Net State Of Immunosuppression Research Articles

Therapy of Mycobacterium abscessus Infections in Solid Organ Transplant Patients.

Mycobacterium abscessus complex (MABC), a rapidly growing Mycobacterium, is one of the most common causes of non-tuberculous mycobacteria (NTM) infections in the United States of America, and it has been associated with a wide spectrum of infections in immunocompetent and immunosuppressed individuals. Eradicating MABC is very challenging, even with prolonged combination therapies. The management of MABC infections in solid organ transplant (SOT) patients is usually complex given their net state of immunosuppression, associated comorbidities, and potential drug-drug interactions, among other things. In this manuscript, we discussed the antimicrobial management of pulmonary and extrapulmonary MABC infections. In addition, we reviewed promising novel therapies such as clofazimine, omadacycline, bedaquiline, and inhaled tigecycline that could join the existing antimicrobial armamentarium to fight this infection associated with significant morbidity and mortality. However, further studies are needed, especially among the immunocompromised host.

The COVID-19 infection in liver transplant recipients: A Cohort Study

The immunosuppressed state of liver transplant recipients makes them vulnerable to infections after surgery. These infections are directly correlated with the net state of immunosuppression. Higher levels of immunosuppression mean a higher risk of infection, with rates of infection typically highest in the early post-transplant period. Coronavirus disease 2019 (COVID‐19) vaccines have shown efficacy in generating specific immune responses. This study aims to describe the COVID-19 infection before and after vaccination in liver recipients. This was a cohort study including 77 liver transplant recipients with laboratory radiological confirmed COVID-19. COVID-19 infection was present before vaccination in 30 patients. The most frequent COVID-19 clinical presentations before vaccination were cough in 32 patients and myalgia in 21 patients; 27 cases had oxygen depletion and required supplemental oxygen. Of the 30 COVID-19 patients, 4 patients re-experienced the disease about three months after complete vaccination. 33 liver transplant patients had not experienced COVID-19 before vaccination, of which 32 patients received vaccination. In conclusion, liver transplant patients infected with SARS-CoV-2 are at greater risk of severe infection and death compared with immunocompetent individuals. Thus, COVID-19 vaccination for all liver recipients is of paramount importance.

Update on therapeutic approaches for invasive fungal infections in adults.

Invasive fungal infections are increasingly encountered with the expansion of iatrogenic immunosuppression, including not only solid organ and hematopoietic stem cell transplant recipients but also patients with malignancies or autoimmune diseases receiving immunomodulatory therapies, such as Bruton Tyrosine Kinase (BTK) inhibitor. Their attributable mortality remains elevated, part of which is a contribution from globally emerging resistance in both molds and yeasts. Because antifungal susceptibility test results are often unavailable or delayed, empiric and tailored antifungal approaches including choice of agent(s) and use of combination therapy are heterogeneous and often based on clinician experience with knowledge of host's net state of immunosuppression, prior antifungal exposure, antifungal side effects and interaction profile, clinical severity of disease including site(s) of infection and local resistance data. In this review, we aim to summarize previous recommendations and most recent literature on treatment of invasive mold and yeast infections in adults to guide optimal evidence-based therapeutic approaches. We review the recent data that support use of available antifungal agents, including the different triazoles that have now been studied in comparison to previously preferred agents. We discuss management of complex infections with specific emerging fungi such as Scedosporium spp., Fusarium spp., Trichosporon asahii, and Candida auris. We briefly explore newer antifungal agents or formulations that are now being investigated to overcome therapeutic pitfalls, including but not limited to olorofim, rezafungin, fosmanogepix, and encochleated Amphotericin B. We discuss the role of surgical resection or debridement, duration of treatment, follow-up modalities, and need for secondary prophylaxis, all of which remain challenging, especially in patients chronically immunocompromised or awaiting more immunosuppressive therapies.

Approach to vaccinating the pediatric solid organ transplant candidate and recipient.

Solid organ transplantation (SOT) candidates and recipients are at increased risk for morbidity and mortality from vaccine-preventable infections. Children are at particular risk given that they may not have completed their primary immunization series at time of transplant or have acquired natural immunity to pathogens from community exposures. Multiple society guidelines exist for vaccination of SOT candidate and recipients, although challenges remain given limited safety and efficacy data available for pediatric SOT recipients, particularly for live-vaccines. After transplant, individual patient nuances regarding exposure risks and net state of immunosuppression will impact timing of immunizations. The purpose of this review is to provide readers with a concise, practical, expert-opinion on the approach to vaccinating the SOT candidate and recipient and to supplement existing guidelines. In addition, pediatric-specific knowledge gaps in the field and future research priorities will be highlighted.

Immune monitoring of prevalent kidney transplant recipients using Torque Teno Virus: Protocol for a single-centre prospective cohort study

IntroductionKidney transplant recipients (KTRs) suffer from immunosuppression-related adverse events (iRAEs), such as infections and malignancy from chronic immunosuppression, but are also at risk of graft loss from rejection with underimmunosuppression....

Reduction in the risk of progression of solid organ transplant recipients infected by SARS-CoV-2 treated with monoclonal antibodies.

Recipients of solid organ transplants (SOT) are at higher risk of infection by SARS-CoV-2 virus especially due to chronic immunosuppression therapy and frequent multiple comorbid conditions. COVID-19 is a potentially life-threatening disease in SOT recipients, with an increased likelihood of progressing to severe disease, with the need of hospitalization, admission to the intensive care unit (ICU) and mechanical ventilatory support. This article presents an updated review of different aspects related to the outcome of COVID-19 in SOT recipients. In nvaccinated SOT recipients, COVID-19 is associated with a high mortality rate, in-patient care and ICU admission, and impaired graft function or rejection in severe disease. In vaccinated SOT recipients even after full vaccination, there is a reduction of the risk of mortality, but the course of COVID-19 may continue to be severe, influenced by the time from transplant, the net state of immunosuppression and having suffered graft rejection or dysfunction. SOT recipients develop lower immunity from mRNA vaccines with suboptimal response. Treatment with mAbs provides favorable outcomes in non-hospitalized SOT recipients at high risk for severe disease, with lower rates of hospitalization, emergency department visits, ICU care, progression to severe disease, and death. However, broad vaccination and therapeutic options are required, particularly in light of the tendency of the SARS-CoV-2 virus to adapt and evade both natural and vaccine-induced immunity.

Perioperative antibiotic stewardship in the organ transplant setting.

Solid organ transplant (SOT) recipients can benefit from traditional antimicrobial stewardship (AMS) activities directed to improve judicious perioperative prescribing and management, but evidence is lacking. The aim of this expert opinion review is to provide an update on the current landscape of application of AMS practices for optimization of perioperative prophylaxis (PP). We reviewed the available literature on early postoperative infectious complications in SOT and PP management, on modified perioperative approaches in case of infection or colonization in recipients and donors and on AMS in transplantation PP. SOT recipients are at high risk for early postoperative infectious complications due to the complexity of surgical procedures, severity of end stage organ disease, net state of immunosuppression in the posttransplant period and to the high risk for multidrug resistant organism. Moreover, SOT may be exposed to preservation fluid infections and expected or unexpected donor-derived infections. We summarize main factors to take into account when prescribing transplant PP. Creating personalized PP to avoid unwanted consequences of antimicrobials while improving outcomes is an emerging and critical aspect in SOT setting. Further studies are needed to offer best PP tailored to SOT type and to evaluate interventions efficacy and safety.

POS-816 DE NOVO KIDNEY ALLOGRAFT RENAL CELL CARCINOMA: A RARE UNSALVAGEABLE CAUSE OF ALLOGRAFT LOSS IN A VERY LATE POST-TRANSPLANT PERIOD

Renal cell carcinoma (RCC) is a common malignancy in end-stage kidney disease (ESKD) from acquired cystic kidney disease (ACKD). With a net state of immunosuppression, kidney transplant recipients (KTR) are even at higher risk for RCC; however, RCC in the kidney allograft is uncommon unless it results from donor-derived disease. We report a case of old-aged woman with kidney allograft masses at the very late post-transplant period. Explanted transplant allograft revealed RCC.

Monitoring of Torque Teno virus DNAemia in critically ill COVID-19 patients: May it help to predict clinical outcomes?

Background: Torque teno virus (TTV) DNA load in plasma directly associates with the net state of immunosuppression and inflammation in different clinical settings, including transplantation and chronic inflammatory diseases.Objectives: We investigated whether plasma TTV DNA load may predict the occurrence of certain infectious events and overall mortality in critically ill COVID-19 patients.Patients and Methods: 50 patients (median age, 65.5 years) were recruited. TTV DNA load was quantitated in serial plasma specimens by real-time PCR. Serum levels of interleukin-6, C-reactive protein, ferritin, lactate dehydrogenase, Gamma-Glutamyl Transferase (GGT), alanine transaminase (ALT) and aspartate transaminase (AST) and absolute lymphocyte counts (ALC) in paired specimens were available. Nosocomial bloodstream infections and ventilator-associated pneumonia and overall mortality were the clinical outcomes.Results: TTV DNA was detected in 38 patients (76%). A weak inverse correlation (Rho=-0.28; P = 0.004) was observed between TTV DNA loads and ALC. No direct correlation was found between TTV DNA load and serum levels of any of the above biomarkers. Patients with detectable TTV DNA had an increased risk of subsequently developing infectious events (HR 9.28; 95% CI, 1.29–69.5; P = 0.03). A trend (P = 0.05) towards higher TTV DNA area under a curve between days 7 and 17 after ICU admission (AUC7–17) was observed in patients who died, as compared to survivors.Conclusion: Our findings suggested that plasma TTV DNA load monitoring may be helpful for predicting the occurrence of severe nosocomial infections and mortality in critically ill COVID-19 patients.

Risk constellations, viral infections, and prophylaxis in uterine transplantation.

Uterine transplantation (UTx) is a burgeoning new category of solid organ transplantation (SOT) that is practiced at several centers worldwide (first transplantation in 2013). Although there are still relatively low numbers of transplants (<75 published in literature), they are increasing in frequency and thus we attempt to discuss the current documented infections in this population as well as theoretical infectious risks and summarize prophylaxis and treatment strategies of centers current performing these procedures. The most reported posttransplantation infection is not surprisingly urinary tract infections, with other documented infections including bacterial infections at site of graft (Enterococcus), herpes simplex virus, cytomegalovirus (CMV), human papillomavirus, Candida, and reportedly posttransplant lymphoproliferative disorder. The net state of immunosuppression and host factors (host colonization and serologic status of viral exposures) plays a significant role in infectious risk and with low numbers of infections documented, much of our guidance surrounding prophylaxis is inferred from SOT literature. In this review, we give an overview of described infections in UTx and theoretical infectious risks, detailing how to tailor prophylaxis base on host risk, with specific focus that the goal of transplantation is completion of a successful pregnancy as the desired outcome. Special considerations should be given to pregnant recipients when managing infectious complications and further data collection and reporting regarding infectious complications is crucial to advance this field as numbers of transplantation continue to increase.

Immunosuppressive Agents and Infectious Risk in Transplantation: Managing the "Net State of Immunosuppression".

Successful solid organ transplantation reflects meticulous attention to the details of immunosuppression, balancing risks for graft rejection against risks for infection. The "net state of immune suppression" is a conceptual framework of all factors contributing to infectious risk. Assays that measure immune function in the immunosuppressed transplant recipient relative to infectious risk and allograft function are lacking. The best measures of integrated immune function may be quantitative viral loads to assess the individual's ability to control latent viral infections. Few studies address adjustment of immunosuppression during active infections; thus, confronted with infection in solid organ recipients, the management of immunosuppression is based largely on clinical experience. This review examines known measures of immune function and the immunologic effects of common immunosuppressive drugs and available studies reporting modification of drug regimens for specific infections. These data provide a conceptual framework for the management of immunosuppression during infection in organ recipients.

A CRISPR-based assay for the detection of opportunistic infections post-transplantation and for the monitoring of transplant rejection.

In organ transplantation, infection and rejection are major causes of graft loss. They are linked by the net state of immunosuppression. To diagnose and treat these conditions earlier, and to improve long-term patient outcomes, refined strategies for the monitoring of patients after graft transplantation are needed. Here, we show that a fast and inexpensive assay based on CRISPR-Cas13 accurately detects BK polyomavirus DNA and cytomegalovirus DNA from patient-derived blood and urine samples, as well as CXCL9 messenger RNA (a marker of graft rejection) at elevated levels in urine samples from patients experiencing acute kidney transplant rejection. The assay, which we adapted for lateral-flow readout, enables-via simple visualization-the post-transplantation monitoring of common opportunistic viral infections and of graft rejection, and should facilitate point-of-care post-transplantation monitoring.

How Long Do We Need to Treat an Invasive Mold Disease in Hematology Patients? Factors Influencing Duration of Therapy and Future Questions.

Treatment duration for invasive mold disease (IMD) in patients with hematological malignancy is not standardized and is a challenging subject in antifungal stewardship. Concerns for IMD relapse during subsequent reinduction or consolidation chemotherapy or graft versus host disease treatment in hematopoietic stem cell transplant recipients often results in prolonged or indefinite antifungal treatment. There are no validated criteria that predict when it is safe to stop antifungals. Decisions are individualized and depend on the offending fungus, site and extent of IMD, comorbidities, hematologic disease prognosis, and future plans for chemotherapy or transplantation. Recent studies suggest that FDG-PET/CT could help discriminate between active and residual fungal lesions to support decisions for safely stopping antifungals. Validation of noninvasive biomarkers for monitoring treatment response, tests for quantifying the "net state of immunosuppression," and genetic polymorphisms associated with poor fungal immunity could lead to a personalized assessment for the continued need for antifungal therapy.

Immunosuppression after renal transplantation

Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episodes and loss of the renal allograft. Most centers rely on a triple IS after induction with either interleukin‑2 receptor antibodies or antithymocyte globulin. The most frequently used substances for maintenance IS are glucocorticoids, antimetabolites, mTOR inhibitors (mTORi), calcineurin inhibitors (CNI) and the costimulation blocker belatacept. Guidelines recommend a triple combination consisting of CNIs, antimetabolites and corticosteroids for the majority of patients. The long-term risk for malignancy in general is increased in solid organ recipients compared to the general population. Modification of IS may result in reduced risk for non-melanoma skin cancers but results in higher graft rejection rates and in the case of mTORi, deaths. In the case of posttransplantation lymphoproliferative disorders (PTLD) treatment options are reduction of IS, rituximab, chemotherapy, radiation therapy or a combination of these. The optimal protocol has not yet been established and depends on patient age and status, tumor load, laboratory findings, organ functions (heart, kidney, liver) and PTLD subtype. Posttransplantation diabetes mellitus is a frequent complication after kidney transplantation. Tacrolimus more than cyclosporine A, sirolimus and corticosteroids are considered to be diabetogenic; however, tacrolimus remains the first choice as the mainstay of IS. In general, the IS regimen should be tailored for optimal kidney allograft survival rather than better diabetic control. Concerning infections, cytomegalovirus and Pneumocystis jerovecii are best managed by prophylaxis. In the case of virus reactivation or opportunistic infections, targeted therapy is applied and the net state of IS is most often reduced.

Pneumonia in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

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.

CMV Viral Load after Peripheral Blood Stem Cell Transplantation (PBSCT) and Posttransplant High-Dose Cyclophosphamide (PTCy)

CMV viral load after allogeneic hematopoietic PBSCT is strongly associated with overall and non-relapse mortality. Recent studies suggest graft-versus-host-disease (GVHD) prevention with PTCy reduces GVHD risk through an immunomodulatory mechanism rather than T-cell ablation (Kanakry et al. Sci Transl Med 2013), which may preserve virus-specific adaptive immune responses. Lower rates of chronic GVHD with PTCy may also preserve thymic function and reduce cumulative corticosteroid use. We hypothesized that GVHD prophylaxis using PTCy leads to lower CMV viral load and disease compared to calcineurin-inhibitor (CNI) and methotrexate (MTX) or mycophenolate (MMF) GVHD regimens after PBSCT. We retrospectively analyzed subjects undergoing first HLA-matched unrelated or sibling donor PBSCT for hematologic malignancy between July 2007 and August 2017 at Fred Hutchinson Cancer Research Center. Inclusion criteria were CMV seropositive recipient and/or donor status and myeloablative or reduced-intensity conditioning. Subjects receiving ATG were excluded. We calculated the mean CMV viral load (obtained weekly posttransplant) for each subject divided by number of days survived through one year and compared these normalized average levels across patients using the Kruskal-Wallis test. A spline curve plotting the median viral load Log10 (CMV PCR +1) between the 3 groups was created for data visualization. Cox regression was used to compare cause-specific hazards of CMV reactivation at >0, ≥250 or ≥1000 IU/ml and CMV disease between groups, each modeled as a time-to-event outcome. 594 subjects met inclusion criteria (33 PTCy, 423 MTX, 138 MMF). Table 1 shows normalized median CMV viral load before and after day 70 in PTCy vs. MTX vs. MMF groups. The spline curve depicts median viral load across the 3 cohorts (Figure 1). The hazard ratios for CMV reactivation for MTX and MMF compared to PTCy at >0, ≥250 or ≥1000 IU/ml are shown in Table 2. CMV disease was not significantly different between PTCy vs. MTX and MMF: HR 1.13 (0.27-4.76, p = .87) and 0.93 (0.19-4.49, p = .93), respectively. While the time to first CMV reactivation at various levels and CMV disease was not statistically significantly different between the 3 groups, the kinetics of CMV viral load show initially higher, but later lower levels in subjects receiving PTCy compared to MTX or MMF regimens. This may be due to an initial period of T cell compromise associated with reduced viralimmunity in PTCy recipients, followed by rapid recovery of virus-specific T cells in the later posttransplant period. The net state of immunosuppression after PTCy may prove favorable for viral immunity and overall immune reconstitution posttransplant. Prospective randomized trials are underway.

The Relationship Between CMV Seropositivity and Fungal Pneumonia in Renal Transplant Patients

Introduction Invasive fungal infections are major problem in solid organ transplant (SOT) recipients because of their net state of immuno-suppression. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis. Cytomegalovirus (CMV) is the most common viral infection following renal transplant (RT). About one-quarter of renal transplant recipients developed Seropositivity (CMVSP). CMSP is also described as a risk factor for fungal pneumonia because it led to a pronounced cellular immunosuppression in the SOT patients. To date, the role of CMVSP on the development of fungal pneumonia in SOT patients has not been investigated so far. In this study, we aimed to investigate the role of CMVSP on the development of Aspergillus pneumonia in renal transplant patients retrospectively. Materials and Methods We evaluated a total of 401 patients (male/female=273/128) who underwent renal transplant between 2011 and 2017. Medical records of these patients were reviewed for demographic, clinical, radiographic, laboratory and microbiology data, laboratory method for determining CMV. The diagnosis of pneumonia based on clinical respiratory symptoms and signs, imaging findings (chest radiography and/or computed tomography), positive microbiological tests and laboratory findings. Immune suppressive drugs and clinical outcome data were also noted. Results Our study included in 153 (38%) (male/female= 97/55 and with the mean age of 35 ± 14 years) renal transplantation patients (44 cadaveric, 109 living donors) who had pneumonia in our study population. The most frequently determined immunosuppression therapy included prednisolone plus cyclosporine, tacrolimus, or rapamycin. CMVSP was found in 77 (%0.3) of the patients. Twenty-one of the patients had positive culture from respiratory specimens. Fungal agents were detected in 16 (77%) of the patients and Aspergillus fumigatus was the most common (38%) fungus species. No statistical significant correlation was found between Seropositivity and microbiological agents of pneumonia (p>0.05) in our study group. Conclusions Our results suggest that Seropositivity may not be a risk for fungal pneumonia in RT patients. Further studies needed to reveal whether CMVSP is a risk for fungal pneumonia or not in larger fungal pneumonia series in RT patients.

Analysis of the QuantiFERON-CMV assay, CMV viraemia and antiviral treatment following solid organ transplantation in Western Australia

Prevention of cytomegalovirus (CMV) infection remains an important aspect of improving long term outcomes of solid organ transplantation and currently relies on prophylactic antiviral medication and early detection of viraemia or disease. Uptake of diagnostic tools to personalise assessment of CMV immunity and guide interpretation of viral testing remains low. We assessed the QuantiFERON-CMV assay in 54 Western Australian recipients of renal, heart, lung or liver allografts to determine the relationship between CMV-specific immunity, viraemia and disease following cessation of antiviral prophylaxis. We carried out an initial validation study which demonstrated that the QuantiFERON-CMV assay is highly precise and strongly correlated with CMV-specific antibodies in 30 healthy blood donors (sensitivity 82%, specificity 95%). In the solid organ transplant recipients we examined, the prevalence of asymptomatic CMV viraemia was high at 61% but only two patients ultimately developed CMV disease, both of whom had negative QuantiFERON-CMV responses, indicating lack of CMV T-cell immunity. The vast majority (94%) of patients who had spontaneous resolution or stability of asymptomatic CMV viraemia without any antiviral treatment had positive QuantiFERON-CMV responses. Positive QuantiFERON-CMV responses at cessation of antiviral prophylaxis were significantly associated with pre-transplant CMV seropositivity and the development of asymptomatic viraemia post-transplantation. Overall, 27% of patients were recommenced on antiviral therapy because of asymptomatic CMV viraemia. Patients with non-reactive QuantiFERON-CMV responses had earlier onset, higher level CMV viraemia compared to those with positive QuantiFERON-CMV responses, although the difference did not reach statistical significance. QuantiFERON-CMV results may contribute to decision making in concert with the serological risk profile, net state of immunosuppression and CMV viral load.

A Study of Viral Infections in Renal Transplant Recipients Risk Factors, Clinical Profile And Outcome Analysis

Introduction: Renal transplantation has become the most effective means of rehabilitating patients with end stage renal disease. In well-established centers, 90% 1 year graft survival and 95% patient survival is achieved. In spite of this, infection occurs more than 60% of renal transplant recipients and being the one of the main cause of death in renal transplant recipients. If the net state of immunosuppression is minimal then an overwhelming exposure only causes the disease. . Routine antimicrobiologic prophylaxis is aimed at common infection i.e. That includes trimethoprim-sulphamethoxazole (toxoplasmosis , pneumocystis, Nocardia, UTI) and valganciclovir( CMV and herpes groups) and antifungal (Kidney-pancreas transplantation). In this study, attempt has been made to analyze the risk factors, clinical profile and outcome of viral infection in renal transplant recipient. Methods: It is a cross-sectional, descriptive, prospective and retrospective study of 356 patients conducted in the department of Nephrology. Renal transplant recipients diagnosed with viral infections were included in the study. Results: Bacterial, viral, fungal and parasitic infection contributes to 45%,30.5%,9.5%,5.3% respectively to the total infective episodes. Most of the viral episodes occurred after 6 months post-transplant. Commonest viral infection is the CMV and its prevalence 17.4% and mean time of onset is between 1-6 months after transplantation. On Univariate analysis, antirejection therapy and NODAT had statistical significant risk factor for developing viral infection (P<0.05). In patients affected with viral infection on univariate analysis, there is a statistical significance for graft dysfunction, graft loss and death (P<0.05). CMV infection has a statistical significant risk factor for bacterial, fungal and other viral infections. (P<0.05). Hepatitis C infection is the second most common virus found in our study. The mean onset of infection is seen 6 months after transplant. Nearly 50% HCV infected patients developed NODAT. Conclusion: The clinical profile of the patients in post renal transplant cases is studied. In this study, attempt has been made to analyze the risk factors and outcome of viral infection in renal transplant recipient.

Monitoring pharmacologically induced immunosuppression by immune repertoire sequencing to detect acute allograft rejection in heart transplant patients: a proof-of-concept diagnostic accuracy study.

BackgroundIt remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.Methods and FindingsIn this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.ConclusionsIf confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.