Mycoplasma hominis infections in solid organ transplant recipients: Clinical characteristics, treatment outcomes, and comparison of phenotypic and genotypic susceptibility profiles.

BACKGROUND: Mycoplasma hominis can cause significant infections after solid organ transplantation (SOT). Treatment should be guided by susceptibility testing, but conventional lab methods are laborious with prolonged turnaround time (TAT). This case series compares the phenotypic and genotypic susceptibility profiles of M. hominis isolates identified from SOT patients. METHODS: This is a single-center retrospective study evaluating SOT recipients with confirmed M. hominis infections. Patients' demographic, clinical, microbiological, and radiographic data were collected. Culture of M. hominis isolates was performed according to current Clinical and Laboratory Standards Institute guidelines. Phenotypic susceptibility testing was performed by University of Alabama Diagnostic Mycoplasma Laboratory. Whole genome sequencing (WGS) was performed followed by bioinformatic analysis of known genetic determinants of resistance. RESULTS: Seven SOT recipients with M. hominis infections were identified. Two out of seven (28.5%) patients had resistance detected by phenotypic susceptibility testing (Case 5 to levofloxacin and Case 7 to tetracycline). Genomic analyses confirmed the presence of mutations in the parC and parE topoisomerase genes at positions conferring to fluoroquinolone resistance in the isolate from Case 5, while the tetracycline-resistant isolate from Case 7 harbored the tetM gene. The median TAT from the date of specimen collection was 24 days for phenotypic susceptibility testing and 14 days for genotypic susceptibility testing. All seven patients received antimicrobials directed toward M. hominis and recovered with complete resolution of infection. CONCLUSIONS: WGS may offer a novel and more rapid methodology for M. hominis susceptibility testing to help optimize antimicrobial usage, but more data are needed.

Heart transplantation in the early phase of the COVID-19 pandemic: A single-center case series.

The infectious disease coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID-19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re-evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID-19 screening scrutiny and recipient waiting list management in anticipation of COVID-19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end-stage cardiomyopathies is challenging. Here, we describe our center's experience with orthotopic heart transplantation (OHT) in one of the country's pandemic epicenters, where we performed eight OHTs in the first 2 months after community spread began in late February 2020.

Successful Treatment of Scedosporium Sinusitis in Two Lung Transplant Recipients: Review of the Literature and Recommendations for Management.

BACKGROUND: Scedosporium fungal infection is an emerging disease which is difficult to diagnose and treat. Patients undergoing lung transplant may be colonized prior to transplantation and are at risk for lethal allograft infection after transplantation. OBJECTIVES: To identify and evaluate treatment options. METHODS: This study is a retrospective review of patients treated at a tertiary academic medical center from 2007 to 2017 with positive sinonasal cultures. A review of the literature was also performed to identify additional cases. RESULTS: Two lung transplant patients had a positive culture for Scedosporium. The literature search resulted in 37 citations, which yielded only 2 prior cases of Scedosporium paranasal sinus colonization or infection in lung transplant recipients. Three of the 4 patients had cystic fibrosis. Two of the patients were colonized before initial transplant, while 1 patient was colonized before subsequent transplant. Three of the 4 patients survived, and all 3 had disease isolated to their sinuses and lungs treated with sinus surgery, while the fourth had disseminated disease and did not undergo sinus surgery. All patients were treated with multiple antifungals due to resistance patterns. One surviving patient cleared both sinus and lung cultures in less than 1 month, while the other 2 surviving patients achieved negative cultures after a minimum of 6 months. CONCLUSIONS: Surgery may be especially important in patients with fungal sinus colonization or infection before or after lung transplantation. Chronic sinusitis is an important source for persistent fungal colonization and reinfection of the allograft which could be removed with surgical debridement before causing highly morbid pulmonary disease.

Clinical phenomapping and outcomes after heart transplantation.

BACKGROUND: Survival after heart transplantation (HTx) is limited by complications related to alloreactivity, immune suppression, and adverse effects of pharmacologic therapies. We hypothesize that time-dependent phenomapping of clinical and molecular data sets is a valuable approach to clinical assessments and guiding medical management to improve outcomes. METHODS: We analyzed clinical, therapeutic, biomarker, and outcome data from 94 adult HTx patients and 1,557 clinical encounters performed between January 2010 and April 2013. Multivariate analyses were used to evaluate the association between immunosuppression therapy, biomarkers, and the combined clinical end point of death, allograft loss, retransplantation, and rejection. Data were analyzed by K-means clustering (K = 2) to identify patterns of similar combined immunosuppression management, and percentile slopes were computed to examine the changes in dosages over time. Findings were correlated with clinical parameters, human leucocyte antigen antibody titers, and peripheral blood mononuclear cell gene expression of the AlloMap (CareDx, Inc., Brisbane, CA) test genes. An intragraft, heart tissue gene coexpression network analysis was performed. RESULTS: Unsupervised cluster analysis of immunosuppressive therapies identified 2 groups, 1 characterized by a steeper immunosuppression minimization, associated with a higher likelihood for the combined end point, and the other by a less pronounced change. A time-dependent phenomap suggested that patients in the group with higher event rates had increased human leukocyte antigen class I and II antibody titers, higher expression of the FLT3 AlloMap gene, and lower expression of the MARCH8 and WDR40A AlloMap genes. Intramyocardial biomarker-related coexpression network analysis of the FLT3 gene showed an immune system-related network underlying this biomarker. CONCLUSIONS: Time-dependent precision phenotyping is a mechanistically insightful, data-driven approach to characterize patterns of clinical care and identify ways to improve clinical management and outcomes.

Extended spectrum ß-lactamase-producing Enterobacteriaceae infection in heart and lung transplant recipients and in mechanical circulatory support recipients.

BACKGROUND: Extended spectrum ß-lactamase (ESBL)-producing gram-negative bacilli are increasingly reported in patients with a variety of risk factors including prior cephalosporin and antibiotic usage, prolonged hospitalizations, existence of comorbid conditions, and critical illness. METHODS: Retrospective review of infections caused by ESBL-producing Enterobacteriaceae was performed in heart transplant (HTx), lung transplant (LTx), and mechanical circulatory support (MCS) device recipients at a large transplant center. RESULTS: Among 1065 patients transplanted/implanted, the incidence of ESBL-related infections (bacteremia, urinary tract infections, pneumonia, central venous catheter-associated infection, and wound infections) in HTx, LTx, and MCS device recipients was reported at 2.2%, 5.5%, and 10.7%, respectively, caused by ESBL-producing Klebsiella pneumoniae, Escherichia coli, Klebsiella oxytoca, and Citrobacter freundii. CONCLUSIONS: Early detection and adequate duration of therapy for ESBL-producing Enterobacteriaceae in solid organ transplants and MCS device recipients are essential in successful patient outcomes including prevention of recurrent infection.

Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation.

RATIONALE: Pseudomonas aeruginosa is the most commonly isolated gram-negative bacterium after lung transplantation and has been shown to up-regulate glutamic acid-leucine-arginine-positive (ELR(+)) CXC chemokines associated with bronchiolitis obliterans syndrome (BOS), but the effect of pseudomonas on BOS and death has not been well defined. OBJECTIVES: To determine if the influence of pseudomonas isolation and ELR(+) CXC chemokines on the subsequent development of BOS and the occurrence of death is time dependent. METHODS: A three-state model was developed to assess the likelihood of transitioning from lung transplant (state 1) to BOS (state 2), from transplant (state 1) to death (state 3), and from BOS (state 2) to death (state 3). This Cox semi-Markovian approach determines state survival rates and cause-specific hazards for movement from one state to another. MEASUREMENTS AND MAIN RESULTS: The likelihood of transition from transplant to BOS was increased by acute rejection, CXCL5, and the interaction between pseudomonas and CXCL1. The pseudomonas effect in this transition was due to infection rather than colonization. Movement from transplant to death was facilitated by pseudomonas infection and single lung transplant. Transition from BOS to death was affected by the length of time in state 1 and by the interactions between any pseudomonas isolation and CXCL5 and aspergillus, either independently or in combination. CONCLUSIONS: Our model demonstrates that common post-transplantation events drive movement from one post-transplantation state to another and influence outcomes differently depending upon when after transplantation they occur. Pseudomonas and the ELR(+) CXC chemokines may interact to negatively influence lung transplant outcomes.

Usefulness of immune monitoring in lung transplantation using adenosine triphosphate production in activated lymphocytes.

BACKGROUND: The ImmuKnow (Cylex Inc, Columbia, MD) assay measures the amount of adenosine triphosphate (ATP) produced by helper CD4(+) cells after stimulation with a T-cell mitogen. We hypothesized that this assay can be used to assess the immune function of lung transplant recipients and identify those at risk of developing acute cellular rejection and respiratory infection. METHODS: Lung transplant recipients at University of California Los Angeles between January 1, 2006 and December 31, 2009 received a bronchoscopy with broncheoalveolar lavage, transbronchial biopsy and ImmuKnow values drawn at regular intervals as well as during episodes of clinical deterioration. The recipient's clinical condition at each time-point was classified as healthy, acute cellular rejection, or respiratory infection. Mixed-effects models were used to compare the ATP levels among these groups, and odds ratios for rejection and infection were calculated. RESULTS: The mean ATP level was 431 ± 189 ng/ml for the rejection group vs 377 ± 187 ng/ml for the healthy group (p = 0.10). A recipient with an ATP level > 525 ng/ml was 2.1 times more likely to have acute cellular rejection (95% confidence interval [CI] 1.1-3.8). Similarly, the mean ATP level was 323 ± 169 ng/ml for the infection group vs 377 ± 187 ng/ml for the healthy group (p = 0.03). A recipient with an ATP level < 225 ng/ml was 1.9 times more likely to have respiratory infection (95% CI, 1.1-3.3). However, the test was associated with poor performance characteristics. It had low sensitivity, specificity with an area under the receiver operating characteristic curve of only 0.61 to diagnose rejection and 0.59 to diagnose infection. CONCLUSIONS: The ImmuKnow assay appears to have some ability to assess the overall immune function of lung transplant recipients. However, this study does not support its use as a reliable predictor of episodes of acute cellular rejection or respiratory infection.

Risk stratification in patients with advanced heart failure requiring biventricular assist device support as a bridge to cardiac transplantation.

BACKGROUND: Prior studies have identified risk factors for survival in patients with end-stage heart failure (HF) requiring left ventricular assist device (LVAD) support. However, patients with biventricular HF may represent a unique cohort. METHODS: We retrospectively evaluated a consecutive cohort of 113 adult, end-stage HF patients at University of California Los Angeles Medical Center who required BIVAD support between 2000 and 2009. RESULTS: Survival to transplant was 66.4%, with 1-year actuarial survival of 62.8%. All patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1 or 2 and received Thoratec (Pleasanton, CA) paracorporeal BIVAD as a bridge to transplant. Univariate analyses showed dialysis use, ventilator use, extracorporal membrane oxygenation use, low cardiac output, preserved LV ejection fraction (restrictive physiology), normal-to-high sodium, low platelet count, low total cholesterol, low high-density and high-density lipoprotein, low albumin, and elevated aspartate aminotransferase were associated with increased risk of death. We generated a scoring system for survival to transplant. Our final model, with age, sex, dialysis, cholesterol, ventilator, and albumin, gave a C-statistic of 0.870. A simplified system preserved a C-statistic of 0.844. Patients were divided into high-risk or highest-risk groups (median respective survival, 367 and 17 days), with strong discrimination between groups for death. CONCLUSIONS: We have generated a scoring system that offers high prognostic ability for patients requiring BIVAD support and hope that it may assist in clinical decision making. Further studies are needed to prospectively validate our scoring system.

Benefit of immune monitoring in heart transplant patients using ATP production in activated lymphocytes.

BACKGROUND: Balancing immunosuppression to prevent rejection while minimizing infection or drug toxicity risk is a major challenge in heart transplantation. Therapeutic drug monitoring alone is inadequate to measure the immune response. An immune monitoring (IM) assay (ImmuKnow; Cylex, Columbia, MD) performed on peripheral blood measures adenosine triphosphatase (ATP) release from activated lymphocytes and may predict the immune state. Therefore, we sought to determine the utility of IM in heart transplant recipients. METHODS: Between November 2005 and July 2008, 296 heart transplant recipients had a total of 864 IM assays performed at 2 weeks to 10 years post-transplant and were correlated with infection and rejection events that occurred within 1 month after IM testing. All patients received standard triple-drug immunosuppressive therapy with tacrolimus, mycophenolate mofetil and corticosteroids, without induction therapy. RESULTS: There were 38 infectious episodes and 8 rejection episodes. The average IM score was significantly lower during infection than steady state (187 vs 280 ng ATP/ml, p < 0.001). The average IM score was not significantly different during rejection when compared with steady state (327 vs 280 ng ATP/ml, p = 0.35). Interestingly, 3 of 8 rejection episodes were antibody-mediated rejections and had hemodynamic compromise and, for these, the mean IM score was significantly higher than for steady-state patients (491 vs 280 ng ATP/ml, p < 0.001). CONCLUSIONS: The non-invasive IM test appears to predict infectious risk in heart transplant patients. The association between high IM scores and rejection risk is inconclusive due to the small number of rejection episodes. Further studies with larger sample sizes for rejection episodes are required.

Use of hearts transplanted from donors with severe sepsis and infectious deaths.

BACKGROUND: The reluctance to use organs from donors who have died from severe infections is based on the potential transmission of an infectious agent to the recipient and on the uncertainty about allograft function in the setting of severe donor sepsis. METHODS: From 1999 to 2007, donor hospital records were reviewed which focused on microbiology cultures and sensitivity results; type and duration of antimicrobial therapy; hemodynamic data, results of echocardiogram, and imaging studies. Preliminary positive and negative results from pre-harvest blood, respiratory, urine, and cerebrospinal fluid cultures were verified with the procurement agency. The harvesting surgeon performed gross inspection of donor valvular structures. RESULTS: Nine donor hearts were transplanted from patients who expired from community onset infections with severe septic shock, meningitis, and/or pneumonia caused by Streptococcus pneumoniae (n = 4), Streptococcus milleri (n = 2), Neisseria meningitidis (n = 2), and unidentified gram- positive cocci (n = 1). Four donors had probable infection-induced intracranial hemorrhage, and all donors were vasopressor-dependent before organ procurement. No evidence of donor-transmitted infection, sepsis, or rejection was observed, and long-term function remained excellent; allograft dysfunction in three patients resolved after transplant. Our series of nine donors represents approximately 1.3% of successfully transplanted cardiac allografts during the respective period of review. CONCLUSIONS: Patients succumbing to severe infections (meningitis, pneumonia, and septic shock) should not be arbitrarily excluded for possible heart donation. Assessing the suitability of donors with severe infections requires flawless communication between the donor and transplant facility, including a comprehensive evaluation of donor infection and pathogen(s), severity of sepsis, adequacy of antimicrobial treatment, and the degree of sepsis-induced myocardial dysfunction.

Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.

BACKGROUND: We have previously shown antigenuria in patients with coccidioidomycosis through use of the Histoplasma antigen enzyme immunoassay (EIA), and now we have developed a specific Coccidioides antigen EIA. METHODS: The Coccidioides EIA uses antibodies to Coccidioides galactomannan. The sensitivity of the Coccidioides and Histoplasma EIAs was evaluated in patients with more-severe coccidioidomycosis, and the specificity of these EIAs was evaluated in patients with nonfungal infections, in patients with other endemic mycoses, and in healthy individuals. RESULTS: Among patients in the present study, antigenuria was detected in 70.8% of patients with coccidioidomycosis with use of the Coccidioides EIA and in 58.3% of patients with use of the Histoplasma EIA. Antigenuria was absent in 99.4% of healthy individuals, patients with nonfungal infections, and patients with noninfectious conditions. Cross-reactions with other endemic mycoses were observed in 10.7% of patients. CONCLUSIONS: The Coccidioides EIA has potential to be useful in the rapid diagnosis of more-severe forms of coccidioidomycosis.

Bronchoalveolar immunologic profile of acute human lung transplant allograft rejection.

Bronchoalveolar lavage fluid (BALF) offers a potential means to diagnose acute rejection and could provide insight into the immune mechanisms responsible for lung allograft rejection. Transbronchial biopsies from 29 bronchoscopic procedures were assessed for rejection. Concurrent BALF lymphocyte subsets were examined by flow cytometry, including CD4 and CD8 T cells and their activation status by CD38 expression, natural killer (NK), NK-like T (NT), B, regulatory T, and invariant receptor NK-T cells. Percentages of CD4 were reduced, and CD8 and activation of CD4 T cells correlated with rejection. There were trends for increased NT, reduced NK, and increased B cell percentages with rejection, suggesting potential roles of these cells. Among regulatory cells, the percentages of regulatory T cells decreased and CD4/CD8 invariant NK-T cells increased during rejection, suggesting a proinflammatory profile. A unique BALF lymphocyte profile was associated with rejection and may provide insight into the pathogenesis of allograft rejection.

Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.

BACKGROUND: In 2005, patients with coccidioidomycosis were observed to have positive Histoplasma antigen test results. METHODS: We performed a review of the records of patients with coccidioidomycosis who were under our care who underwent testing for Histoplasma antigen to determine the value of this test in the diagnosis of coccidioidomycosis. Many of the patients were immunosuppressed and critically ill. RESULTS: The Histoplasma antigen test had positive results when urine samples from 11 (58%) of 19 patients who had acute or chronic coccidioidomycosis were tested. The sensitivity was highest for patients who had acute coccidioidomycosis, and antigenuria was detected in 11 (79%) of 14 patients. One patient who had chronic coccidioidomycosis but who had a negative result when a urine sample was tested had antigen detected in bronchoalveolar lavage fluid. CONCLUSIONS: Physicians should be alerted that infections with Coccidioides species may cause positive Histoplasma antigen test results. There is potential for the use of this test in the diagnosis of coccidioidomycosis by taking advantage of this observed cross-reactivity. The greatest benefit appears to be in the population of seriously ill patients with acute pneumonia who live in areas that are endemic for Coccidioides infection.

Transmission of mycobacterium tuberculosis via lung transplantation.

Organ donors are not routinely screened for tuberculosis (TB) in the United States. We investigated a case of pulmonary TB in a double-lung transplant recipient. We reviewed the donor's and recipient's records, and used molecular methods to compare the lung recipient's isolate with others from three sources: her hospital, the California state health department's genotyping database, and the donor's resident-nation of Guatemala. A respiratory specimen obtained from the lung recipient 1 day after transplantation grew Mycobacterium tuberculosis. Donor chest radiograph had a previously unnoticed pulmonary opacity that was present on post-transplant recipient chest radiographs and computed tomographs. The recipient's isolate was molecularly distinct from others at her hospital and in the state database, but was identical to two isolates from Guatemala. Tuberculosis was transmitted from lung donor to recipient. As organ transplantation becomes more common worldwide, similar cases could occur. Screening for TB in potential organ donors should be considered.

Mycobacterium haemophilum infections in heart transplant recipients: case report and review of the literature.

Non-tuberculous mycobacteria are becoming increasingly important pathogens among transplant recipients. We report a case of disseminated Mycobacterium haemophilum infection in a heart transplant recipient, manifesting as cellulitis, subcutaneous nodules, septic arthritis, and pneumonitis. Our case illustrates diverse challenges in the identification and treatment of this pathogen, such as its unique culture requirements and variable antimicrobial susceptibilities. Heightened clinical suspicion is necessary to establish a timely diagnosis so that optimal treatment can be administered.

Leptospirosis, water sports, and chemoprophylaxis.

Recreational activities, such as water sports and adventure travel, are emerging as an important risk factor for leptospirosis, a potentially fatal zoonosis. We report the clinical course of 2 patients who acquired leptospirosis through participation in water sports. Physicians caring for patients who participate in adventure travel involving water sports should be familiar with the risk factors for and diagnosis, prevention, and treatment of leptospirosis.

Mycobacterium abscessus empyema in a lung transplant recipient.

Non-tuberculous mycobacteria (NTM) have emerged as important pathogens in organ transplant recipients. Because NTM pulmonary infections vary in their clinical and radiographic presentations, heightened clinical suspicion is necessary for accurate diagnosis. We report a case of Mycobacterium abscessus empyema in a lung transplant recipient. Repeated attempts at identifying the organism from a variety of clinical specimens led to the correct diagnosis and treatment.

Cluster of cases of invasive aspergillosis in a transplant intensive care unit: evidence of person-to-person airborne transmission.

In October 1998, a patient developed deep surgical-site and organ-space infection with Aspergillus fumigatus 11 days after undergoing liver retransplantation; subsequently, 2 additional patients in the transplant intensive care unit had invasive pulmonary infection with A. fumigatus diagnosed. It was determined that debriding and dressing wounds infected with Aspergillus species may result in aerosolization of spores and airborne person-to-person transmission.