Infections In Lung Transplant Recipients Research Articles

Extent of Cytomegalovirus Replication in the Human Host Depends on Variations of the HLA-E/UL40 Axis.

Human cytomegalovirus (HCMV) may cause severe infections in lung transplant recipients (LTRs). In response to HCMV infections, a subset of NKG2C+ NK cells expands, which limits HCMV replication and is characterized by high expression of the activating NKG2C/CD94 and absence of the inhibitory NKG2A/CD94 receptor. Both receptors bind to HLA-E, which is stabilized by HCMV-encoded UL40 peptides. HLA-E and UL40 occur as different genetic variants. In this study, we investigated the interplay between the human NK cell response and the infecting HCMV-UL40 strain, and we assessed the impact of HCMV-UL40 and of donor- and recipient-encoded HLA-E*0101/0103 variants on HCMV replication after lung transplantation. We included 137 LTRs displaying either no or low- or high-level (>1,000 copies/ml plasma) viremia. HCMV-UL40 and HLA-E*0101/0103 variants were determined. UL40 diversity was investigated by next-generation sequencing. UL40 peptide-dependent NK cell cytotoxicity was assessed by flow cytometry. Donor-encoded HLA-E*0101/0103 was significantly associated with development of high-level viremia after transplantation (P = 0.007). The HCMV-UL40 variant VMAPRTLIL occurred significantly more frequently in highly viremic LTRs, and the variant VMTPRTLIL occurred significantly more frequently in low-viremic LTRs (P = 0.004). This difference was associated with a better inhibition of NKG2A+ NKG2C- NK cells by VMAPRTLIL (P < 0.001). In LTRs with repeated high-level viremic episodes, HCMV strains with UL40 variants displaying low affinity to the patients' HLA-E variant emerged over time. The HLA-E-UL40 axis has a substantial impact on the level of HCMV replication in LTRs. The interplay between UL40 peptide variants, the recipient HLA-E status, and the activation of inhibitory NKG2A+ NKG2C- cells is of major importance for development of high-level viremia after lung transplantation.IMPORTANCE Infection with human cytomegalovirus (HCMV) is associated with substantial morbidity in immunosuppressed patients and after congenital infections. Therefore, development of a vaccine against HCMV is a main public health priority. Revealing the complex interaction between HCMV and host responses, is of utmost importance for understanding viral pathogenesis and for vaccine design. The present data contribute to the understanding of HCMV-specific host immune responses and reveal specifically the interaction between HLA-E and the virus-encoded UL40 peptide, which further leads to a potent NK cell response. We demonstrate that this interaction is a key factor for reduction of virus replication in immunosuppressed patients. We further show that distinct naturally occurring HCMV-UL40 variants reduce the activation of a specific subpopulation of host NK cells and thereby are associated with high-level viremia in the patients. These findings will allow the characterization of patients at risk for severe HCMV infection and contribute to strategies for HCMV vaccine development.

Review of Pharmacologic Considerations in the Use of Azole Antifungals in Lung Transplant Recipients.

Mold-active azole antifungals are commonly prescribed for the prevention of invasive fungal infections in lung transplant recipients. Each agent exhibits a unique pharmacologic profile, an understanding of which is crucial for therapy selection and optimization. This article reviews pharmacologic considerations for three frequently-used azole antifungals in lung transplant recipients: voriconazole, posaconazole, and isavuconazole. Focus is drawn to analysis of drug-interactions, adverse drug reactions, pharmacokinetic considerations, and the role of therapeutic drug monitoring with special emphasis on data from the post-lung transplant population.

Incidence and risk factors for respiratory tract bacterial colonization and infection in lung transplant recipients

To evaluate incidence of and risk factors for respiratory bacterial colonization and infections within 30 days from lung transplantation (LT). We retrospectively analyzed microbiological and clinical data from 94 patients transplanted for indications other than cystic fibrosis, focusing on the occurrence of bacterial respiratory colonization or infection during 1 month of follow-up after LT. Thirty-three percent of patients developed lower respiratory bacterial colonization. Bilateral LT and chronic heart diseases were independently associated to a higher risk of overall bacterial colonization. Peptic diseases conferred a higher risk of multi-drug resistant (MDR) colonization, while longer duration of aerosol prophylaxis was associated with a lower risk. Overall, 35% of lung recipients developed bacterial pneumonia. COPD (when compared to idiopathic pulmonary fibrosis, IPF) and higher BMI were associated to a lower risk of bacterial infection. A higher risk of MDR infection was observed in IPF and in patients with pre-transplant colonization and infections. The risk of post-LT respiratory infections could be stratified by considering several factors (indication for LT, type of LT, presence of certain comorbidities, and microbiologic assessment before LT). A wider use of early nebulized therapies could be useful to prevent MDR colonization, thus potentially lowering infectious risk.

Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study

IntroductionImmune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. MethodsA multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. ResultsTwenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225–525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). ConclusionAlthough ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.

Evaluation of Quantiferon®-Monitor as a biomarker of immunosuppression and predictor of infection in lung transplant recipients.

Optimizing immunosuppression in lung transplant recipients (LTR) is crucially important in minimizing the risk of infection and rejection. Quantiferon®-Monitor (QFM) is a candidate immune function biomarker which has not yet been rigorously evaluated in the lung transplant setting. The aim of this prospective cohort study was to explore relationships between QFM results, immunosuppression, and infection/rejection in LTR. QFM, which measures interferon-γ after stimulation with innate and adaptive immune antigens, was tested before and at 2, 6, 12, 24 and 52weeks post-transplant. Immunosuppression relationships were assessed with linear mixed effects models. Clinical outcomes were analyzed based on the preceding QFM result. Eighty LTR were included. Median pre-transplant QFM levels were 171IU/mL (IQR 45-461), decreasing to 3IU/mL (IQR 1-8) at 2weeks post-transplant then progressively recovering toward baseline with time from transplant. Prednisolone was strongly inversely associated with QFM level (0.1mg/kg dose increase correlating with 88IU/mL QFM decrease, 95% CI 61-114, P<.001). Patients with QFM values <10 and <60IU/mL were more likely to develop a serious opportunistic infection between 3 and 6months (HR 6.38, 95% CI 1.37-29.66, P=.02) and 6-12months (HR 3.25, 95% CI 1.11-9.49, P=.03) post-transplant, respectively. QFM values declined significantly post-transplant, with patients recovering at different rates. Prednisolone dose significantly impacted QFM results. Low levels were associated with infection beyond 3months post-transplant, suggesting that QFM may be able to identify overly immunosuppressed patients who could be targeted for dose reduction. Larger prospective studies are needed to further evaluate this promising assay.

COVID-19 in lung transplant recipients: A multicenter study.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

Nocardia prophylaxis, treatment, and outcomes of infection in lung transplant recipients: A matched case-control study.

Lung transplant recipients are at heightened risk for nocardiosis compared to other solid organ transplant recipients, with incidence rates as high as 9% and up to 30% associated mortality. No controlled studies assessing risk factors for nocardiosis in this high-risk population have been reported. Patients undergoing lung transplantation at a single center between 2012 and 2018 and diagnosed with nocardiosis post-transplant were matched 1:2 to uninfected control subjects on the basis of age, transplant date, and sex. The incidence of nocardiosis in this lung transplant population was 3.4% (20/586), occurring a median of 9.4months (range 4.4-55.2) post-transplant. In multivariable analysis, consistent use of trimethoprim/sulfamethoxazole (TMP/SMX) in the 12weeks prior to diagnosis was independently associated with protection against nocardiosis (OR 0.038; 95% CI 0.01-0.29; P=.002). Augmented immunosuppression in the 6months prior to diagnosis was independently associated with the development of nocardiosis (OR 9.94; 95% CI 1.62- 61.00; P=.013). Six case patients (30%) had disseminated disease; all-cause 6-month mortality was 25%. The most common species was Nocardia farcinica (7/17 isolates), which was associated with dissemination and mortality. The most active antibiotics were TMP/SMX (100%), linezolid (100%), and amikacin (76%). Imipenem was only active against 4/17 isolates (24% susceptibility), with two isolates becoming non-susceptible later in therapy. Trimethoprim/sulfamethoxazole prophylaxis was shown to be protective against nocardiosis in lung transplant recipients, while augmented immunosuppression conferred increased risk. Institutional epidemiologic data are needed to best guide empiric therapy for Nocardia, as historical in vitro data may not predict local susceptibilities.

PHAEOHYPHOMYCOTIC OSTEOMYELITIS AFTER BILATERAL LUNG TRANSPLANTATION

SESSION TITLE: Fellows Transplantation Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Phaeohyphomycoses are a heterogenous group of infections caused dematiaceous fungi, which are characterized by melanin pigmentation in the cell wall. While rare, these infections are being increasingly seen in both immunocompromised and immunocompetent individuals.1 Transplant patients are at a higher risk due to prolonged immunosuppression. We present a case of Bipolaris spp. osteomyelitis in a lung transplant recipient. CASE PRESENTATION: A 43 year-old female status post bilateral lung transplant for interstitial lung disease secondary to dermatomyositis on tacrolimus and prednisone, with a history of multiple surgical debridements of a chronic polymicrobial open chest wall wound infected with Vancomycin-resistant Enterococcus (VRE) and Enterobacter spp., presented with poor wound healing of the chest wound. She was taken to the operating room, and areas of devitalized tissue and purulence were debrided to create a single wound. Her empiric antibiotics were adjusted to daptomycin, and liposomal amphoptericin B upon identification of VRE and a mold. Final fungal cultures demonstrated Bipolaris, so voriconazole was substituted for amphotericin. After a fourteen day course of daptomycin, the patient was discharged with voriconazole and wound dressings with Iodasorb. Three weeks later, the patient was readmitted and started on broad spectrum antibiotics and continued on voriconazole after a CT Chest concerning for osteomyelitis was performed. She underwent surgical debridement by thoracic and plastic surgery of the chest wound and sternum. Bone specimens were noted to have invasive fungal elements in the bone consistent with osteomyelitis. Fontana-Masson staining was positive for melanin. Bacterial wound cultures grew VRE, Methicillin-sensitive Staphylococcus aureus, and Beta-Hemolytic Streptococci. She was discharged on oral linezolid and voriconazole for at least 6 weeks. DISCUSSION: Phaeohyphomycosis accounts for approximately for 2.6% of all fungal infections seen and are evenly distributed between stem cell and solid organ transplant patients.2 Bipolaris is an environmental mold associated with allergic fungal sinusitis with a higher prevalence in Southwest United States. Other less common presentations include cutaneous, subcutaneous skin infections, osteomyelitis and keratitis.1 Bipolaris in wound infections is rare, with cases reported only in cardiothoracic surgical patients, typically associated with delayed sternal closures. CONCLUSIONS: Bipolaris infection has not been reported in any other surgery except cardiac in literature. No standardized therapy exists, but in vitro sensitivity study show that itraconazole and voriconazole have excellent activity against Bipolaris.1 This case highlights the importance of considering phaeohyphomycotic infections in lung transplant recipients. Reference #1: Revankar S. G. (2015). Phaeohyphomycosis in Transplant Patients. Journal of fungi (Basel, Switzerland), 2(1), 2. https://doi.org/10.3390/jof2010002. Reference #2: McCarty, T. P., Baddley, J. W., Walsh, T. J., Alexander, B. D., Kontoyiannis, D. P., Perl, T. M., Walker, R., Patterson, T. F., Schuster, M. G., Lyon, G. M., Wingard, J. R., Andes, D. R., Park, B. J., Brandt, M. E., Pappas, P. G., & TRANSNET Investigators (2015). Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET). Medical mycology, 53(5), 440–446. https://doi.org/10.1093/mmy/myv018. DISCLOSURES: No relevant relationships by Sravya Brahmandam, source=Web Response No relevant relationships by Sruti Brahmandam, source=Web Response No relevant relationships by Dibson Gondim, source=Web Response No relevant relationships by ALLAN RAMIREZ, source=Web Response

COVID-19 in lung transplant recipients.

Solid organ transplant recipients are considered at high risk for COVID‐19 infection due to chronic immune suppression; little data currently exists on the manifestations and outcomes of COVID‐19 infection in lung transplant recipients. Here we report 8 cases of COVID‐19 identified in patients with a history of lung transplant. We describe the clinical course of disease as well as preexisting characteristics of these patients.

Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients.

Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV1) at 3 and 6 months postinfection, expressed as a percentage of pre‐infection FEV1 and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV1 loss at infection) and 51 mild infections (37%) (≤10% FEV1 loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV1 for ribavirin vs no ribavirin (+13.2% [95% CI: 7.79; 18.67]) and severe vs mild infection (−11.1% [95% CI: −14.76; −7.37]). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR [95% CI]) 0.24 [0.10; 0.59]), severe infection (OR [95% CI] 4.63 [1.66; 12.88]), and mycophenolate mofetil use (OR [95% CI] 0.38 [0.14; 0.97]). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long‐term outcomes. Well‐designed prospective trials are needed to confirm these findings.

Human Metapneumovirus Infections in Lung Transplant Recipients: The Effects on Lung Allograft and Clinical Outcomes

Human metapneumovirus infection (HMPVi) is a common community acquired infection in lung transplant recipients (LTRs), but data is very limited. This retrospective study of HMPVi in LTRs at the Johns Hopkins Hospital from Jan 2010 - April 2019 examined mortality, acute cellular rejection (ACR), donor specific antibody (DSA), chronic allograft dysfunction (CLAD) progression at 1 year after HMPVi as well as readmission, secondary bacterial/fungal infection at 90 days after HMPVi. The center's viral treatment practice included education for prompt diagnosis and consideration of ribavirin (RBV) usually with intravenous immunoglobulin (IVIG) for HMPVi. Of 31 HMPV infected LTRs, 22 received RBV (13 oral and 9 inhaled ribavirin) and 9 received supportive care only (SC). Baseline characteristics and infection parameters were similar among the 2 groups except concomitant respiratory bacterial pathogens at diagnosis, use of IVIG, and persistent HMPV shedding. In patients, whose respiratory viral PCR was repeated during day7-day30 post HMPVi, the SC group had significantly higher persistent viral shedding (66.7% vs 9.1% (RBV), p=0.03). There were no significant differences in readmission, death, CLAD progression, and DSA development among the 2 groups. The SC group had higher ACR rate (25% vs 0% (RBV), p = 0.03). Of 27 patients with complete pulmonary function tests, 11 (40.7%) developed CLAD progression within 1 year [50% (SC) vs 36.9% (RBV), p=0.53]. The SC group tended to have more fungal pathogen in respiratory samples (44.4% vs 13.6% (RBV), p= 0.06), but there were no significant differences in invasive fungal or bacterial infection at 90 days post HMPVs. Three patients reported side effects from RBV (nausea, diarrhea, and headache); none prematurely stopped RBV. RBV and IVIG may reduce risk of ACR and may help clear viral shedding. CLAD progression post HMPVi was 40% in this cohort and CLAD progression rates were not different among the 2 groups.

Ten Years of Ribavirin Treatment for Pneumovirus and Paramyxovirus Infections in Lung Transplant Recipients

Respiratory tract infection with respiratory syncytial virus (RSV), human metapneumo virus (hMPV) or parainfluenza virus (PIV) are increasingly associated with chronic lung allograft dysfunction in the form of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTR). Ribavirin as treatment option is under debate since its effectiveness is unclear, especially in light of infection severity. We retrospectively analyzed 10 years of RSV, hMPV and PIV infections in LTR in our center. Main endpoints were FEV1 at 3 and 6 months post-infection, expressed as a percentage of pre-infection FEV1 (by hierarchical linear mixed model) and incidence of new or progressed BOS 6 months post infection (by logistic regression). Patients with acute rejection < 3 mo. or transplantation <6 mo. prior to infection or with concomitant fungal infection were excluded. Time since transplantation, virus type (RSV, hMPV or PIV), viral co-infection, bacterial co-infection, presence of BOS prior to infection, severe or mild infection, follow-up time point (three vs. six months), tacrolimus use, mycophenolate mofetil (MMF) use, and ribavirin treatment (any form) were used as covariates in the multivariable models. A total of 139 infections were included, 88 (63%) with a severe infection (defined as a >10% FEV1 decline at infection), and 51 (37%) with a mild infection (≤10% FEV decline). Median [IQR] FEV1 decline during infection was notable and similar across the viruses (RSV 14% [22], hMPV 15% [14], PIV 16% [20]. Overall post-infection BOS incidence was 20% (27% for severe, 10% for mild). There were no virus related deaths. The linear mixed model found estimated associations on post-infection FEV1 for ribavirin treatment vs. no ribavirin (+13.2% [7.79;18.67]) and severe infection vs. mild infection (-11.1% [-14.76; -7.37). Ribavirin treatment (aOR 0.24 [0.10-0.59]), severe infection (aOR 4.63 [1.66;12.88]) and surprisingly also MMF use (aOR 0.38 [0.14;0.97]) were factors associated with new or progressed BOS at 6 months. LTR with a mild infection tended to recover well, regardless of antiviral therapy. We conclude that ribavirin should be considered as treatment option to possibly prevent allograft dysfunction in LTR with severe RSV, hMPV or PIV infection. We found no reason to discontinue MMF during these infections.

Human Cytomegalovirus (HCMV)-Specific Antibody Response and Development of Antibody-Dependent Cellular Cytotoxicity Against HCMV After Lung Transplantation.

Human cytomegalovirus (HCMV) may cause severe infections in lung transplant recipients (LTRs). The impact of the host antibody (AB)-dependent cytotoxicity (ADCC) on HCMV is still unclear. Therefore, we analyzed the AB-response against HCMV glycoprotein B (gB) and the pentameric complex (PC) and the ADCC response in HCMV-seropositive (R+) LTRs and in seronegative recipients of positive organs (D+/R-). Plasma samples were collected from 35 R+ and 28 D+/R- LTRs for 1 (R+) or 2 (D+/R-) years posttransplantation and from 114 healthy control persons. The PC- and gB-specific ABs were assessed by enzyme-linked immunosorbent assay. The ADCC was analyzed by focal expansion assay and CD107 cytotoxicity assay. In R+ LTRs, significantly higher gB-specific AB levels developed within 1 year posttransplantation than in controls (immunoglobulin [Ig]G1, P < .001; IgG3, P < .001). In addition, higher levels of ADCC were observed by FEA and CD107 assay in R+ patients compared with controls (P < .001). In 23 D+R- patients, HCMV-specific ABs developed. Antibody-dependent cytotoxicity became detectable 3 months posttransplantation in these, with higher ADCC observed in viremic patients. Depletion of gB- and PC-specific ABs revealed that, in particular, gB-specific Abs were associated with the ADCC response. We show that a strong ADCC is elicited after transplantation and is especially based on gB-specific ABs.

Infection prophylaxis and management of fungal infections in lung transplant.

Lung transplantation has emerged as a lifesaving treatment for a wide range of advanced lung diseases. While the survival of lung transplant recipients continues to improve, infectious complications contribute substantially to morbidity and mortality following lung transplantation. The incidence of invasive fungal infections is variable, with a mean occurrence of 8.6%. The majority of fungal infections in lung transplant recipients are caused Aspergillus and Candida species. This review provides an update in the current approaches for the diagnosis, management and prevention of fungal infections and the late complications that are associated.

Clinical outcomes of ceftazidime-avibactam in lung transplant recipients with infections caused by extensively drug-resistant gram-negative bacilli.

Infections produced by extensively drug-resistant (XDR) gram-negative bacilli (GNB) in solid organ transplant (SOT) are an important cause of morbidity and mortality. Ceftazidime/avibactam (CAZ-AVI) is a novel β-lactam/β-lactamase combination antibiotic with anti-GNB activity, but experience in real clinical practice with CAZ-AVI in lung transplant (LT) recipients is limited. We conducted a retrospective study of patients with XDR-GNB infection who received at least 3 days of CAZ-AVI in the Department of Lung Transplantation Between December 2017 and December 2018 at China-Japan friendship hospital (CJFH). The general information, clinical manifestations, laboratory examinations, treatment course, and outcomes were summarized. A total of 10 patients who underwent LT at our center were included. They were all males with a mean age 51 years. Infections after LT included pneumonia and/or tracheobronchitis [n=9; 90% (9/10)], cholecystitis and blood stream infection (BSI) (n=1, patient 8). In these 10 LT recipients, the incidence of various airway complications was 70% (7/10). Carbapenem-resistant Klebsialla pneumoniae (CRKP) was the predominant pathogen, being detected in 9 patients. Multilocus sequence typing (MLST) analysis showed that all 9 CRKP isolates belonged to ST11. Six patients (6/10, 60%) started CAZ-AVI as salvage therapy after a first-line treatment with other antimicrobials. CAZ-AVI was administered as monotherapy or in combination regimens in 20% (2/10) and 80% (8/10) of patients respectively. There were no difference in temperature before and after CAZ-AVI treatment (P>0.05). White blood cell (WBC) at 7 days, and procalcitonin (PCT) at 7 days and 14 days significantly dropped (P<0.05). After 7-14 days of CAZ-AVI treatment, the PaO2/FiO2ratio (P/F ratio) significantly improved (P<0.05). Nine patients (9/10, 90%) obtained negative microbiologic culture of CRKP/CRPA, with a median time to was 6.7 days (range, 1-15 days). However, 5 patients (5/10, 50%) had relapse of CRKP/CRPA infections in the respiratory tract regardless of whether negative microbiologic culture was obtained or not. The 30-day survival rate was 100%, and the 90-day survival rate was 90% (1/10). No severe adverse events related to CAZ-AVI occurred. CAZ-AVI treatment of CRKP/ CRPA infection in LT recipients was associated with high rates of clinical success, survival, and safety, but recurrent CRKP/CRPA infections in the respiratory tract did occur.

Mucormycosis in lung transplant recipients: A systematic review of the literature and a case series.

Mucormycosis is a rare infection in lung transplant recipients (LTR). Our objective was to better define the clinical presentation and optimal management of this frequently lethal infection. A systematic review of the literature was performed to identify all published cases of mucormycosis in LTR using PubMed/MEDLINE. These cases were analyzed together with a new case series from our clinic. Literature search yielded 44 articles matching the inclusion criteria, describing 121 cases. Six additional cases were identified from our clinic. Data regarding infection site and outcome were available for a total of 53 patients. The lungs were the most common site of infection (62%), followed by rhinocerebral and disseminated disease. Most cases (78%) developed in the first post-transplant year, with over 40% of them in the first month. Additional risk factors for mucormycosis were identified in over half of the patients. Surgical debridement was uncommon in pulmonary infection (9%). Posaconazole therapy was used in 35% of cases, mostly in combination with amphotericin B. Overall mortality was 32% but varied according to site of infection. Mucormycosis in LTRs tends to be an early post-surgical infection, associated with additional risk factors and intensified immunosuppressive states, and most often affects the lungs, where surgical debridement is rarely feasible. Posaconazole as first-line therapy should be further explored.

Infections in Lung Transplant Recipients during and after Prophylaxis

BackgroundThe timeline of infections after lung transplantation has been changed with the introduction of new immunosuppressants and prophylaxis strategies. The study aimed to investigate the epidemiological characteristics of infectious diseases after lung transplantation in the current era.Materials and MethodsAll patients who underwent lung or heart–lung transplantation at our institution between October 29, 2008 and April 3, 2019 were enrolled. We retrospectively reviewed the patients' medical records till April 2, 2020.ResultsIn total, 100 consecutive lung transplant recipients were enrolled. The median follow-up period was 28 months after lung transplantation. A total of 127 post–lung transplantation bacterial infections occurred. Catheter-related bloodstream infection (25/84, 29.8%) was the most common within 6 months and pneumonia (23/43, 53.5%) was the most common after 6 months. Most episodes (35/40, 87.5%) of respiratory viral infections occurred after 6 months, mainly as upper respiratory infections. The remaining episodes (5/40, 12.5%) mostly manifested as lower respiratory tract infections. Seventy cytomegalovirus infections observed in 43 patients were divided into 23 episodes occurring before and 47 episodes occurring after discontinuing prophylaxis. Of 10 episodes of cytomegalovirus disease, four occurred during prophylaxis and six occurred after prophylaxis. Of 23 episodes of post–lung transplantation fungal infection, 7 were aspergillosis and all occurred after the discontinuation of prophylaxis.ConclusionLung transplant recipients experienced a high burden of infection even after 6 months, especially after the end of the prophylaxis period. Therefore, these patients should be continued to be monitored long-term for infectious disease.

Donor-derived bacterial infections in lung transplant recipients in the era of multidrug resistance

ObjectivesOur aim was to analyze the prevalence of multidrug-resistant bacterial infections in lung transplant donors and to evaluate its influence on donor-derived bacterial infections. MethodsWe conducted a retrospective study of adult patients who underwent lung transplantation (2013–2016) at our hospital. Donor-derived bacterial infection was defined as the isolation of the same bacteria with identical antibiotic susceptibility patterns in the recipient and the perioperative cultures from the donor during the first month posttransplantation. We utilized a preventive antibiotic strategy adapted to the bacteria identified in donor cultures using systemic and nebulized antibiotics. Results252 lung transplant recipients and 243 donors were included. In 138/243 (56.8%) donors, one bacterial species was isolated from at least one sample; graft colonization (118/243; 48.6%), blood cultures (5/243; 2.1%) and the contamination of preservation fluids (56/243; 23%). Multidrug-resistant bacteria were isolated from 12/243 (4.9%) donors; four Enterobacterales, four Stenotrophomonas maltophilia, three Pseudomonas aeruginosa and one methicillin-resistant Staphylococcus aureus. There was no transmission of these multidrug-resistant bacteria. Donor-derived infections, primarily tracheobronchitis due to non-MDR bacteria, were diagnosed in 7/253 (2.9%) recipients, with good clinical outcomes. ConclusionsThe lungs of donors colonized with multidrug-resistant bacteria may be safely used when recipients receive prompt tailored antibiotic treatment.

2673. Risk Factors for Clostridium difficile Infection in Lung Transplant Patients

Background Clostridium difficile infection is a serious and common illness affecting almost 500,000 people in the United States each year. Solid-organ transplant recipients are at increased risk for this infection, with lung transplant patients being at the highest risk. Temple University Hospital (TUH) in Philadelphia has performed the most lung transplants in the United States over the last 2 years.MethodsA retrospective case–control study was performed to identify patients diagnosed with C. difficile following lung transplantation at our institution between January 1, 2014 and April 30, 2018 (N = 35). We randomly selected control patients (N = 35) who had lung transplantation performed during this time but did not develop C. difficile infection. The study objectives were to characterize risk factors that are associated with C. difficile infection in lung transplant recipients and compare clinical outcomes in recipients with and without C. difficile. Statistical analysis was performed using Epi Info (CDC, Atlanta GA).ResultsThe average age was 62.4 years, 64.7% were male, 75% were white and 69.1% of transplants were performed for underlying idiopathic pulmonary fibrosis. 52.9% of patients had “non-severe” C. difficile infection as defined by the 2018 Infectious Disease Society of America guidelines. Patients with C. difficile infection were more likely to have been treated for cytomegalovirus (CMV) viremia (OR 8.2, 95% CI 2.4–28.2, P = 0.0006) and were more likely to have received third- to fifth-generation cephalosporins (OR 4.0, 95% CI 1.4–11.2, P = 0.01) and/or carbapenems (OR 3.7, 95% CI 1.4–9.9, P = 0.02). Patients with C. difficile infection were more likely to experience multiple hospitalizations when compared with C. difficile-negative patients (3.6 vs. 8.4, P = 0.003). 22 of the 68 evaluable patients died during the study period, 9 of whom had C. difficile infection (P = NS).ConclusionPatients who received lung transplants and developed C. difficile infection were more likely to be treated for CMV viremia, receive antibiotics including cephalosporins and/or carbapenems and require repeat hospitalizations when compared with control patients who did not develop C. difficile infection following transplant.Disclosures All authors: No reported disclosures.

2640. Aerosol vs. Oral Ribavirin for the Treatment of Community-Acquired Respiratory Virus Infections in Lung Transplant Recipients

BackgroundCommunity-acquired respiratory virus (CARV) infections are associated with an increased risk of chronic lung allograft dysfunction (CLAD) and graft loss in lung transplant recipients (LTR). Administration of ribavirin by aerosol was the standard of care at Stanford Health Care in the management of CARV infections. Given the sparse evidence of benefit with aerosol ribavirin (AR) and its increasing cost and teratogenic risk for exposed healthcare personnel, AR was restricted to the treatment of respiratory syncytial virus (RSV) in 2016 and was ultimately removed from formulary in 2017. Oral (PO) ribavirin was used at the discretion of the transplant team. The objective of this study was to evaluate the clinical outcomes of AR compared with PO ribavirin in lung transplant recipients.MethodsWe performed a retrospective cohort analysis of adult lung transplant recipients diagnosed with CARV (metapneumovirus, parainfluenza virus, and RSV) infections treated with either AR or PO ribavirin. The analysis included the first treatment course of ribavirin by either route and patients were excluded if they received ribavirin in the prior 12 months. The primary outcome was the development/progression of CLAD, acute organ rejection, and overall mortality.ResultsOf 85 patients, 41 received AR and 44 received PO ribavirin. There was no significant difference in the following clinical outcomes with AR and oral ribavirin, respectively: development or progression of CLAD (30 days: 9.7% vs. 4.5%, P = 0.4227; 90 days: 14.6% vs. 6.8%, P = 0.303; 6 months: 17% vs. 9%, P = 0.3413; 12 months: 24% vs. 15.9%, P = 0.4188), acute organ rejection (90 days: 7.3% vs. 4.5%, P = 0.6689; 6 months: 12.1% vs. 9%, P = 0.7329; 12 months: 19.5% vs. 13.6%, P = 0.5635), and overall mortality (30 days: 0% vs. 4.5%, P = 0.4947; 90 days: 7.3% vs. 4.5%, P = 0.6689; 6 months: 7.3% vs. 9%, P = 1.0; 12 months: 7.3% vs. 13.6%, P = 0.4858). There was no observable difference in reported adverse effects between AR and PO ribavirin.ConclusionLung transplant recipients with CARV infections had similar outcomes when treated with AR or PO ribavirin. Oral ribavirin is a less costly treatment than AR, but the efficacy of ribavirin by any route remains questionable. Disclosures All authors: No reported disclosures.