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Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P= .03) and history of pneumonia (aOR, 48.7; P= .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P= .01), systemic antibiotic usage (aOR, 5.03; P= .04), and antimold prophylaxis (aOR, 11.9; P= .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergilluscolonization (adjusted hazard ratio [aHR], 86.9; P< .001), intensive care unit stay (aHR, 3.67; P= .02), disseminated IA (aHR, 8.98; P< .001), and dialysis (aHR, 2.93; P= .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P= .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA.

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.

Immunocompromised patients may be at increased risk for complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, comprehensive data of SARS‐CoV‐2 infection in solid organ transplant (SOT) recipients are still lacking. We performed a multicenter nationwide observational study within the Swiss Transplant Cohort Study (STCS) to describe the epidemiology, clinical presentation, treatment and outcomes of the first microbiologically documented SARS‐CoV‐2 infection among SOT recipients. Overall, 21 patients were included with a median age of 56 years (10 kidney, 5 liver, 1 pancreas, 1 lung, 1 heart and 3 combined transplantations). The most common presenting symptoms were fever (76%), dry cough (57%), nausea (33%), and diarrhea (33%). Ninety‐five percent and 24% of patients required hospital and ICU admission, respectively, and 19% were intubated. After a median of 33 days of follow‐up, 16 patients were discharged, 3 were still hospitalized and 2 patients died. These data suggest that clinical manifestations of SARS‐CoV‐2 infection in middle‐aged SOT recipients appear to be similar to the general population without an apparent higher rate of complications. These results need to be confirmed in larger cohorts. This study describes the epidemiology, clinical presentation, treatment, and outcome of the first 21 solid organ transplant recipients infected with SARS‐CoV‐2 in the Swiss Transplant Cohort Study.

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%] Campylobacterspp. 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 Campylobacterand Salmonellainfections, 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. Implementation of food‐safety recommendations is supported by data from a large, nationwide, prospective cohort of solid organ transplant recipients that shows that bacterial foodborne infections occur late after transplant and are associated with significant morbidity such as high hospitalization rates.

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.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor‐Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut‐specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living‐donor kidney recipients. All pollen‐specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor‐derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid‐organ transplantation from donors with a history of fatal anaphylaxis. Based on the Swisstransplant donor registry, the Swiss‐Transplant‐Cohort‐Study, and a prospective analysis on allergy maintenance in atopic recipients, this study makes new recommendations for the management of allergy transfer upon solid organ transplantation, emphasizing the poor effect of immunosuppression on IgE sensitization and the need of early allergological investigation in the donor and respective recipients.

New‐onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune‐ or inflammation‐related genes contribute to NODATin SOTrecipients. The association between 263 SNPs and NODATwas investigated in a discovery sample of SOTrecipients from the Swiss Transplant Cohort Study (STCS, n1= 696). Positive results were tested in a first STCSreplication sample (n2= 489) and SNPs remaining significant after multiple test corrections were tested in a second SOTreplication sample (n3= 156). Associations with diabetic traits were further tested in several large general population‐based samples (n > 480 000). Only SP110 rs2114592C>Tremained associated with NODATin the STCSreplication sample. Carriers of rs2114592‐TThad 9.9 times (95% confidence interval [CI]: 3.22‐30.5, P= .00006) higher risk for NODATin the combined STCSsamples (n = 1184). rs2114592C>Twas further associated with NODATin the second SOTsample (odds ratio: 4.8, 95% CI: 1.55‐14.6, P= .006). On the other hand, SP110 rs2114592C>Twas not associated with diabetic traits in population‐based samples, suggesting a specific gene‐environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect. A genetic polymorphism in SP110, an immune‐ and inflammation‐related gene, is associated with new‐onset diabetes posttransplantation in a cohort of solid organ transplantation recipients, with carriers of the rs2114592‐TT genotype having nearly a 10 times increased risk of diabetes.

Surgical site infections (SSI) are common healthcare-associated infections. SSIs after kidney transplantation (K-Tx) can endanger patient and allograft survival. Multicenter studies on this early post-transplant complication are scarce. We analyzed consecutive adult K-Tx recipients enrolled in the Swiss Transplant Cohort Study (STCS) that received a K-tx between May 2008 and September 2020. All data were prospectively collected with the exception of the categorization of SSI that was performed retrospectively according to the Centers for Disease Control and Prevention criteria. A total of 58 out of 3059 (1.9%) K-Tx recipients were affected by SSIs. Deep incisional (15, 25.9%) and organ/space infections (34, 58.6%) predominated. In the majority of SSIs (52, 89.6%) bacteria were detected, most frequently Escherichia coli(15, 28.9%), Enterococcusspp. (14, 26.9%), and coagulase-negative staphylococci (13, 25.0%). A BMI ≥25kg/m2(multivariable OR 2.16, 95% CI 1.07-4.34, P=0.023) and delayed graft function (multivariable OR 2.88, 95% CI 1.56-5.34, P=0.001) were independent risk factors for SSI. In Cox proportional hazard models, SSI was independently associated with graft loss (multivariable HR 3.75, 95% CI 1.35-10.38, P=0.011). In conclusion, SSI was a rare complication after K-Tx. BMI ≥25kg/m2and delayed graft function were independent risk factors. SSI were independently associated with graft loss.

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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.

A posthoc analysis of a trial of denosumab administered for bone loss after transplantation shows this anti-RANKL (receptor of activated nuclear factor kB ligand) monoclonal antibody is associated with a higher incidence of urinary tract infections in the first year after kidney allografting.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jiroveciipneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, examined whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day in-hospital death, or a composite outcome (ICU admission or death).

There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2polymorphisms were genotyped. Low MBL serum levels and deficient MBL2diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18–2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

Solid organ transplant recipients with KIR B haplotypes are associated with protection from cytomegalovirus. This study shows that they area also associated with protection from varicella zoster infection, but not Epstein-Barr virus (another herpes virus) or BK, a polyomavirus.

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.

ABSTRACTWe recently described the novel species Streptococcus tigurinussp. nov. belonging to the Streptococcus mitisgroup. The type strain AZ_3aTof S. tigurinuswas originally isolated from a patient with infective endocarditis. According to its phenotypic and molecular characteristics, S. tigurinusis most closely related to Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pseudopneumoniae, Streptococcus oralis, and Streptococcus infantis. Accurate identification of S. tigurinusis facilitated by 16S rRNA gene analysis. We retrospectively analyzed our 16S rRNA gene molecular database, which contains sequences of all clinical samples obtained in our institute since 2003. We detected 17 16S rRNA gene sequences which were assigned to S. tigurinus, including sequences from the 3 S. tigurinusstrains described previously. S. tigurinusoriginated from normally sterile body sites, such as blood, cerebrospinal fluid, or heart valves, of 14 patients and was initially detected by culture or broad-range 16S rRNA gene PCR, followed by sequencing. The 14 patients had serious invasive infections, i.e., infective endocarditis (n= 6), spondylodiscitis (n= 3), bacteremia (n= 2), meningitis (n= 1), prosthetic joint infection (n= 1), and thoracic empyema (n= 1). To evaluate the presence of Streptococcus tigurinusin the endogenous oral microbial flora, we screened saliva specimens of 31 volunteers. After selective growth, alpha-hemolytic growing colonies were analyzed by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and subsequent molecular methods. S. tigurinuswas not identified among 608 strains analyzed. These data indicate that S. tigurinusis not widely distributed in the oral cavity. In conclusion, S. tigurinusis a novel agent of invasive infections, particularly infective endocarditis.

Cytomegalovirus (CMV) infection and disease are major complications in the renal transplant recipient. The occurrence of CMV is associated with acute rejection, allograft dysfunction, significant end-organ disease, and mortality. Several clinical studies have indicated that the use of certain immunosuppressive drugs can delay the reconstitution of CMV-specific cell-mediated immune responses, thereby leading to uncontrolled CMV replication. Accumulating evidence indicates, however, that the use of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, may decrease the incidence and severity of CMV infection in renal transplant recipients. The purpose of this article is to review CMV infection data from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo renal transplantation. The mTOR inhibitor clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors’ discretion. This review will summarize these studies to discuss whether mTOR inhibitor-based immunosuppressive therapy can reduce the magnitude of CMV-related complications in the de novo renal transplantation setting.

As clinical trials are in progress involving porcine islet cell transplantation, microbial safety remains a key issue. Therefore, in the context of pig-to-human xenotransplantation, we provide an overview of the recent progress in the studies of relevant viruses including well known problematic viruses, such as herpesviruses and porcine endogenous retroviruses (PERV) in addition to some emerging issues regarding other pathogens.

Xenotransplantation of tissues from swine into humans poses the threat of bidirectional transfer of porcine or human microorganisms to the recipient or to the xenograft, respectively. This review focuses on recipient-derived infection. Recent data are reviewed that assess the susceptibility of porcine cells to human viruses. On the basis of the experience in allotransplantation, potential consequences for the xenograft are discussed.

Potential xenozoonosis is a concern for the clinical application of xenotransplantation. Human cytomegalovirus (HCMV) is one of the most important pathogens in allotransplantation, but the consequences of HCMV cross-species infection of porcine xenografts are unknown. Therefore, we investigated the effects of HCMV infection of porcine endothelial cells (pEC) on cell surface molecule expression and human leukocyte recruitment.

Objectives To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART).Design Multicentre cohort of HIV-infected adults.Methods We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated.Results At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART.Conclusions Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.

Xenotransplantation of tissues from swine into humans poses the threat of transfer of known and unknown porcine microorganisms to xenograft recipients and to the general population. Recent data are reviewed that offer a perspective on the risk for, and prevention of, xenozoonotic infections.

Xenotransplantation using pigs as the source species for organs carries a potential risk for transmission and activation of porcine herpesviruses. Activation of porcine cytomegalovirus (PCMV) in pig-to-baboon xenotransplantation is associated with xenograft injury and possibly an increased incidence of consumptive coagulopathy (CC).

A high incidence of a post-transplant lymphoproliferative disorder (PTLD) is observed in miniature swine conditioned for allogeneic hematopoietic cell transplantation using a protocol involving T-cell depletion and cyclosporine therapy. This study was designed to assess contributing factors to disease development. Forty-six animals were studied including 12 (26%) that developed PTLD. A number of risk factors for PTLD were examined, including degree of immunosuppression, degree of MHC mismatch and infection by a porcine lymphotrophic herpesvirus (PLHV-1). Flow cytometry was used to measure host and donor T- and B-cell levels in the peripheral blood. Porcine lymphotrophic herpesvirus viral load was determined by quantitative PCR. Animals developing PTLD had significantly lower levels of T cells on the day of transplant. Cyclosporine levels did not differ significantly between animals with and without PTLD. Animals receiving transplants across a two-haplotype mismatch barrier showed an increased incidence of PTLD. All animals with PTLD had significant increases in PLHV-1 viral loads. Porcine lymphotrophic herpesvirus viral copy numbers remained at low levels in the absence of disease. The availability of a preclinical large-animal model with similarities to PTLD of humans may allow studies of the pathogenesis and treatment of that disorder.

Spleen transplantation (SpTx) was performed in miniature swine across full major histocompatibility complex barriers to study the tolerogenic effect of the spleen. This study describes the development of posttransplant lymphoproliferative disease (PTLD) after allogeneic SpTx. Recipient pigs underwent whole body irradiation (100 cGy), thymic irradiation (700 cGy), and native splenectomy (day 0), and received a 45-day course of intravenous cyclosporine (trough level 400–800 ng/ml). After SpTx, two of seven pigs developed PTLD (1 donor-type, 1 host-type). These two pigs had greater T cell depletion and higher trough levels of cyclosporine. Early changes that occurred prior to the development of clinical features of PTLD were increased porcine lymphotropic herpesvirus-1 viral loads in blood and tissues, and increased numbers of leukocytes, B cells, and total serum IgM. PTLD can occur after allogeneic SpTx in swine. This model may be useful in studies of the pathogenesis of PTLD.

We have explored biochemical and hematologic parameters that might indicate acute humoral xenograft rejection (AHXR) following pig organ transplantation in baboons.

In pig-to-baboon xenotransplantation, porcine cytomegalovirus (PCMV) causes viremia, consumptive coagulopathy, and tissue-invasive disease. Baboon cytomegalovirus (BCMV) is associated with invasive disease in xenograft recipients. The efficacy of prophylaxis with intravenous ganciclovir (GCV) was studied for prevention of PCMV and BCMV infections in pig-to baboon xenotransplantation. GCV prophylaxis did not alter the incidence of BCMV activation in recipients, but reduced the amount of virus in tissues (mean 8.38 × 10² vs. 3.24 × 10⁵ copies/µg DNA without treatment) and prevented tissue-invasive infections. PCMV viral loads were unaltered by GCV prophylaxis (8.36 × 10⁸ copies/µg DNA without prophylaxis vs. 1.20 × 10⁹ copies/µg DNA with prophylaxis). In vitro, PCMV was relatively resistant to GCV [90% inhibitory concentration (IC₉₀) of 10 µm, IC₅₀ = 3 µm], acyclovir (100 µm), and leflunomide (not achievable). Only cidofovir (IC₉₀ 1 µm) and foscarnet (IC₉₀ 100 µm) might have therapeutic efficacy for PCMV in vivo in achievable concentrations, although these agents often carry significant toxicity in transplant recipients. GCV has limited activity against BCMV and no therapeutic efficacy against PCMV at standard doses in vivo. GCV and other antiviral agents have limited activities against PCMV in vitro. Breeding of PCMV-free xenograft donors may be necessary to prevent PCMV infections in clinical trials.

A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC.

ABSTRACTXenotransplantation of porcine organs carries the risk of reactivation of latent virus in donor and recipient tissues as well as transmission of viruses between species. We have investigated the activation of baboon cytomegalovirus (BCMV) and porcine CMV (PCMV) in a pig-to-primate model of xenotransplantation. Tissues originating from a series of six swine-to-baboon composite thymokidney xenotransplants were investigated. Four immunosuppressed baboons died (survival range, 7 to 27 days) with the graft in situ. Increases in BCMV DNA copy numbers occurred in three (75%) of these baboons and was thought to be responsible for pneumonitis and the death of one animal. In two baboons, disseminated intravascular coagulation was successfully treated by graftectomy and discontinuation of immunosuppression. PCMV was upregulated in five of six xenografts (83%). PCMV infection was associated with ureteric necrosis in one xenograft. Although significantly increased in native tissues, low levels of BCMV and PCMV were also detected in tissues other than that of the native viral host species. The cross-species presence of CMV did not appear to cause clinical or histological signs of invasive disease. Thus, viral infections with clinical disease were restricted to tissues of the native species of each virus. Intensive immune suppression currently required for xenotransplantation results in a significant risk of reactivation of latent infections by BCMV and PCMV. It is not yet known whether viral DNA detected across species lines represents cellular microchimerism, ongoing viral infection, or uptake of free virus. The observation of graft injury by PCMV demonstrates that CMV will be an important pathogen in immunosuppressed xenograft recipients. Strategies must be developed to exclude CMV from porcine organ donors.

ABSTRACTCaspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1β [IL-1β]-converting enzyme), Cas11 is directly involved in the maturation of IL-1β and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11−/−) mice during infection with Listeria monocytogenes. Cas11−/−and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11−/−and wild-type mice infected with Listeriahad similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1β levels were similar in Cas11−/−mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11−/−mice were deficient in the production of gamma interferon. IL-1β responses in Cas11−/−were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1β were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.

Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1beta [IL-1beta]-converting enzyme), Cas11 is directly involved in the maturation of IL-1beta and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11(-/-)) mice during infection with Listeria monocytogenes. Cas11(-/-) and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11(-/-) and wild-type mice infected with Listeria had similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1beta levels were similar in Cas11(-/-) mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11(-/-) mice were deficient in the production of gamma interferon. IL-1beta responses in Cas11(-/-) were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1beta were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.

We report on a patient with Klippel-Trenaunay (KT) syndrome, a factor VII deficiency and a copper metabolism disorder. The KT syndrome involved the left leg and, histologically, the liver. Dermatological examination, duplex ultrasonography and a skin and liver biopsy verified the KT syndrome. A long prothrombin time prompted clotting studies revealing a factor VII deficiency while the other factors were in the normal range. Further laboratory examinations showed a copper metabolism disorder similar to Wilson’s disease with a low serum ceruloplasmin level, elevated copper concentration in the urine and increased copper deposition in the liver. Neither liver cirrhosis nor a Kayser-Fleischer corneal ring was present. Sequencing analysis of the Wilson’s disease gene ATB7B showed no mutations. The occurrence of these three uncommon pathologies in a single patient has not been described to date, which may suggest a mutation in a hypothetical common regulatory gene leading to this unusual phenotype.

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.

ABSTRACTWe report the first case of a pulmonary infection with Mycobacterium sherrisiiin a patient with advanced human immunodeficiency virus infection. Mycobacterium sherrisiiis a newly described nontuberculous mycobacterium related to Mycobacterium simiae. Sequencing of the 16S rRNA gene was used for species identification. Treatment and antibiotic susceptibilities are described.

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.