Telehealth platforms with remote phlebotomy and biomarker implementation represent a novel paradigm for surveillance after lung transplantation (LT). In a pilot study, we investigated donor-derived cell-free DNA (dd-cfDNA) in plasma using a clinical-grade "next-generation sequencing" assay.

Methods

dd-cfDNA levels determined in biorepository venous plasma samples obtained during the lung allograft rejection gene expression observation study, implementing a clinical-grade next-generation sequencing assay. Sixty-nine unique LT patients encompassing 9 LT centers, with associated clinical-histopathologic diagnoses, were examined-allograft infection (n = 26), normal histopathology without infection (n = 30), and acute cellular rejection (ACR; n = 13).

Results

dd-cfDNA in ACR patients were significantly elevated (1.52%; interquartile range [IQR], 0.520-2.2550) compared with the normal stable patients (0.485%; IQR, 0.220-0.790) (P = 0.026). During allograft infection, dd-cfDNA values were not different (0.595; IQR, 0.270-1.170) from normal (P = 0.282) and ACR (P = 0.100). AUC-receiver operator characteristics curve analysis for allograft ACR was 0.717 (95% confidence interval, 0.547-0.887; P = 0.025). At a 0.87% threshold dd-cfDNA-sensitivity = 73.1%, specificity = 52.9%, positive predictive value = 34.1%, and negative predictive value = 85.5%.

Conclusions

dd-cfDNA assessment holds promise as a noninvasive biomarker of "allograft injury" with acute rejection following LT while prospective, multicenter studies should further refine utility across the spectrum of allograft rejection and infection.

Sweet's Syndrome (SS), also known as acute febrile neutrophilic dermatosis, is one of several cutaneous inflammatory disorders classified as neutrophilic dermatoses. Respiratory complications are described in <50 cases in the literature,¹ without prior report of lung transplantation (LT). This article explains the clinical course of the first patient to receive LT for pulmonary SS and presents evidence suggesting recurrence of the primary lung disease in the allograft.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.

The association of autoimmune disease (AI) with transplant-free survival in the setting of severe Group 3 pulmonary hypertension and extensive pulmonary fibrosis remains unclear. We report cases of severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg and right ventricular dysfunction) and extensive pulmonary fibrosis after pulmonary arterial hypertension-specific therapy. We used multivariate regression to determine the clinical variables associated with transplant-free survival. Of 286 screened patients, 55 demonstrated severe pulmonary hypertension and extensive pulmonary fibrosis and were treated with parenteral prostacyclin therapy. The (+)AI subgroup (n = 34), when compared to the (-)AI subgroup (n = 21), was more likely to be female (77% versus 19%) and younger (58.7 ± 12.1 versus 66.0 ± 10.7 years), and revealed lower forced vital capacity (absolute) (1.9 ± 0.7 versus 2.9 ± 1.1 L), higher D_LCO (% predicted) (31.1 ± 15.2 versus 23.2 ± 8.0), and increased unadjusted transplant-free survival (1 year (84.6 ± 6.3% versus 45 ± 11.1%)), 3 years (71 ± 8.2% versus 28.6 ± 11.9%), and 5 years (47.6 ± 9.6% versus 6.4 ± 8.2%); (p = 0.01)). Transplant-free survival was unchanged after adjusting for age and gender. The pulmonary hemodynamic profiles improved after parenteral prostacyclin therapy, independent of AI status. The baseline variables associated with mortality included age at pulmonary hypertension diagnosis (heart rate (HR) 1.23 (confidence interval (CI) 1.03-1.47); p = 0.02) and presence of AI (HR 0.26 (confidence interval (CI) 0.10-0.70); p < 0.01). Gas exchange was not adversely affected by parenteral prostacyclin therapy. In the setting of severe Group 3 pulmonary hypertension and extensive pulmonary fibrosis treated with pulmonary arterial hypertension-specific therapy, AI is independently associated with increased transplant-free survival. Pulmonary hypertension/pulmonary fibrosis associated with AI should be considered in future clinical trials of pulmonary arterial hypertension-specific therapy in Group 3 pulmonary hypertension.

Background

Chronic lung allograft dysfunction (CLAD) phenotype determines prognosis and may have therapeutic implications. Despite the clarity achieved by recent consensus statement definitions, their reliance on radiologic interpretation introduces subjectivity. The Center for Computer Vision and Imaging Biomarkers at the University of California, Los Angeles (UCLA) has established protocols for chest high-resolution computed tomography (HRCT)-based computer-aided quantification of both interstitial disease and air-trapping. We applied quantitative image analysis (QIA) at CLAD onset to demonstrate radiographic phenotypes with clinical implications.

Methods

We studied 47 first bilateral lung transplant recipients at UCLA with chest HRCT performed within 90 d of CLAD onset and 47 no-CLAD control HRCTs. QIA determined the proportion of lung volume affected by interstitial disease and air-trapping in total lung capacity and residual volume images, respectively. We compared QIA scores between no-CLAD and CLAD, and between phenotypes. We also assigned radiographic phenotypes based solely on QIA, and compared their survival outcomes.

Results

CLAD onset HRCTs had more lung affected by the interstitial disease (P = 0.003) than no-CLAD controls. Bronchiolitis obliterans syndrome (BOS) cases had lower scores for interstitial disease as compared with probable restrictive allograft syndrome (RAS) (P < 0.0001) and mixed CLAD (P = 0.02) phenotypes. BOS cases had more air-trapping than probable RAS (P < 0.0001). Among phenotypes assigned by QIA, the relative risk of death was greatest for mixed (relative risk [RR] 11.81), followed by RAS (RR 6.27) and BOS (RR 3.15).

Conclusions

Chest HRCT QIA at CLAD onset appears promising as a method for precise determination of CLAD phenotypes with survival implications.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.