Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Delayed pneumothorax post bronchoscopy!

Bronchoscopy is an important diagnostic and therapeutic tool in the management of the lung transplant patient. Surveillance bronchoscopy detects early rejection, airway colonization and airway infections, but does carry a risk of serious complications include bleeding and pneumothorax. Post biopsy fluoroscopic imaging is usually done to rule out pneumothorax. We hereby present two cases that developed a delayed pneumothorax despite negative fluoroscopic imaging. A 63 year old male status post bilateral lung transplant for idiopathic pulmonary fibrosis presented to the clinic with dyspnea on exertion and a 30 % drop in his FEV1. Two weeks prior to this presentation on post-op day 14 he underwent an uneventful surveillance bronchoscopy with transbronchial biopsies followed by a negative fluoroscopic check for pneumothorax. His chest x-ray at presentation to clinic revealed bilateral pneumothorax. Therefore a pleural pigtail catheter was placed and patient noted marked improvement in his symptoms. His donor records did not reveal any predisposing factors for a spontaneous pneumothorax. A 67 year old male status post bilateral lung transplant for pulmonary fibrosis presented to the lung transplant clinic with complaints of exertional dyspnea for 2 weeks following his bronchoscopy. He had a surveillance biopsy performed with negative fluoroscopic imaging following on post-op day 10. Upon presentation his home spirometry numbers were 20% lower than baseline and his chest xray revealed bilateral pneumothorax and pneumopericardium. A pleural pigtail was placed and his dyspnea promptly resolved. A 2D echo did demonstrate signs of tamponade. His donor\u27s records did not show any history of bullae or spontaneous pneumothorax. The risk of acute pneumothorax following transbronchial biopsies is reported between 8 to 61% and is described within the first four hours following bronchoscopy. Delayed pneumothorax is a very rare complication with an incidence of 1.4 to 4.5% with most cases reported within the first 24 hours. The proposed mechanism is secondary to fibrinolysis of blood clots that was sealing the biopsy site. Other postulated contributory factors include underlying infection or subpleural blebs. Our cases are unique with a long delay from the transbronchial biopsy time and clinical presentation. Whether there is a role of immunosuppression contributes to the delayed presentation deserves further study. These cases illustrate the need to still consider pneumothorax in the differential of dyspnea in a lung transplant patient irrespective of timing of the last lung biopsy

Viral infection as a cause for bronchostenosis?

Lung transplant is considered a treatment option for those with end stage lung disease, with more than 32,000 procedures performed to date. Despite the improvements in recipient and donor selection, lung allograft preservation, surgical technique for bronchial anastomosis, perioperative management and immunosuppressive regimen, airway complications are considered an important limitation for the lung transplant patient. We hereby present 2 cases that developed a bronchial stricture secondary to Herpes simplex virus (HSV) infection. A 67 year old male with history of Idiopathic pulmonary fibrosis (IPF) status post bilateral lung transplant and history of HSV stomatitis on maintenance valacyclovir presented to the clinic with cough and shortness which had been worsening over 2 weeks. He also had a 50% decline in his FEV1. Imaging including a chest xray and CT scan of the chest were unchanged when compared to previous studies. His labs were benign without leukocytosis. Bronchoscopy showed an 80% narrowing of the lateral segment of the left lower lobe that improved to 100% post balloon dilation. Endobronchial biopsies stained positive for HSV. Patient\u27s immunosuppression was reduced and he received a trial of cidofovir due to in-vitro resistance to acyclovir. He was discharged on maintenance valacyclovir. A 67 year old male with a history of bilateral lung transplant for IPF and HSV laryngotracheobronchitis maintained on valacyclovir presented to clinic with dyspnea and hypoxemia. His labs were benign with no leukocytosis. CT scan of the chest revealed an occlusion in the left upper lobe bronchus. Rigid bronchoscopy showed a stenotic left upper lobe bronchus, pinpoint in appearance. The right anastomosis and bronchus intermedius revealed almost complete collapse on exhalation, requiring placement of a bare metal stent. Biopsies revealed HSV bronchitis. Treatment included a reduction in immune suppression and IV acyclovir. His dyspnea improved post stent placement and his oxygen requirements returned to baseline. He was discharged on maintenance therapy with valacylcovir. Airway complications post lung transplant fall into several categories including anastomotic stenosis, bronchomalacia, exophytic endobronchial granulation tissue, dehiscence and anastomotic infections. The incidence of a bronchial stricture is between 5-30% and is associated with 40% decrease in survival at 5 years. Early rejection has been shown to be associated with an increase in incidence of this pathology. Our cases developed segmental anastomosis likely related to. Segmental anastomotic stenosis should be considered a different category than the anastomotic complications and viral infection should be included in the differential for the pathology described. (Figure Presented)

Abo compatibility in lung transplantation

Lung transplantation (LT) remains the only definitive treatment for end-stage lung disease (ESLD) refractory to medical therapy. The necessity for an identical blood-type (ABO) match for optimal outcome is controversial. Recent studies have demonstrated equivalent outcomes between ABO identical and compatible LT, but do not differentiate any individual ABO combinations. The purpose of this study was to evaluate whether certain ABO compatible combinations affect outcomes in LT. Methods: Observational analysis of the United Network for Organ Sharing (UNOS) database for adult Double LT (DLT) recipients from May 2005 to September 2014 was performed. Results: Of 9615 DLT, 8941 (93%) were ABO “identical”, with 2347 (26%) of those having A-subtype differences. 674 (7%) compatible patients included 415 (62%) with donor O and recipient A, 93 (14%) with donor O and recipient B, and 84 (12%) donor B and recipient AB. The remaining 72 (11%) patients included multiple combinations and were placed into a single group due to the small number of patients in each subgroup (ABO Compat Oth). ABO compatibility status was not associated with either bronchiolitis obliterans syndrome (BOS, p= 0.389) or overall mortality (p= 0.333) in multivariate analysis. Recipients in the ABO Compat Oth group had a higher risk of acute rejection (HR 1.44, 95% CI 1.05-1.97, p= 0.023), but showed no increased risk of BOS (p= 1.0) or mortality (p= 0.826). The other groups showed no association with acute rejection, though the AB-B group trended toward significantly less risk for rejection (HR 0.69, 95% CI 0.47-1.03, p= 0.07).Conclusion: Our results agree with recent findings in ABO compatibility and LT, and do not show negative effect on the short or long term outcome when the different subgroups are analyzed. In light of these findings, the lung allocation system could potentially be changed to consider the identical and compatible blood group combinations as the same to give patients with higher LAS a better chance at a shorter wait time

Risks and Outcomes Associated with Pleural Space Infections After Lung Transplantation

Purpose: Pleural space infections (PSI) are a serious complication after lung transplantation (LT) however there is limited data on the associated risk factors and outcomes of PSI. We examined: 1) risk factors associated with PSI after LT; 2) effect of PSI on LT outcomes. Methods: This is a retrospective single center cohort study of 74 consecutive LT recipients (1/2018- 6/2020). Patients were divided into infected and non-infected groups, where PSI were defined as post-LT pleural effusions with pathogen(s) isolated from pleural fluid. Data were collected and compared between two groups with two-sample t-test or Fisher-exact. Multivariable logit model was performed with estimations of odds ratio (OR) and its confidence interval [CI]. Results: Among 74 LT recipients, 38 (51%) developed pleural effusions requiring drainage; of them 16 (42%) had PSI. Baseline demographics were similar in patients with and without PSI (Table). Notably, 88% of PSI group received steroids pre-LT compared to 55% in the non-infected group (p\u3c0.05); 88% of the PSI group had an underlying diagnosis of interstitial lung disease versus 45% of the non-infected group (p\u3c0.01). Overall post-operative complications occurred more frequently in the PSI group vs. non-infected group 77% vs. 25% (p\u3c0.01) and airway complications in 86% vs. 44% (p\u3c0.01). Hospital length of stay was longer in the PSI group with the median of 78 versus 31 days in the non-infected group (p\u3c0.01). Results of logistical modeling showed high risk of PSI with presence of post-LT airway complications (OR =10.8 95% CI 1.7- 72.5) and presence of post operative complications (OR=10.6, 95% CI 1.8-63.5). There was no difference in the incidence of readmissions, acute cellular rejection or 1 year mortality between the two cohorts. Conclusion: PSI remain a prevalent yet under-studied complication. Airway or post-operative complications after LT were associated with PSI. One-year outcomes were similar in LT recipients with and without PSI

Early Outcomes of Lung Transplantation for COVID-19 Related Lung Disease. Single Center Experience

Purpose: Lung transplantation (LT) is a lifesaving treatment for Covid-19 related lung disease with early outcomes similar to other indications. Methods: Seven patients underwent LT for Covid-19 related lung disease at our center: 5 for ARDS and 2 for IPF exacerbation post SARS-CoV-2 infection. Results: Seven patients (5 men) with single organ failure underwent bilateral LT. Median age was 47 years old. All ARDS cases had poor lung mechanics on invasive mechanical ventilation with radiographic evidence of lung fibrosis: pneumatocele, GGO, consolidations, subpleural reticulations and traction bronchiectasis. vvECMO was bridge to transplant in 5 cases (bridge to recovery in 2). Median ECMO duration for ARDS was 32 days (range 7-99). Median time to LT from Covid diagnosis was 59 days (Q1-IQ3, 54-62). Two patients were post-partum women with ARDS. Explanted pathology showed UIP, DAD, diffuse hemorrhage and one case of fibrosing NSIP. Pulmonary hypertension was seen in 4 cases. One patient did not survive. Organizing pneumonia and granuloma were present in this patient. Most ARDS patients were unable to tolerate lower sedation and consent by a substitute decision-makers was obtained. Post operative ECMO decannulation was possible in all cases. Induction, maintenance immunosuppression and antimicrobials were standard for our program. Donated grafts were from deceased brain death donors and negative for 2019-nCoV. Rehabilitation potential and strong social support were absolute inclusion criteria. All survivors have excellent lung function. Conclusion: In the USA, over 130 LT have listed Covid-19 as the diagnosis indication. Although Covid-19 ARDS makes up for the majority of these LT, other diagnosis are post Covid pulmonary fibrosis and underlying fibrosis with SARS-CoV-2 induced exacerbation. LT for ARDS poses several challenges and is reserved for the minority of carefully selected patients dependent on extracorporeal life support. As others have reported, good short-term survival is described

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

Purpose: Outcomes 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. Methods: Retrospective chart review study of adult LTr with confirmed SARS-CoV-2 infection from March 2020 to August 2021. Results: Thirty 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. Conclusion: Outcomes 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

Comparison of prophylactic regimens to prevent aspergillus infections in lung transplant recipients

Lung transplantation is a lifesaving therapy for a variety of end stage lung diseases. However, infections remain a significant threat after lung transplantation; Aspergillus infections are a serious limitation to long term survival. Despite this, there is no defined prophylactic treatment strategy to prevent Aspergillus infection following lung transplantation. This single center retrospective cohort describes our experience with multiple regimens that were used to prevent the colonization with Aspergillus spp. after lung transplantation: no antifungal therapy (none), oral voriconazole for three months (voriconazole), and inhaled liposomal amphotericin B for six months (amphotericin). Methods: All consecutive patients that underwent lung transplantation at an urban academic teaching hospital from 2003 through 2013 were screened for eligibility (n = 108). Patients who were colonized at baseline and those who had multiple treatment strategies (crossover) before first colonization were excluded. All fungal cultures from bronchoalveolar lavages and bronchial washings for the first two years following transplantation (or death within two years) were assessed. A total of 79 patients were analyzed in groups determined by their initial prophylactic regimen: none (n=32), voriconazole (n = 12), and amphotericin (n = 35). The event-free survival from colonization in the 31-730 days after transplant (post-transplant period) was calculated by the Kaplan-Meier product limit estimator and survival curves were compared using the log-rank test. Results: The study was underpowered to detect statistically significant differences among the three different prophylactic groups. There were no differences in time to colonization with Aspergillus spp. in lung transplant recipients among the groups in post-transplant period. Although not statistically significant, the point estimate for the hazard ratio for colonization in the post-transplant period was lower with voriconazole when compared to either amphotericin (hazard ratio [HR] = 0.669, p = 0.5542) or none (HR = 0.746, p = 0.6648). A Kaplan-Meier survival curve comparing the three groups is depicted in Figure 1. Conclusions: Although more expensive and more likely to induce drug interactions with immunosuppressive medications, voriconazole may be more effective than amphotericin in preventing colonization with Aspergillus spp. in lung transplant patients in the first two years following transplantation. One advantage of oral voriconazole over inhaled amphotericin is ease of use. Due to a limitation in sample size and bias by indication, a dedicated randomized control trial is needed to determine the optimal prophylactic regimen in this patient group. (Figure Presented)

Measurement of physical activity and frailty in the early post-operative period after kidney transplant: Single-center prospective pilot study using Fitbit watch

Background: Physical activity monitors (PAMs) allow patients to track multiple health parameters and may be helpful tools to assess patient’s physical recovery after kidney transplant (KT). We performed a pilot study to quantify early postoperative physical activity after KT. Methods: Adult KT candidates were screened prospectively for inclusion and provided with a PAM (Fitbit® Inspire 2) for the first 30 days after KT. Patients who did not speak English and had undergone multi-organ transplants were excluded. Several frailty tests were performed prior to KT and on post-operative day 30: Fried Frailty Phenotype and 6-minute walk test. Results: 14 patients were enrolled since February 2021 with baseline characteristics described in Table 1. There was a significant difference in the average daily steps during the 1st week compared to the 4th week after KT (Week 1: 3200 steps vs. Week 4: 6978 steps, p\u3c0.001). The number of steps during the first 30 days after KT correlated negatively with hospital length of stay (r -0.53,p=0.02). There was no difference in the average daily steps between pre-frail and non-frail patients [Figure 1A]. Having a post-operative complication (Clavien grade 1-3: n=5) significantly dropped the average daily steps for the first 30 days after KT (complication 6811 steps [SD 2810] vs. no-complication 2275 steps [SD 740];p=0.009) [Figure 1B]. Conclusion: PAM effectively captures post-operative biophysical parameters and can be successfully implemented to monitor patient’s recovery after KT