Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology.

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Neutralization, effector function and immune imprinting of Omicron variants.

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Immunogenicity of High-Dose Versus MF59-Adjuvanted Versus Standard Influenza Vaccine in Solid Organ Transplant Recipients: The Swiss/Spanish Trial in Solid Organ Transplantation on Prevention of Influenza (STOP-FLU Trial).

BACKGROUND: The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. METHODS: Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity. RESULTS: A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS: In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT03699839.

Pulmonary Recovery 12 Months after Non-Severe and Severe COVID-19: The Prospective Swiss COVID-19 Lung Study.

BACKGROUND: Lung function impairment persists in some patients for months after acute coronavirus disease 2019 (COVID-19). Long-term lung function, radiological features, and their association remain to be clarified. OBJECTIVES: We aimed to prospectively investigate lung function and radiological abnormalities over 12 months after severe and non-severe COVID-19. METHODS: 584 patients were included in the Swiss COVID-19 lung study. We assessed lung function at 3, 6, and 12 months after acute COVID-19 and compared chest computed tomography (CT) imaging to lung functional abnormalities. RESULTS: At 12 months, diffusion capacity for carbon monoxide (DLCOcorr) was lower after severe COVID-19 compared to non-severe COVID-19 (74.9% vs. 85.2% predicted, p < 0.001). Similarly, minimal oxygen saturation on 6-min walk test and total lung capacity were lower after severe COVID-19 (89.6% vs. 92.2%, p = 0.004, respectively, 88.2% vs. 95.1% predicted, p = 0.011). The difference for forced vital capacity (91.6% vs. 96.3% predicted, p = 0.082) was not statistically significant. Between 3 and 12 months, lung function improved in both groups and differences in DLCO between non-severe and severe COVID-19 patients decreased. In patients with chest CT scans at 12 months, we observed a correlation between radiological abnormalities and reduced lung function. While the overall extent of radiological abnormalities diminished over time, the frequency of mosaic attenuation and curvilinear patterns increased. CONCLUSIONS: In this prospective cohort study, patients who had severe COVID-19 had diminished lung function over the first year compared to those after non-severe COVID-19, albeit with a greater extent of recovery in the severe disease group.

Epidemiology and outcomes of medically attended and microbiologically confirmed bacterial foodborne infections in solid organ transplant recipients.

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.

Epidemiology and outcomes of bone and joint infections in solid organ transplant recipients.

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.

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein-Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV- PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199-1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751-6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077-0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.

Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.

BACKGROUND: The infectious coronavirus disease 2019 (COVID-19) pandemic is an ongoing global healthcare challenge. Up to one-third of hospitalised patients develop severe pulmonary complications and acute respiratory distress syndrome. Pulmonary outcomes following COVID-19 are unknown. METHODS: The Swiss COVID-19 lung study is a multicentre prospective cohort investigating pulmonary sequelae of COVID-19. We report on initial follow-up 4 months after mild/moderate or severe/critical COVID-19 according to the World Health Organization severity classification. RESULTS: 113 COVID-19 survivors were included (mild/moderate n=47, severe/critical n=66). We confirmed several comorbidities as risk factors for severe/critical disease. Severe/critical disease was associated with impaired pulmonary function, i.e. diffusing capacity of the lung for carbon monoxide (D LCO) % predicted, reduced 6-min walk distance (6MWD) and exercise-induced oxygen desaturation. After adjustment for potential confounding by age, sex and body mass index (BMI), patients after severe/critical COVID-19 had a D LCO 20.9% pred (95% CI 12.4-29.4% pred, p=0.01) lower at follow-up. D LCO % pred was the strongest independent factor associated with previous severe/critical disease when age, sex, BMI, 6MWD and minimal peripheral oxygen saturation at exercise were included in the multivariable model (adjusted odds ratio per 10% predicted 0.59, 95% CI 0. 37-0.87; p=0.01). Mosaic hypoattenuation on chest computed tomography at follow-up was significantly associated with previous severe/critical COVID-19 including adjustment for age and sex (adjusted OR 11.7, 95% CI 1.7-239; p=0.03). CONCLUSIONS: 4 months after severe acute respiratory syndrome coronavirus 2 infection, severe/critical COVID-19 was associated with significant functional and radiological abnormalities, potentially due to small-airway and lung parenchymal disease. A systematic follow-up for survivors needs to be evaluated to optimise care for patients recovering from COVID-19.

Differences Between Infectious Disease Events in First Liver Transplant Versus Retransplantation in the Swiss Transplant Cohort Study.

Retransplantation after graft failure is increasingly performed, and inferior graft survival, patient survival, and quality of life has been reported. The role of infectious disease (ID) events in this less favorable outcome is unknown. We analyzed ID events after first liver transplantation (FLTpx) and retransplantation (reLTpx) in the Swiss Transplant Cohort Study. Clinical factors were compared after FLTpx and reLTpx, and survival analysis was applied to compare the time to ID events after FLTpx and after reLTpx, adjusted for age, sex, Model for End-Stage Liver Disease score, donor type, liver transplant type (whole versus split liver), and duration of transplant surgery. In total, 60 patients were included (65.0% male, median age of 56 years). Overall, 343 ID events were observed: 204 (59.5%) after the FLTpx and 139 (40.5%) after reLTpx. Bacterial infections were most frequent (193/343, 56.3%), followed by viral (43/343, 12.5%) and fungal (28/343, 8.2%) infections, with less infections by Candida spp. but more by Aspergillus spp. after reLTpx (P = 0.01). The most frequent infection site was bloodstream infection (86, 21.3%), followed by liver and biliary tract (83, 20.5%) and intraabdominal (63, 15.6%) infections. After reLTpx, more respiratory tract and surgical site infections were observed (P < 0.001). The time to first infection was shorter after FLTpx (adjusted hazard ratio [HR], 0.5; 95%-confidence interval [CI], 0.3-1.0; P = 0.04). Reduced hazards for ID events after reLTpx were also observed when modelling recurrent events (adjusted HR, 0.5; CI, 0.3-0.8; P = 0.003). The number of infections was comparable after FLTpx and reLTpx; however, differences regarding infection sites and fungal species were observed. Hazards were reduced for infection after reLTpx.

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

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.

First experience of SARS-CoV-2 infections in solid organ transplant recipients in the Swiss Transplant Cohort Study.

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.

Vitamin D deficiency is common in kidney transplant recipients, but is not associated with infections after transplantation.

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25-OH vitamin D (25-OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri-transplant and 6 months post-transplant. Logistic regression was used to address the associations of 25-OHD and overall infections and bacterial infections, respectively. For the first 6 months post-transplant, 25-OHD peri-transplant, and for the second period (after 6 to 30 months post-transplant), 25-OHD at 6 months post-transplant was considered. Vitamin D deficiency was common peri-transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25-OHD levels increased from 12.0 ng/mL (IQR 5.3-19.5) peri-transplant to 16.5 ng/mL (IQR 10.6-22.6) 6 months post-transplant (P = .005). We did not detect a significant association between 25-OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44-2.51; aOR 0.67, 95%CI 0.31-1.43) or bacterial infections (aOR 0.79, 95%CI 0.32-1.96; aOR 0.79, 95%CI 0.35-1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25-OHD in the longitudinal course was observed. No significant association between 25-OHD and infections was detected.

Vitamin D status and risk of infections after liver transplantation in the Swiss Transplant Cohort Study.

Increasing evidence indicates a role of vitamin D in the immune system affecting response to infections. We aimed to characterize the role of vitamin D status, i.e. deficiency [25-OH vitamin D (25-OHD) <50 nmol/l] and no deficiency (25-OHD ≥50 nmol/l) in incident infections after liver transplantation. In 135 liver transplant recipients, blood samples drawn at time of liver transplantation and 6 months afterwards were used to determine 25-OHD levels. Incident infections episodes were prospectively collected within the Swiss Transplant Cohort Study database. Poisson regression was applied to address associations between vitamin D status and incident infections. Vitamin D deficiency was common at time of transplantation and 6 months afterwards without a significant change in median 25-OHD levels. In univariable analyses, vitamin D deficiency was a risk factor for incident infections in the first 6 months post-transplant incidence rate ratio (IRR 1.52, 95% CI 1.08-2.15, P = 0.018) and for bacterial infections occurring after 6 up to 30 months post-transplant (IRR 2.29, 95% CI 1.06-4.94, P = 0.034). These associations were not detectable in multivariable analysis with adjustment for multiple confounders. Efforts to optimize vitamin D supplementation in liver transplant recipients are needed. Our data question the role of vitamin D deficiency in incident infections.

Incidence and outcome of invasive fungal diseases after allogeneic hematopoietic stem cell transplantation: A Swiss transplant cohort study.

Contemporary, comprehensive data on epidemiology and outcomes of invasive fungal disease (IFD) including breakthrough IFD among allogeneic hematopoietic stem cell transplantation (HSCT) recipients are scarce. We included 479 allogeneic HSCT recipients with 10 invasive candidiasis (IC) and 31 probable/proven invasive mold disease (IMD) from the Swiss Transplant Cohort Study from 01.2009 to 08.2013. Overall cumulative incidence was 2.3% for IC and 8.5% for probable/proven IMI: 6% for invasive aspergillosis (IA) and 2.5% for non-AspergillusIMI. Among 41 IFD, 46% IFD were breakthrough, with an overall incidence of 4.6%, more frequently caused by other-than-Aspergillus fumigatus molds than primary IFD (47.6% (10/21) vs 13% (3/23), P = 0.04). Twelve-week mortality among patients with IC was 20% and 58.6% for probable/proven IMD (60% IA and 54.6% non-Aspergillus). Our results reveal that breakthrough IFD represent a marked burden of probable/proven IFD postallogeneic HSCT and mortality remains above 50% in patients with probable/proven IMD, underscoring the ongoing challenges to prevent and treat IFD in these patients.

Human MicroRNA Responses Predict Cytomegalovirus Replication Following Solid Organ Transplantation.

Background: Homo sapiens mature micro-ribonucleic acid (miRNA)-200b-3p and 200c-3p are predicted to bind to 3' untranslated region of mRNA encoding human cytomegalovirus (HCMV) immediate early protein 2 (IE2). We hypothesized that expression of these miRNAs pretransplant could predict HCMV replication after solid organ transplantation (SOT). Methods: A total of 272 SOT recipients were HCMV-seropositive pretransplant and were managed using preemptive therapy. Pretransplant peripheral blood mononuclear cells were stimulated with HCMV followed by collection of RNA 1 day poststimulation. The miRNAs were quantified using real-time reverse transcription-polymerase chain reaction. Human foreskin fibroblasts were transfected with 200b-3p and 200c-3p and infected with HCMV 1 hour post-transfection. Protein was collected at 3 days postinfection (dpi) and 7 dpi underwent immunoblotting for IE2. Results: Medians of 200b-3p and 200c-3p were significantly lower in recipients with HCMV replication (n = 144) (361.6 vs 552.6, P = .035; 3586.8 vs 12986.8 copies/µL, P = .03, respectively). Multivariate regression revealed that 200b-3p ≥100 copies/µL (odds ratio [OR]: 0.53; P = .02), was associated with less HCMV replication. Transfection with 200b-3p resulted in 2.7- and 2.5-fold decreased IE2 at 3 dpi and 7 dpi, respectively, compared to mock cells. Conclusions: MicroRNAs may play a biologically relevant role in controlling HCMV replication post-transplant.