Infections In Lung Transplant Recipients Research Articles

Routine Donor and Recipient Screening for Mycoplasma hominis and Ureaplasma Species in Lung Transplant Recipients.

Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum may cause post-transplant infections in lung transplant recipients. We evaluated routine pretransplant screening for these Mollicutes. We retrospectively reviewed records of lung transplant recipients at our tri-site institution from 01/01/2015 to 11/15/2019. M. hominis and/or Ureaplasma polymerase chain reaction (PCR) was performed on pretransplant recipient urine specimens and donor bronchial swabs at the time of transplantation. Development of Mollicute infection and hyperammonemia syndrome (HS) was recorded. A total of 268 patients underwent lung transplantation during the study period, of whom 105 were screened with at least 1 Mollicute PCR. Twelve (11%) screened positive; 10 donors, 1 recipient, and 1 both. Among positive donors, 3 were positive for M. hominis, 5 for U. urealyticum, and 4 for U. parvum. Preemptive therapy included doxycycline, levofloxacin, and/or azithromycin administered for 1-12 weeks. Despite therapy, 1 case of M. hominis mediastinitis and 1 case of HS associated with Ureaplasma infection occurred, both donor-derived. Of those screened before transplant, cases with positive screening were more likely (P < 0.05) to develop Mollicute infection despite treatment (2/12, 17%) than those who screened negative (1/93, 1%). Pretransplant recipient urine screening had a low yield and was not correlated with post-transplant Mollicute infection, likely because most M. hominis and U. parvum/urealyticum infections in lung transplant recipients are donor-derived. Routine donor bronchus swab PCR for M. hominis, U. urealyticum, and U. parvum followed by preemptive therapy did not obviously impact the overall incidence of Mollicute infection or HS in this cohort.

Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients.

Posaconazole is used for prophylaxis and treatment of invasive fungal infections in lung transplant recipients (LTR). Previous studies have not described the relationship between elevated posaconazole trough concentrations and adverse drug reactions in this population. This IRB-approved, retrospective cohort study at NewYork-Presbyterian Hospital included LTR who had posaconazole trough concentrations measured. The primary aim of this study was to evaluate elevated posaconazole trough concentrations and changes in liver function tests as well as QTc interval. A secondary aim of this study was to identify patient factors associated with elevated posaconazole trough levels. A total of 109 LTR were included. The average age was 58.1years (IQR, 48-65), the majority were male (56%). A total of 932 trough levels were assessed with a median number of 8 (IQR, 5-15) levels per patient. The median posaconazole trough concentration was 1.7mg/L (IQR, 1.1-2.5). Hepatotoxicity, as defined by common terminology criteria for adverse events (CTCAE), was observed in 73.4% of subjects, with the majority classified as grade 1 (67.5%). However, there was no correlation between elevated posaconazole levels and aspartate aminotransferase (r=.03), alanine aminotransferase (r=.04), alkaline phosphatase (r=.04), and total bilirubin (r=.02). There was also no correlation between posaconazole trough concentrations and QTc interval (r=.03). This analysis demonstrates that no correlation exists between whole blood posaconazole levels and hepatotoxicity or QTc prolongation. Based on these results, posaconazole dose reductions may not be warranted for posaconazole levels that are significantly above the therapeutic target to avert risk for hepatotoxicity or QTc prolongation.

PROLONGED COLONIZATION AND COISOLATION OF SARS-COV-2 IN UNVACCINATED RECIPIENTS OF LUNG TRANSPLANTS

PROLONGED COLONIZATION AND COISOLATION OF SARS-COV-2 IN UNVACCINATED RECIPIENTS OF LUNG TRANSPLANTS

P16.07: Association Between SARS-CoV-2 Infection and de Novo HLA Donor Specific Antibody Production in Lung Transplant Recipients: Single-Center Study

Introduction: COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impacting lung transplant outcome. Methods: Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. Results: We observed no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies. Conclusion: SARS-CoV-2 infection was not associated with a significant increase in de-novo HLA DSA production or MFI levels of pre-existing HLA DSA compared to pre-COVID-19 diagnosis in lung transplant recipients. These results provide a valuable insight on the effects of SARS-CoV-2 infection on immunogenicity in lung transplant recipients.

415.6: Exploring Cell-Specific Mechanisms of Ischemia/Reperfusion Injury Mediated Reactivation of Cytomegalovirus From Latency in the Orthotopic Mouse Lung Transplantation

Purpose: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplant recipients, with the highest risk seen in CMV seronegative recipients (R-) of seropositive organs (D+). This study aims to explore key molecular pathways responsible for transplant-mediated CMV reactivation by using single-cell RNA sequencing (scRNA-seq) in a mouse model of syngeneic D+/R- lung transplantation. Methods: Left lungs from naïve (D-) mice or MCMV latently infected (D+) mice were transplanted to syngeneic R- recipients, while the contralateral right lungs served as controls. Lung tissues from the transplants at day 2 post-transplant (POD) or controls were harvested for viral RNA analysis and single cell isolation. CD31+ and CD45+ enriched single cell suspensions were processed using 10X Genomics, followed by sequencing. The sequenced data were processed using Cell Ranger pipeline and Seurat. Additional transplants were treated with small molecule Myd88 inhibitor to determine whether innate immunity plays a role in transplant induced CMV reactivation. Results: MCMV IE-1 mRNA transcripts were significantly upregulated at POD 2, but were not detectable in the controls, indicating that transcriptional activation is induced in the early phase of transplant and ischemia/reperfusion (I/R) injury associated with the transplant procedures is an important contributing factor. In addition, viral DNA amplification was detected in the salivary glands of D+/R- recipients at POD14, confirming that transplant of a D+ graft results in viral reactivation and dissemination. These data support the mouse lung transplant model as a viable approach to study mechanisms of CMV reactivation. Data from scRNAseq analysis showed distinct lung and immune cell clusters in lung transplants and controls. There were minimal differences in transcriptome landscapes between D- and D+ lungs prior to transplant (controls). In contrast, the differences were prominent between lungs from D-/R- transplant vs D+/R- lung grafts in the myeloid populations [e.g. neutrophils, macrophages (Macs)] and endothelial cells. Gene expression of Macs showed more differences between transplant lungs and control lungs than any endothelial cells or neutrophils. Pathway analysis of differentially expressed genes for myeloid cell types showed several significant immune response pathways including MIF regulation of innate immunity and communication between innate and adaptive immune cells. Expression of Myd88 and c-fos were increased in the lung grafts regardless of latent MCMV infection. Furthermore, our preliminary study using a Myd88 inhibitor showed a trend of CMV viral load reduction in lung grafts. Conclusions: Early I/R injury following lung transplant resulted significant alterations of transcriptome landscape unique to different cell types. Myd88/AP-1 plays a critical role in CMV reactivation; thus targeting Myd88 has a great therapeutic potential to prevent I/R injury-mediated CMV reactivation. NIH NIAID R21AI163876. NIH/NIAID P01AI112522.

Association between SARS-CoV-2 infection and de novo HLA donor specific antibody production in lung transplant recipients: Single-center study

The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impact lung transplant outcome. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. We observed no significant differences in the CPRA or MFI levels of HLA class I and II antibodies pre- COVID-19 compared to 1 and 6 months post-COVID-19 diagnosis in 11/24 (45.8 %) LTR (p = 0.98 and p = 0.63 respectively). HLA class I and II DSA were detected in 5/24 LTR pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.89). De-novo HLA class I and II DSA were detected in 1/24 (4.2 %) LTR at one month post-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis (p = 0.54). Our results suggest that there was no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies.

The Evolving Landscape of Diagnostics for Invasive Fungal Infections in Lung Transplant Recipients

The Evolving Landscape of Diagnostics for Invasive Fungal Infections in Lung Transplant Recipients

Antibiotic Therapy for Difficult-to-Treat Infections in Lung Transplant Recipients: A Practical Approach.

Lung transplant recipients are at higher risk to develop infectious diseases due to multi-drug resistant pathogens, which often chronically colonize the respiratory tract before transplantation. The emergence of these difficult-to-treat infections is a therapeutic challenge, and it may represent a contraindication to lung transplantation. New antibiotic options are currently available, but data on their efficacy and safety in the transplant population are limited, and clinical evidence for choosing the most appropriate antibiotic therapy is often lacking. In this review, we provide a summary of the best evidence available in terms of choice of antibiotic and duration of therapy for MDR/XDR P. aeruginosa, Burkholderia cepacia complex, Mycobacterium abscessus complex and Nocardia spp. infections in lung transplant candidates and recipients.

Donor-Derived Disseminated Mycobacterium Tuberculosis Infection in a Lung Transplant Recipient Three Months After Transplant

<h3>Introduction</h3> Reactivation of latent mycobacterium tuberculosis (MTB) infection in lung transplant recipients is common, which is why pre-transplant screening is recommended to guide treatment. However, MTB transmission from a donor organ is much rarer and there is no consistent screening process of donors. We describe a consequence of this, a rare case of donor-derived disseminated MTB infection in a bilateral lung transplant (BLTx) recipient. <h3>Case Report</h3> A 61-year-old female three months post BLTx complicated by post-operative right lung torsion requiring pneumonectomy presented with a swollen and tender right index finger, tender nodules along her occiput, and a recurrent left sided pleural effusion, which was drained on presentation and culture negative. She improved initially with linezolid and ceftriaxone for presumed septic arthritis, however re-presented two weeks later with similar features, which prompted further evaluation. CT and subsequently MRI of the abdomen demonstrated multiple rim-enhancing liver lesions. A finger aspirate and liver biopsy were obtained that were both culture and smear positive for MTB. Sputum acid fast bacilli samples were negative, and she was started on quadruple therapy with rifabutin, isoniazid, pyrazinamide, and ethambutol with clinical improvement, including resolution of her culture-negative pleural effusion. We suspect that this was a donor-derived infection as the donor lived in an endemic region for many years and the recipient was latent TB negative pre-transplant. <h3>Summary</h3> Donor-derived MTB infection can be difficult to diagnosis due to the atypical way it can present, especially in patients who reside in non-endemic areas. As the world becomes more globalized, and access to lung transplant more accessible, we believe that more donor organs will come from individuals who have lived in endemic areas increasing the risk of donor-derived MTB infections making this an important diagnosis to consider.

Donor and Peri-Transplant Hospitalization Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients

<h3>Purpose</h3> Invasive fungal infections (IFIs) remain a frequent complication in the lung transplant (LTx) population even in the current era of antifungal prophylaxis. The organ donor and peri-transplant period risk factors for IFI remain ill-defined. Our study goal is to identify novel risk factors for IFI, focusing on the organ donor and the recipient's transplant hospitalization. <h3>Methods</h3> We performed a single-center, case-control study. The source cohort included all adults who underwent LTx between 1/1/12-3/31/17. The primary outcome was a Probable or Proven IFI within 6 months of transplantation, as defined by EORTC/MSG criteria. Multivariable logistic regression and Cox proportional hazard regression analyses were used to identify independent risk factors for IFI. <h3>Results</h3> Of 329 LTx recipients, 45 (14%) developed IFI. The median time to IFI was 50 days (IQR: 25-110) after transplantation. Independent risk factors for IFI included: donor steroid pre-conditioning (aOR 2.24, 95%CI: 1.05-4.77, p=0.04); cardiopulmonary bypass (aOR 3.07, 95%CI: 1.06-8.87, p=0.04); ICU length of stay >30 days (aOR 3.34, 95%CI: 1.48-75, p<0.01); and bronchial anastomotic dehiscence (aOR 14.06, 95%CI: 1.99-99.34, p=0.01). Mold isolated on donor respiratory culture increased the hazard of IFI in LTx recipients (Table 1). Peri-transplant hospitalization complications that increased the hazard of IFI included: multiple positive fungal cultures, airway ischemia, and prolonged ICU stay (Table 1). Fungal treatment for ≥90 days after transplant was protective against development of IFI (Table 1). <h3>Conclusion</h3> IFI was common in our LTx cohort. Certain donor characteristics and peri-transplant complications increased the likelihood of IFI. Interventional studies, targeting the modifiable risk factors identified in this study, are needed to reduce IFI risk in LTx recipients.

Utility of Turbidimetric Beta-D-Glucan in Lung Transplant Recipients

<h3>Purpose</h3> Beta-D-Glucan (BDG) is a cell wall polysaccharide and its detection in serum can be indicative of fungal infection. Evidence for BDG testing in solid organ transplantation has been derived from data using a colorimetric assay. We introduced a turbidimetric assay for BDG (Wako) into our center and assessed its utility in the diagnosis of fungal infections in lung transplant recipients. Furthermore, BDG can be used as an antimicrobial stewardship tool if results are available promptly, as a high negative predictive value can give clinicians confidence in stopping or avoiding empiric antifungal therapy. <h3>Methods</h3> Data were collected on 115 BDG tests undertaken from February 2020 through to December 2020 on 66 post lung transplant recipients with suspected or confirmed fungal infection. Tests were ordered following multidisciplinary team discussions with transplant physicians and clinical microbiologists. <h3>Results</h3> Of 115 tests, 50 were positive of which 12 contributed to the early diagnosis of a fungal infection, 36 were used to follow response to treatment in a confirmed fungal infection and 2 were falsely positive. Infections diagnosed were invasive aspergillosis (8), invasive candidiasis (1), Pneumocystis jirovecii pneumonia (1), cryptococcal meningitis (1) and invasive Scedosporium apiospermun infection (1). Of the 65 negative tests, 43 contributed to an invasive fungal infection being ruled out and empiric antifungal therapy being discontinued or avoided without any adverse consequences. 5 negative tests did not result in de-escalation from antifungal therapy. 17 tests were repeat tests undertaken as follow-up. <h3>Conclusion</h3> In our cohort, the turbidimetric BDG had a sensitivity and specificity of 100% and 97% respectively, with a positive predictive value of 96% and negative predictive value of 100%. The high efficiency of this test is likely influenced by the diagnostic stewardship applied in ordering the test, raising the pre-test probability. Turn-around times were 1 day average with a range of 1-7 days. The high negative predictive value allowed negative BDG results to be used as an antimicrobial stewardship tool. A direct saving of €9,053 was made as a result of empiric antifungal therapy being stopped following a negative BDG result. In conclusion, the turbidimetric assay for BDG is efficacious for confirming or ruling out fungal infection in post-lung transplant patients.

Secondary Bacterial and Fungal Pneumonia Complicating SARS-CoV-2 and Influenza Infections in Lung Transplant Recipients

PurposeSelect bacterial and mold infections are known risk factors for chronic allograft dysfunction (CLAD) in a subset of lung transplant recipients (LTR). Secondary bacterial (SBI) and fungal infections (SFI) have been described among people with severe influenza infection and COVID-19 requiring mechanical ventilation, but the incidence and clinical outcomes of LTR who develop secondary infections following respiratory viral infections (RVI) are not well described.MethodsWe conducted a retrospective study of LTR who were diagnosed with either influenza or COVID-19 from January 2011-May 2021. Infection definitions and CLAD stage were defined according the International Society of Heart and Lung Transplantation guidelines.ResultsFifty-seven LTR with influenza and 33 with COVID-19 were identified. Eleven (19%) of the LTR with influenza developed SBI and seven (21%) with COVID-19 developed SBI (p=0.83). Among patients who developed SBI, Pseudomonas aeruginosa was the most common isolated pathogen (44%). Five (9%) and 7 (21%) LTR developed SFI within 90 days post Influenza and COVID-19 infection, respectively (p = 0.09). Among patients with fungal infection, Aspergillus species were the most common pathogen (75%). At 180 days post RVI, all-cause mortality was higher in LTR with SBI (17%) compared to those without (3%), p=0.02. Mortality was similarly higher in LTR with SFI (33%), compared to those without (1.3%), p<0.0001. At 180 days post RVI, LTR with SBI had progression of CLAD stage 43% vs 11%, p=0.004. Based on univariable logistic regression, LTR who had augmented corticosteroids at time of RVI, and lower respiratory tract infection (LRTI) had higher risk of SFI (odds ratio (OR) of 6.57 (1.8, 23.9), p=0.002 and 12.5 (2.53, 61.7), p=0.004, respectively). There were trends of increased OR of SBI among LTR with LRTI and LTR requiring ICU admission due to RVI with the ORs of 2.78 (0.98, 8.01), p=0.06 and 3.77 (0.90, 15.84), p=0.07, respectively.ConclusionSecondary bacterial and fungal infections are associated with increased all-cause mortality in LTR with influenza and COVID-19, and in the case of SBI, also associated with CLAD stage progression. LTR with LRTI and augmented steroids may be at increased risk of secondary fungal infections. Strategies to mitigate and improve diagnosis may warrant further examination.

Short and Intermediate Term Effects of COVID-19 Infection on Lung Transplant Recipients

PurposeThe characteristics and outcomes, including acute cellular rejection (ACR), of lung transplant recipients (LTR) post COVID-19 infection are incompletely studied. We sought to show whether or not COVID-19 infection in LTR is associated with ACR.MethodsThis single center, retrospective study of LTR examined data among those who contracted COVID-19 between June 2020 and May 2021. Patient demographics, immunosuppression regimen, and hospital course related to COVID-19 infection were recorded. Subsequent spirometry, imaging, and biopsy results were documented.ResultsWe identified 16 LTR who tested positive for COVID by PCR testing. Acute radiographic changes were detected in half (8) of the cohort, 3 patients eventually required ICU admission, 1 which required venovenous extracorporeal membrane oxygenation. The median drop in FEV1 and FVC after COVID-19 infection was -375 (-1140 to +120) and -260mL (-1790 to +410), respectively. ACR was diagnosed in 2 patients at 6 weeks post COVID-19 infection. Both of the patients who were diagnosed with ACR required hospitalization, and one required ICU admission. There was 1 death at >6 months after infection due to progressive chronic lung allograft dysfunction and renal failure.ConclusionThis analysis characterizes short and intermediate term outcomes of LTR after COVID-19 infection. Specifically, the association between such infection and both rates of ACR and allograft function is uniquely described. ACR was observed in 12.5% of patients 6 weeks post COVID-19 infection. There was a notable reduction in lung function, which was mostly accounted for by the 3 patients in our cohort who required ICU admission. This study has several limitations. The sample size is small and involves a single center. It is also retrospective in nature, and there were a large number of asymptomatic patients included. Further analyses, to further assess the incidence of ACR in LTR are warranted to determine the associated factors and optimize management in this at risk patient population.

COVID19 in Lung Transplanted Patients: Chronicles from an Italian Epicenter

PurposeLombardy was one of the hardest hit regions in Italy during the COVID19 pandemic. We hereby report our experience with SARS-CoV2 infection in lung transplant recipients.MethodsWe retrospectively collected clinical data on all the consecutive cases of COVID19 in our centre, based in Milan, from March 2020 to August 2021. Diagnosis was always confirmed by a positive nucleic acid amplification test (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab and/or tracheal aspirate.Results21 patients were diagnosed with COVID19. Figure 1 summarizes the clinical course of these individuals. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; when hospitalized, everybody received initial empiric antibiotic treatment with piperacillin/tazobactam and high-dose LMWH. Hydroxychloroquine was used only in the "first wave" (4 patients). One patient was compassionately administered anakinra and remdesivir as a “rescue therapy”. Lymphocitopenia was a common presenting sign (14 patients, 66%). Aspergillus co-infection occurred in 5 patients (24%). Mortality rate was 29%; 4 out of these 6 patients were affected by CLAD and 3 had chronic kidney disease. Of note, in March 2021, we tested all our patients for anti-SARS-CoV-2 nucleocapsid antibodies before starting vaccinations: we found three additional seropositive patients, who were not included in the present analysis, but had been presumably affected by an asymptomatic/mild form of the disease.ConclusionApart from immunosuppression, the majority of our patients presented at least one risk factor for mortality in COVID-19 (diabetes, chronic kidney disease, arterial hypertension) and, for this reason, we felt that they should be hospitalized to enable close monitoring and prompt management of possible complications and deterioration. Clinical course seemed favorable in only two thirds of our patients but, for the time being, none of these individuals showed sign of new-onset CLAD after COVID19.

Outcomes of SARS-CoV-2 Infection in Lung Transplant Recipients: A Single Center Experience

PurposeOutcomes of Covid-19 in lung transplant recipients (LTr) were reported in the beginning of the pandemic. Only few centers reported on their experience since December 2020 when vaccines received emergency use authorization. We aim to investigate the outcome of SARS-CoV-2 infection in a cohort of LTr at our center in Detroit, Michigan.MethodsRetrospective chart review study of adult LTr with confirmed SARS-CoV-2 infection from March 2020 to August 2021.ResultsThirty LTr were diagnosed with SARS-CoV-2 infection confirmed by RT PCR of nasopharynx. Median age at diagnosis was 63; 53% were males; 57% Caucasians and 40% of African descendance. Most patients underwent bilateral LT for interstitial lung disease (46%) and for pulmonary sarcoidosis (23%). The median time post LT was 3.1 years. Most patients needed hospitalization for respiratory failure secondary to Covid-19 (73%). Eleven patients were initially managed as outpatient. Five patients received outpatient combination of monoclonal antibodies with three of them later requiring hospitalization for development of hypoxia. None of the patients with initial out of the hospital management died. Amongst 21 hospitalized LTr, six patients were diagnosed with severe pneumonia and ARDS requiring heated high flow and invasive mechanical ventilation (IMV) in 4 patients. 28-day mortality was 10% and ICU mortality was 25% (50% mortality in those on IMV). Twelve hospitalized patients (57%) were treated with remdesivir. Augmented systemic corticosteroids was used in 85% of cases. Cycle cell inhibitor was held in 71% of the cases. Bilateral ground glass opacities of the allografts were common. None of the patients that received at least one dose of mRNA vaccine died.ConclusionOutcomes in LTr infected with SARS-CoV-2 varies. Early reports showed high mortality rate in severe and critical Covid-19 in LTr. Although hospitalization rate in this cohort was high, only four patients in our cohort required IMV during acute Covid-19. Two of them died; both were unvaccinated. Another unvaccinated patient died due to allograft rejection two months after testing positive to SARS-CoV-2. Most cases were mild to moderate despite frequent radiographic findings of pneumonia. Underreporting and exclusion of mild cases as well as likely protective effect of vaccination and use of monoclonal antibodies may explain our different outcomes.

Metagenomic Next-Generation Sequencing for Diagnosing Infections in Lung Transplant Recipients: A Retrospective Study.

Background: Accurate identification of pathogens is essential for the diagnosis and control of infections. We aimed to compare the diagnostic performance of metagenomic next-generation sequencing (mNGS) and conventional detection methods (CDM) in lung transplant recipients (LTRs). Methods: We retrospectively analyzed 107 LTRs with suspected infection of pulmonary, blood, central nervous system or chest wall between March 2018 and November 2020. Bronchoalveolar lavage fluid and other body fluids were subject to pathogen detection by both mNGS and CDM. Results: Of the 163 specimens, 84 (51.5%) tested positive for both mNGS and culture, 19 (11.7%) of which were completely consistent, 44 (27.0%) were partially congruent, and 21 (12.9%) were discordant (kappa = .215; p = .001). Compared with CDM, mNGS detected a higher diversity of pathogens. Moreover, the turn-around time was significantly shorter for mNGS compared with culture (2.7 ± .4 vs. 5.5 ± 1.6 days, p < .001). As an auxiliary method, treatment strategies were adjusted according to mNGS findings in 31 cases (29.0%), including eight patients with non-infectious diseases, who were finally cured. Conclusion: mNGS can identify pathogens with a shorter turn-around time and therefore provide a more accurate and timely diagnostic information to ascertaining pulmonary infections. mNGS might have a role in differentiating infectious from non-infectious lung diseases in LTRs.

Management of Multidrug Resistant Infections in Lung Transplant Recipients with Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited multisystem disease characterised by bronchiectasis and chronic respiratory infections which eventually cause end stage lung disease. Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated lung disease, improving survival and quality of life. Navigating recurrent infections in the setting of LTx is often difficult, where immune suppression must be balanced against the constant threat of infection. Sepsis/infections are one of the major contributors to post-LTx mortality and multiresistant organisms (eg, Burkholderia cepacia complex, Mycobacterium abscessus complex, Scedosporium spp. and Lomentospora spp.) pose a significant threat to survival. This review will summarize current and novel therapies to assist with the management of multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort.

A Retrospective Review of Calcineurin Inhibitors’ Impact on Cytomegalovirus Infections in Lung Transplant Recipients

Immunosuppressive therapy reduces the risk for allograft rejection but leaves recipients susceptible to infections. Cytomegalovirus (CMV) is one of the most frequent causes for infection after transplantation and increases the risk for allograft rejection. As lung transplant recipients (LTRs) need to be under immunosuppression for life, they are a vulnerable group. To determine the potential association between the development of CMV infection and the calcineurin inhibitor (CNI) blood levels within previous 90 days, a retrospective review of LTRs was performed. Data from recipients who underwent a lung transplantation (LTx) at our center from January 2011 to December 2018 were collected. The studied recipients, after case/control matching, included 128 CMV-infection cases. The median time from the transplant to the first positive CMV viral load was 291.5 days. In our study, more patients were treated with tacrolimus (91.9%) than with cyclosporine (8.1%). Drug blood levels at selected timepoints showed no statistically significant difference between cases and controls. However, we found that CMV infection was more frequent in the donor-seropositive/recipient-seronegative group, interstitial lung disease (ILD) recipients, LTRs who underwent basiliximab induction, cyclosporine treated recipients, and LTRs with lymphopenia (at the time of CMV infection and 90 days before). In this review of LTRs, no association between the CNI blood level and CMV infection was seen, although other immunity-related factors were found to be influencing, i.e., basiliximab induction, cyclosporine treatment, and lymphopenia.

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

Human metapneumovirus (HMPVi) and parainfluenza virus (PIVi) infections are common community-acquired infections in lung transplant recipients (LTRs), but data are extremely limited. A retrospective study including all LTRs at the Johns Hopkins Hospital during July 2010-June 2019 with positive HMPV and PIV polymerase chain reaction respiratory specimens was performed. Thirty-one HMPV- and 53 PIV-infected LTRs were identified. LTRs with HMPVi and PIVi had similar baseline characteristics, infection parameters, treatment allocation, and allograft function outcomes. Among entire cohort, 31.6% had chronic allograft dysfunction (CLAD) stage progression within 1 y postinfections (29.2% versus 35.5% for PIVi versus HMPVi, respectively, P = 0.56). In forced expiratory volume in 1 s percent (FEV1%) trajectory analysis showed steadily decline of FEV1 across time among CLAD stage progressors from both viruses. FEV1% decline ≥10% at 90 d had adjusted hazard ratio for CLAD stage progression of 18.4 (4.98-67.76) and 4.6 (1.36-15.34) for PIVi and HMPVi, respectively. PIVi caused higher donor-specific antigen development (11.8% versus 3.2%, P = 0.18) and 1-y mortality (9.4% versus 0%, P = 0.11), compared with HMPVi, even though the results were not statistically significant. Ribavirin did not show protective effect, and mycophenolate discontinuation during infection did not increase risk of CLAD stage progression. One-third of HMPV- and PIV-infected LTRs developed CLAD stage progression within 1 y. The lack of early lung function recovery may predict long-term CLAD progression.

Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients: A Systematic Review of Outcomes and Treatment Strategies.

BackgroundRespiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). This systematic review primarily aimed to assess outcomes of RSV/PIV/hMPV infections in LTR and secondarily to assess evidence regarding the efficacy of ribavirin.MethodsRelevant databases were queried and study outcomes extracted using a standardized method and summarized.ResultsNineteen retrospective and 12 prospective studies were included (total 1060 cases). Pooled 30-day mortality was low (0–3%), but CLAD progression 180–360 days postinfection was substantial (pooled incidences 19–24%) and probably associated with severe infection. Ribavirin trended toward effectiveness for CLAD prevention in exploratory meta-analysis (odds ratio [OR] 0.61, [0.27–1.18]), although results were highly variable between studies.ConclusionsRSV/PIV/hMPV infection was followed by a high CLAD incidence. Treatment options, including ribavirin, are limited. There is an urgent need for high-quality studies to provide better treatment options for these infections.