 80% of countries, screening of organ donors in 100%. SOT recipients were systematically screened in 6 countries. Targeted anti-Toxoplasma chemoprophylaxis was heterogeneous. A total of 87 toxoplasmosis cases were recorded (58 allo-HSCTs, 29 SOTs). The 6-month survival rate was lower among Toxoplasma-seropositive recipients and among allo-hematopoietic stem cell and liver recipients. Chemoprophylaxis improved outcomes for SOT recipients. Toxoplasmosis remains associated with high mortality rates among transplant recipients. Guidelines are urgently needed to standardize prophylactic regimens and optimize patient management.