Marie Budev

Pulmonary hypertension (PHTN) can be seen in patients with connective tissue disease (CTD). The typical pathology associated with CTD is interstitial fibrosis and hypertensive pulmonary arteriopathy. We describe 4 patients with CTD and PHTN unexpectedly found to have pulmonary capillary hemangiomatosis (PCH) at explant after lung transplantation or autopsy. Pulmonary capillary hemangiomatosis is defined as a proliferation of capillaries in alveolar walls and can clinically cause PHTN. We detail the pathologic findings of PCH, describe the differential diagnosis, and present a review of the literature on the possible association of PCH with CTD. Although PCH may present clinically as PHTN, it is critical to differentiate between the typical CTD-associated interstitial fibrosis with hypertensive pulmonary arteriopathy and PCH because the treatment is different. We provide the largest case series to date and highlight the need for pathologists to have a high level of suspicion for PCH ...

Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation usually occurring during the luteal phase or during the early part of pregnancy. OHSS is a potential complication of ovarian induction by almost every agent used for ovarian stimulation. Today, due to aggressive treatment protocols including the development of in vitro fertilization and cryopreservation with the goal of obtaining sufficient numbers of oocytes and embryos, an increased risk of developing OHSS is present. OHSS is now becoming increasingly more recognized due to the higher number of women undergoing assisted reproductive techniques. Review of the literature regarding ovarian hyperstimulation syndrome. A review of the epidemiology, pathophysiology, risk factors, classification, clinical features, and treatment and prevention of OHSS. OHSS can be thought of as the loss of control over the hyperstimulation of the ovaries. Although the prevalence of the severe form of OHSS is ...

The diagnosis of pulmonary hypertension (PH) relies on a high index of suspicion. In patients with symptoms or chest radiographic findings suggestive of PH, a detailed history and physical examination followed by early assessment with a transthoracic echocardiogram, ventilation-perfusion scanning, chest computed tomography, pulmonary function testing, and nocturnal oximetry screening can provide valuable information about etiology and severity. Right heart catheterization should follow in patients who are symptomatic or who demonstrate moderate to severe PH by echocardiography and are candidates for treatment. Patients at risk for developing PH should undergo serial echocardiography and pulmonary function testing to assess for disease development and progression. Genetic testing is not currently recommended in the routine evaluation of patients with a diagnosis of primary pulmonary hypertension.

Cytomegalovirus (CMV) viremia that is resistant or refractory to the standard antiviral therapy still constitutes a major threat to high-risk transplant recipients. In addition, multiple CMV recurrences may lead to neutropenia because of repeated courses of therapy with ganciclovir derivatives. Leflunomide, a drug for rheumatoid arthritis, has been reported to have anti-CMV activity. This study reports on its use in 17 transplant recipients with complex CMV syndromes who had failed or were intolerant to other therapies. Single-center, retrospective study. Clinical data were extracted from the electronic medical record. CMV DNA viral loads were performed by quantitative hybrid capture assay. Leflunomide was initiated after a median of three episodes of CMV viremia, with a mean peak viral load of 245,826 copies/mL. Initial clearance of CMV viremia was observed in 14 of 17 patients (82%), and 9 of 17 (53%) patients achieved a long-term suppression of CMV recurrences. Higher peak viral load and higher viral load at the start of leflunomide therapy were associated with failure to suppress viremia. The duration of leflunomide therapy ranged from 1 to 24 months (median 3.5 months, interquartile range 2.6-7 months), and the mean time to an undetectable CMV-DNA was 1.9 months. Adverse effects included diarrhea (35%), anemia (18%), and increased liver function tests (12%). Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.

... There is no conflict of interest. Reprints: Atul C. Mehta, MD, FCCP, FACP, Pulmonary and Critical Care Medicine, Head Section of Bronchology, Lung Transplant Team/A90, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: mehtaa1@ccf.org). ... B, Sutton DA, Rinaldi MG, et al. ...

We investigated the effects of lung transplantation on right ventricular (RV) function as well as the prognostic value of pre- and post-transplantation RV function. Although lung transplantation success has improved over recent decades, outcomes remain a challenge. Identifying predictors of mortality in lung transplant recipients may lead to improved long-term outcomes after lung transplantation. Eighty-nine (age 60 ± 6 years, 58 men) consecutive patients who underwent single or double lung transplantation and had pre- and post-transplantation echocardiograms between July 2001 and August 2012 were evaluated. Echocardiographic measurements were performed before and after lung transplantation. Left ventricular (LV) and RV longitudinal strains were analyzed using velocity vector imaging. Cox proportional prognostic hazard models predicting all-cause death were built. There were 46 all-cause (52%) and 17 cardiac (19%) deaths during 43 ± 33 months of follow-up. After lung transplantation, echocardiography showed improved systolic pulmonary artery pressure (SPAP) (50 ± 19 mm Hg to 40 ± 13 mm Hg) and RV strain (-17 ± 5% to -18 ± 4%). No pre-transplantation RV parameter predicted all-cause mortality. After adjustment for age, sex, surgery type, and etiology of lung disease in a Cox proportional hazards model, both post-transplantation RV strain (hazard ratio: 1.13, 95% confidence interval: 1.04 to 1.23, p = 0.005), and post-transplantation SPAP (hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.05, p = 0.011) were independent predictors of all-cause mortality. When post-transplantation RV strain and post-transplantation SPAP were added the clinical predictive model based on age, sex, surgery type, and etiology, the C-statistic improves from 0.60 to 0.80 (p = 0.002). Alterations of RV function and pulmonary artery pressure normalize, and post-transplantation RV function may provide prognostic data in patients after lung transplantation. Our study is based on a highly and retrospectively selected group. We believe that larger prospective studies are warranted to confirm this result.

Alloreactive T cells and anti-human leukocyte antigen antibodies mediate transplant injury. Environmental exposures, including vaccinations, may activate the alloimmune repertoire leading to accelerated allograft injury. To test whether vaccination impacts human alloimmunity, we analyzed humoral and cellular immune reactivity in subjects undergoing influenza vaccination. We serially obtained blood samples from 30 healthy subjects and 8 kidney and 9 lung transplant recipients who received influenza vaccination, and from 20 healthy unvaccinated controls. We measured cellular and humoral anti-influenza responses, anti-human leukocyte antigen antibodies, and alloreactive T-cell immunity (interferon-gamma ELISPOT) at 0, 2, 4, and 12 weeks after vaccination. Vaccination induced influenza-reactive humoral and cellular responses in control subjects and in transplant recipients. Only two of 30 vaccinated volunteers developed new alloantibodies, but none of the transplant patients. Vaccination also specifically and significantly augmented cellular alloimmunity based on reactivity to a panel of stimulators in both healthy subjects and in transplant recipients within 4 weeks of vaccination. The enhanced cellular alloresponse waned toward prevaccine levels by week 12. Our findings newly demonstrate that influenza vaccination can have a significant impact on the potency of the alloimmune repertoire. Because the strength of the alloresponse influences long-term graft function, our results suggest that further investigation of alloimmune monitoring after vaccination is needed.

Primary graft dysfunction, formerly termed reperfusion pulmonary edema, is the leading cause of short-term complications after lung transplantation. New evidence shows that alveolar type I epithelial cells play an active role in alveolar fluid transport and are therefore presumed to be critical in the absorption of pulmonary edema. We tested the potential relevance of a novel marker of alveolar type I cell injury, the receptor for advanced glycation end-products (RAGE), to short-term outcomes of lung transplantation. The study was a prospective, observational cohort study of 20 patients undergoing single lung, bilateral lung or combined heart-lung transplantation. Plasma biomarkers were measured 4 hours after allograft reperfusion. Higher plasma RAGE levels were associated with a longer duration of mechanical ventilation and longer intensive care unit length of stay, in contrast to markers of alveolar type II cell injury, endothelial injury and acute inflammation. Specifically, for every doubling in plasma RAGE levels, the duration of mechanical ventilation increased on average by 26 hours, adjusting for ischemia time (95% confidence interval [CI] 7.4 to 44.7 hours, p = 0.01). Likewise, for every doubling of plasma RAGE levels, intensive care unit length of stay increased on average by 1.8 days, again adjusting for ischemia time (95% CI 0.13 to 3.45 days p = 0.04). In contrast, the clinical diagnosis of primary graft dysfunction was not as predictive of these short-term outcomes. Higher levels of plasma RAGE measured shortly after reperfusion predicted poor short-term outcomes from lung transplantation. Elevated plasma RAGE levels may have both pathogenetic and prognostic value in patients after lung transplantation.

A broncholith is a calcified lymph node that erodes into and partially or completely obstructs the bronchial lumen. The natural history of broncholiths is poorly understood. They are frequently encountered in residents of areas that are endemic for Histoplasma capsulatum and Mycobacterium tuberculum. We report the first case of a broncholith in which the fungus Histoplasma capsulatum was transferred from a donor to a lung transplant (LTx) recipient. Our report highlights the time course of broncholith development and its successful management. We suspect that broncholithiasis and transmission of Histoplasma capsulatum from a donor to the recipient are under-reported in the LTx literature. We hypothesize that histoplasmosis can be transmitted from the donor to the recipient and the duration in the formation of calcification of the lymph node or the broncholith can be anywhere from 2 to 10 months.

Scedosporium apiospermum, the asexual counterpart of the teleomorph Pseudallescheria boydii, is increasingly recognized as an important opportunistic pathogen in transplant recipients. Infection is associated with a high rate of dissemination and poor outcome overall. A retrospective analysis of The Cleveland Clinic lung transplant database identified 5 patients with S. apiospermum isolated from respiratory tract specimens. Demographic data and lung transplant outcomes were obtained by review of medical records. S. apiospermum was isolated from respiratory culture in 5 lung transplant recipients. Disseminated disease developed in 3 patients, whereas 2 appeared only to be colonized. Our experience and review of the literature highlights the importance of early diagnosis and differentiation from Aspergillus, since Scedosporium is inherently resistant to amphotericin B. Effective therapeutic approaches being explored include combinations of anti-fungals, because even the newer triazoles have a 50% response rate in clinical studies. Surgical débridement and immune recovery are associated with improved prognosis, favoring the use of agents that expedite immune reconstitution in these patients. Close monitoring of clinical improvement and frequent reevaluation of treatment is essential.

Atrial fibrillation occurs frequently after lung transplantation and is commonly treated with amiodarone. Pulmonary toxicity may result from amiodarone exposure and is characterized by non-specific respiratory manifestations. To our knowledge, there are no reports of this complication occurring after lung transplantation. We present a patient who developed radiologic evidence of amiodarone deposition in the lungs after bilateral lung transplantation.

ABSTRACT Immune responses to lung self-antigens (SAgs), Kα1Tubulin (Kα1T) and Collagen V (ColV), have been implicated as risk factors for chronic rejection following lung transplantation (LTx). The goal is to determine the prevalence of pre-existing antibodies (Abs) to these SAgs in diseases leading to organ failure and investigate their role in primary graft dysfunction (PGD) and chronic rejection.Methods and MaterialsPre- and post-Tx sera from 317 LTx patients for diagnoses (COPD: 161, IPF: 50, CF: 55 and Other: 51) between 2000 and 2011 at Washington University (n: 296) and Cleveland Clinic (n: 21) were analyzed for donor specific Abs (DSA) by Flow PRA, Abs to ColV and Kα1T by ELISA and cytokine levels by LUMINEX assay. Subsequent diagnoses of PGD and bronchiolitis obliterans syndrome (BOS) were made in accordance with ISHLT guidelines.ResultsPre-Tx, 18% with COPD, 44% with IPF (P<0.05), 29% with CF (p<0.05) and 19.6% with other diagnoses (p>0.7) had Abs to Sags. The incidence of PGD was higher in patients with pre-Tx Abs to these Sags compared to those without (80-88% to 42-54%, p<0.05) as was the incidence of BOS at 5 years post-Tx (90% versus 38%). The risk for development of DSA was higher in patients with Abs to Sags (70% versus 28%, p<0.01). In addition, there was elevation in serum pro-inflammatory cytokines, IL-1β (2.5 fold), IL-17 (2.3 fold) and IFN-γ (3.5 fold) and reduction serum IL-10 (1.9 fold) levels (p<0.01) in patients with positive Abs to Sags.Conclusions Patients with CF and IPF demonstrated a significantly increased incidence of Abs to lung Sags, Kα1T and ColV. Patients with pre-Tx Abs to Sags were at increased risk for developing PGD, DSA and BOS, therefore strategies to deplete pre-existing Abs to Sags should be considered in order to improve outcomes after LTx.

ABSTRACT Purpose Despite thorough radiologic evaluation prior to lung transplantation (LTx), explanted lungs occasionally harbor non-small cell lung cancer (NSCLC). However, the incidence and outcomes for this phenomenon are unknown. We describe our center’s experience with unexpected explant NSCLC and its impact on post-transplant survival. Methods and Materials From April 2007 to April 2012, 522 patients underwent LTx at the Cleveland Clinic. Review of medical records was performed which included surgical pathology of the explanted lung(s), pathologic cancer staging and postoperative course. Specific attention was given to cancer progression and recurrence. Overall survival was determined using Kaplan-Meier method. Results Thirteen patients (2.5% incidence) were noted to have explant NSCLC. Listing diagnosis was UIP in 9 (69%) and COPD in 4 (31%) with 8 undergoing double LTx and 5 undergoing single LTx. Mean age at transplantation was 63 ± 6 years. Time from the last chest CT scan to transplantation was 103 ± 83 days. All malignancies were primary NSCLC with adenocarcinoma in 9 (69%) and squamous cell carcinoma in 4 (31%). 8 patients were Stage I, 4 Stage II and 1 Stage IV. 7 (53%) patients underwent post-transplant cancer treatment. Progression of disease occurred in 8 (62%) patients at a mean follow-up of 9.9 ± 6.5 months, with overall survival 14% at 2 years. [figure 1] Conclusions Despite heightened screening, incidence of unsuspected NSCLC is surprisingly high. Moreover, despite the complete resection afforded by native pneumonectomy and adjuvant therapy, overall survival is poor due to rapid malignant progression. A unique pre-transplant surveillance screening program needs to be devised for this high risk population

ABSTRACT Use of extracorporeal membrane oxygenation (ECMO) as a bridge to transplantation (BTT) has raised concerns ECMO support leads to the development of serum antibodies due to multiple blood transfusions. We examined the development of HLA sensitization in a cohort of lung transplant (LT) recipients where ECMO BTT was employed.Methods and MaterialsA retrospective chart review of all LT recipients with ECMO BTT from 2006-2012 was conducted. Data collected included demographics, Luminex, blood product utilization and post-transplant outcomes. HLA sensitization was defined as PRA>10% in either HLA type I or II while highly sensitized was PRA>90%.Results21 patients (12 males) were identified as BTT to LT on ECMO, median ECMO duration of 7.0 days (range:0-38 days). 6 patients (35%) were sensitized prior to ECMO, mean PRA HLA type I 36%±22.7 and type II 27%±2.2. No significant change from baseline PRA was noted, mean difference for HLA type I of 4.3±11.9 (p=0.19) or type II of 2.9±7.7 (p=0.16). During ECMO BTT, 1 sensitized patient became highly sensitized (HLA type I 94%) who received 47 PRBCs. The second highest PRBC usage (31) during BTT resulted in new sensitization (HLA type I 31%). Patients received on average of 14.0±2.7 (range:0-49) during ECMO BTT, which was not associated with the mean difference between baseline-ECMO for HLA type I (p=0.52) or type II (p=0.06). All patients were successfully transplanted, 8 received induction therapy, with no evidence of hyperacute rejection.ConclusionsHLA sensitization does occur rarely in ECMO BTT and may be associated with large amounts of PRBCs received during ECMO BTT. Although sensitization may occur, successful transplantation is possible without evidence of hyperacute rejection.PRBCs Received during ECMO BTTPatientDays on ECMOPRBCs ReceivedΔ Sensitization Status11027No2321No31315Yes41049Yes512No649Yes7718Yes824No93831Yes1010No11815Yes12511No131711No1443No1537No161215Yes1710No1840No192223No202027No21155NoPRBCs-packed red blood cell units

The presence of underlying pulmonary disease in women of childbearing potential can present a significant challenge during pregnancy and the postpartum period. Management of the underlying disease, recognizing and preventing disease progression, and, most important, managing and minimizing toxic side effects of various therapies require the expertise of an interdisciplinary team. This team must involve close collaboration between intensive care physicians, pulmonary physicians, and high-risk obstetricians familiar with these disease states in an effort to minimize fetal and maternal morbidity and mortality. We will review the impact of the pregnant state in lung transplant recipients, patients with pulmonary arterial hypertension, and patients with underlying cystic fibrosis. Review of the literature in regards to pregnancy outcomes and issues for patients with cystic fibrosis, pulmonary hypertension, and lung transplants. A review of the epidemiology, pathophysiology, risk factors, classification, clinical features, and outcomes for pregnant patients with underlying pulmonary diseases. Safety of pregnancy in the female lung transplant recipient concerns three outcomes: maternal outcome, fetal outcome, and transplanted graft outcome.

Many clinical scenarios have been encountered by patients who developed histoplasmosis after receiving a solid organ transplant at a large transplant center in an endemic area. Cases of posttransplantation histoplasmosis were identified by use of multiple methods, including reviews of microbiology test results, transplant databases, and billing codes. Data were obtained retrospectively. Descriptive statistics were used. During the 1997-2007 study period, 3436 patients received a solid organ transplant, and 38 patients were identified as having posttransplantation histoplasmosis. Of these 38 patients, 9 were excluded from our study because the diagnosis was solely clinical. Of the remaining 29 patients, 14 had posttransplantation histoplasmosis (incidence, 1 case per 1000 person-years); 14 showed histologic evidence of histoplasmosis in the recipient or donor tissue, which was encountered unexpectedly at the time of transplantation; and 1 had histoplasmosis before receiving the transplant. Of the 14 patients who developed histoplasmosis after transplantation, 5 were heart transplant recipients, 3 were lung transplant recipients, 3 were kidney transplant recipients, 1 was a liver transplant recipient, 1 was a pancreas transplant recipient, and 1 was a kidney-pancreas transplant recipient. The median time from transplantation to diagnosis was 17 months (interquartile range, 8.1-46 months), and the median time from onset of symptoms to diagnosis 3 weeks (interquartile range, 1.9-6.5 weeks). All recipients had disseminated disease. The most common treatment was amphotericin B and itraconazole. All were cured, or still on treatment, but symptom-free. Of the 14 patients who had an explanted organ or donor tissue that showed histologic evidence of histoplasmosis, 13 (93%) were lung transplant recipients, and 1 (7%) was a liver transplant recipient. None of these patients developed active histoplasmosis, but all received prophylactic treatment. Finally, 1 patient had histoplasmosis before transplantation; he was treated with itraconazole 3 months before and after transplantation, and he did well. In conclusion, posttransplantation histoplasmosis is rare (1 case per 1000 transplant-person-years; 95% confidence interval, 0.6-1.7), even in endemic areas. Prognosis is good but requires protracted therapy. Patients with latent infection did not develop posttransplantation histoplasmosis when prophylaxis was used.

ABSTRACT Transplantation Case Report PosterSESSION TYPE: Case Report PosterPRESENTED ON: Sunday, March 23, 2014 at 01:15 PM - 02:15 PMINTRODUCTION: Lung transplantation is considered a curative therapy for idiopathic pulmonary arterial hypertension (IPAH). We report a case of recurrence of IPAH after lung transplantation. 62-year-old Caucasian man underwent bilateral sequential lung transplant for IPAH that was refractory to medical therapy. He had an uneventful post operative course and was discharged from the hospital on the 9th post operative day on routine immune-suppression. Histologic examination of the pneumonectomy specimens revealed marked pulmonary arterial hypertensive changes with intimal fibroplasia of the small, medium and large arteries with elastic remodeling of the larger arteries. No plexiform lesions were seen. Surveillance transbronchial biopsies over the next year were negative for any pathology and an echocardiogram 3 months after transplant revealed marked improvement from the pre-transplant studies. An year after lung transplantation, patient started having increasing exertional dyspnea and soon developed hypoxemic respiratory failure. Recurrence of pulmonary hypertension was confirmed with right heart catheterization. Investigations for all possible etiologies for recurrence of PH, including chronic thromboembolic pulmonary hypertension as well as possibility of pulmonary artery stenosis, were unrevealing. Patient was re-initiated on triple drug therapy for IPAH and emergently relisted for lung re-transplantation. Unfortunately, thirteen months after his lung transplant procedure, the patient died from refractory hypoxemia and right heart failure. At autopsy, histology of the lungs revealed pulmonary hypertensive vasculopathy with intimal fibrosis and medial hypertrophy of small, medium and large arteries. The histologic changes in the allograft were deemed similar to the changes in the explanted lungs removed at transplantation. In an effort to elucidate the potential etiology for IPAH recurrence, we performed mutational and chromosomal analysis on the original explant that was unrevealing. Despite significant advances in the understanding and medical management of pulmonary vascular disease, particularly idiopathic pulmonary arterial hypertension, lung transplantation still remains an accepted therapy for severe pulmonary vascular disease not responding to medical therapy. Although recurrence of the pulmonary disease after lung transplantation has been reported, recurrence of pulmonary hypertension after lung transplantation is exceedingly rare. There are descriptions of pulmonary hypertension from anastomotic narrowing of the pulmonary artery after lung transplantation, requiring surgical revision. Recurrence has also been reported in a handful of cases with pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. The absence of plexiform lesions in both the explanted and autopsy specimens in our patient is fascinating and raises questions about the possibility of a totally distinct phenotype of IPAH. To the best of our knowledge, there is only one previous case report describing the recurrence of idiopathic pulmonary arterial hypertension after bilateral lung transplantation. The fact that we have not able to elucidate an etiology for recurrence is a reflection of limitations and gaps in our understanding of IPAH. One of the first reports on this front, this case highlights the limitations in our understanding of IPAH. Contrary to common belief, this case suggests that lung transplantation is not an infllible remedy for this confounding illness.Reference #1: Soriano CM, Gaine SP, Conte JV, et al. Anastomotic pulmonary hypertension after lung transplantation for primary pulmonary hypertension: report of surgical correction. Chest. 1999;116(2):564-6.Reference #2: Izbicki G, Shitrit D, Schechtman I, et al. Recurrence of pulmonary veno-occlusive disease after heart-lung transplantation. J Heart Lung Transplant. 2005;24(5):635-7.Reference #3: Snow JL, Palevsky HI, Archer-Chicko C, et al. Idiopathic Pulmonary Arterial Hypertension Recurring Within One Year After Bilateral Lung Transplantation. Abstract presented at the 8th International Pulmonary Hypertension Association (PHA) conference and scientific sessions held in Houston, Texas June 20-22,2008. The following authors have nothing to disclose: Tathagat Narula, Carol Farver, Serpil Erzurum, Micheala Aldred, Charles Lane, Marie Budev, Olufemi AkindipeNo Product/Research Disclosure Information.

To describe infectious and non-infectious ocular complications found in patients with lung transplants. 545 patients underwent lung transplantation from January 1998 to September 2008 at the Cleveland Clinic. Patients who underwent ophthalmic examination at the Cole Eye Institute after lung transplantation were included in the study. Diagnoses, treatments, surgeries, laboratory parameters of immune status and patient survival were examined. Of the 545 patients who received a lung transplant during the study period at the Cleveland Clinic, 46 (8.4%) patients underwent ophthalmology examination after a lung transplant. The most common ocular finding was posterior subcapsular cataract, found in 13/46 (28.3%) patients. Infectious ocular complications were present in 6/46 patients (13.0%) including fungal infections (rhino-orbital mucormycosis (n=1), disseminated Pseudallescheria boydii infection (n=2)), cytomegalovirus retinitis (n=1), varicella-zoster virus keratouveitis (n=1) and herpes zoster ophthalmicus (n=1). Five of six patients with infectious ocular complications died within 6 months of evaluation. Decreased absolute lymphocyte count was associated with infectious ocular complications (p=0.014). Many ocular conditions can occur in patients with lung transplants. Ocular infectious complications were uncommon but may be associated with increased mortality.