Successful lung transplantation in an HIV seropositive patient with desquamative interstitial pneumonia: a case report.

BACKGROUND: Until recently, lung transplantation was not considered in patients with human immunodeficiency virus (HIV). HIV seropositive patients with suppressed viral loads can now expect long-term survival with the advent of highly active antiretroviral therapies (HAART); however, HIV remains a relative contraindication to lung transplantation. We describe, to our knowledge, the first HIV seropositive lung transplant recipient in Canada. We also review the literature of previously reported cases of solid-organ transplantation in patients with HIV with a focus on immunosuppression considerations. CASE PRESENTATION: A 48-year old man received a bilateral lung transplant for a diagnosis of desquamative interstitial pneumonia (DIP) attributed to cigarette and cannabis smoking. His control of HIV infection pre-transplant was excellent on HAART, and he had no other contraindications to lung transplantation. The patient underwent bilateral lung transplantation using basiliximab, methylprednisolone, and mycophenolate mofetil (MMF) as induction immunosuppression. He was maintained on MMF, prednisone, and tacrolimus thereafter, and restarted his HAART regimen immediately post-operatively. His post-transplant course was complicated by Grade A1 minimal acute cellular rejection, as well as an enterovirus/rhinovirus graft infection. Despite these complications, his functional status and control of HIV infection remain excellent 24 months post-transplant. CONCLUSIONS: Our patient is one of only several HIV seropositive lung transplant recipients reported globally. With growing acceptance of transplantation in this population, there is a need for clarification of prognosis post-transplantation, as well as optimal immunosuppression regimens for these patients. This case report adds to the recent literature that suggests HIV seropositivity should not be considered a contraindication to lung transplantation, and that post-transplant patients with HIV can be managed safely with basiliximab, tacrolimus, MMF and prednisone.

Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants.

We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.

Isolated Liver Rejection After Lung and Combined Kidney-Liver Transplantation: A Case Report.

Liver allografts are unique in solid organ transplantation as they are less susceptible to both acute and chronic rejection. Operational tolerance, defined as prolonged graft survival in the absence of immunosuppression, is also achieved more frequently with liver allografts. It is unknown if the presence of multiple allografts in the same individual, levels of immunosuppression, or the presence of cystic fibrosis (CF) impacts the livers ability to ward off rejection or achieve operational tolerance. We describe an unsensitized, ABO-compatible patient with CF who underwent double lung transplantation and several years later a combined liver-kidney transplant. He developed isolated late acute T-cell mediated rejection of his liver allograft despite a high level of immunosuppression (IS) required for his lung and kidney allografts. To our knowledge, this is the first case of isolated liver rejection in a patient with 3 separate organ allografts, or in a patient with CF, to be reported in the literature. This isolated liver rejection is out of keeping with typically accepted ideas about orthotopic liver tolerance.

Small airway dilation measured by endoscopic optical coherence tomography correlates with chronic lung allograft dysfunction.

SIGNIFICANCE: Chronic lung allograft dysfunction (CLAD) is the leading cause of death in transplant patients who survive past the first year post-transplant. Current diagnosis is based on sustained decline in lung function; there is a need for tools that can identify CLAD onset. AIM: Endoscopic optical coherence tomography (OCT) can visualize structural changes in the small airways, which are of interest in CLAD progression. We aim to identify OCT features in the small airways of lung allografts that correlate with CLAD status. APPROACH: Imaging was conducted with an endoscopic rotary pullback OCT catheter during routine bronchoscopy procedures (n = 54), collecting volumetric scans of three segmental airways per patient. Six features of interest were identified, and four blinded raters scored the dataset on the presence and intensity of each feature. RESULTS: Airway dilation (AD) was the only feature found to significantly (p < 0.003) correlate with CLAD diagnosis (R = 0.40 to 0.61). AD could also be fairly consistently scored between raters (κinter-rater = 0.48, κintra-rater = 0.64). There is a stronger relationship between AD and the combined obstructive and restrictive (BOS + RAS) phenotypes than the obstructive-only (BOS) phenotype for two raters (R = 0.92 , 0.94). CONCLUSIONS: OCT examination of small AD shows potential as a diagnostic indicator for CLAD and CLAD phenotype and merits further exploration.

Does community size or commute time affect severity of illness at diagnosis or quality of care in a centralized care model of pulmonary hypertension?

BACKGROUND: Centralized care models are often used for rare diseases like pulmonary hypertension (PH). It is unknown how living in a rural or remote area influences outcomes. METHODS: We identified all patients from our PH database who carried a diagnosis of WHO Group 1 or WHO Group 4 PH. Using Canadian postal code data, patients were classified as living in a rural area; or a small, medium or large community size. The commute time from patient residence to our clinic was determined using mapping software. We compared baseline catheterization data according to community size and commute time. At follow up, we evaluated the association between community size and commute time with prognostic parameters of functional class, walk distance and echocardiography. RESULTS: Of the 342 patients identified, 72(21%) patients lived in rural areas, while 26(8%), 49(14%) and 195(57%) resided in small, medium and large population centres, respectively. The commute time was <1 h for 160(47%), 1-3 h for 62(18%), and >3 h for 120(35%). There was no association seen for any catheterization parameter by either community size or commute time. At last follow up, there was no association between any prognostic parameter and community size or commute time. CONCLUSIONS: We found no association between community size or commute time with severity of illness at diagnosis, or markers of prognosis at follow up. This suggests that patients who reside in rural or remote environments are not experiencing deficiencies in care compared to urban patients.

Chronic Lung Allograft Dysfunction: Review of CT and Pathologic Findings.

Chronic lung allograft dysfunction (CLAD) is the most common cause of mortality in lung transplant recipients after the 1st year of transplantation. CLAD has traditionally been classified into two distinct obstructive and restrictive forms: bronchiolitis obliterans syndrome and restrictive allograft syndrome. However, CLAD may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive physiologic abnormalities. Although the initial CT manifestations of CLAD may be nonspecific, the progression of findings at follow-up should signal the possibility of CLAD and may be present on imaging studies prior to the development of functional abnormalities of the lung allograft. This review encompasses the evolution of CT findings in CLAD, with emphasis on the underlying pathogenesis and pathologic condition, to enhance understanding of imaging findings. The purpose of this article is to familiarize the radiologist with the initial and follow-up CT findings of the obstructive, restrictive, and mixed forms of CLAD, for which early diagnosis and treatment may result in improved survival. Supplemental material is available for this article. © RSNA, 2021.

Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

BACKGROUND: Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants. CASE PRESENTATION: We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation. CONCLUSIONS: This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.

Simultaneous protection against allograft rejection and graft-versus-host disease after total lymphoid irradiation: role of natural killer T cells.

BACKGROUND: The use of combined organ and bone marrow transplantation has been studied extensively in rodent models to induce immune tolerance to organ grafts. However, bone marrow transplants with mature donor T cells can induce graft-versus-host disease even in human leukocyte antigen-matched humans. We determined whether total lymphoid irradiation can simultaneously protect against graft-versus-host disease while facilitating tolerance. METHODS: To more closely model clinical studies, we added mature donor T cells to bone marrow grafts combined with heart grafts, and compared murine graft and host survival after conditioning with nonmyeloablative total body or total lymphoid irradiation and depletive anti-T-cell antibodies. RESULTS: Conditioning with total lymphoid irradiation protected hosts against both graft-versus-host disease and organ graft rejection. Although nonmyeloblative total body irradiation prevented organ graft rejection, all hosts succumbed to lethal graft-versus host disease. Induction of tolerance with total lymphoid irradiation and anti-T-cell antibodies was dependent on the presence of regulatory host natural killer T cells, and expression of CD1d on donor marrow but not heart graft cells. CONCLUSION: Conditioning with total lymphoid irradiation and anti-T-cell antibodies prevented host-versus-donor and donor-versus-host alloimmune responses. Tolerance required host natural killer T-cell recognition of CD1d on donor marrow cells.

Response to Sildenafil in a Patient With Coexisting Post-Liver Transplant Portopulmonary Hypertension and Hepatopulmonary Syndrome.

Hepatopulmonary syndrome and portopulmonary hypertension are complications of portal hypertension with opposing mechanisms that can coexist. Moderate portopulmonary hypertension, which is a contraindication to a liver transplant, must be managed with pulmonary vasodilators to normalize pulmonary arterial pressures before a transplant listing. Concomitant hepatopulmonary syndrome complicates the management of portopulmonary hypertension, as pulmonary vasodilators can theoretically exacerbate the intrapulmonary dilatation believed to cause hepatopulmonary syndrome. We describe a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension safely treated with sildenafil.

Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders.

The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition. During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain reaction analysis, but not by Southern blotting. In situ hybridization demonstrated Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant-appearing cells. In conclusion, polymorphic B-cell lymphoproliferative disorders comparable morphologically and molecularly to those arising after solid organ transplantation also occur in association with HIV infection. As in the case of their polymorphic PT-LPD counterparts, their malignant status, biologic significance, and relationship to monomorphic B-cell lymphomas remain to be elucidated.

Emergence of Aspergillus calidoustus infection in the era of posttransplantation azole prophylaxis.

BACKGROUND: Universal antifungal prophylaxis with azoles is commonly used after lung transplantation. We noted an increase in isolates of Aspergillus calidoustus in our transplant population and hypothesized that increasing azole use (universal prophylaxis since 2008) may be promoting this infection. METHODS: Clinical and microbiologic data for A. calidoustus cases from 2008 to 2011 were extracted from chart review. For lung transplant patients, a case-control study was performed to determine risk factors, and incidence rates were calculated. RESULTS: From 2008 to 2011, we identified seven organ transplant recipients and one hematopoietic stem-cell transplant patient with positive A. calidoustus culture results in bronchoalveolar lavage at a median of 13 months after transplantation (interquartile range, 4-39 months). Chest computed tomographic scan was consistent with fungal infection in six of eight patients, and the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria classified these as "probable" invasive aspergillosis. In the case-control study, there were no differences in immunosuppression, number of respiratory samples taken, length of intensive care unit stay, or rejection rates. Of controls, 33.3% received third-generation azole prophylaxis compared with 83.3% of cases (P=0.13). However, median duration of exposure was greater in cases than in controls (3 vs. 0 months, P=0.045). Fungal minimum inhibitory concentration for voriconazole was 4 µg/mL or greater for six of eight cases. Incidence rates in lung transplants showed an increase of A. calidoustus (0/1000 vs. 11.3/1000 patient-years in 2006-2007 and 2008-2011, respectively; P=0.018), whereas Aspergillus fumigatus cases decreased (73.9/1000 vs. 49.0/1000 patient-years, P=0.0066). CONCLUSIONS: Pulmonary A. calidoustus seems to be an emerging pathogen mainly in lung transplants. We suggest that third-generation azole use reduced the incidence of A. fumigatus, but the incidence of A. calidoustus, an azole-resistant fungus, was increased.

Low-dose intradermal versus intramuscular trivalent inactivated seasonal influenza vaccine in lung transplant recipients.

BACKGROUND: In this study we compared the immunogenicity of influenza vaccine administered intradermally to the standard intramuscular vaccination in lung transplant recipients. METHODS: Patients were randomized to receive the trivalent inactivated seasonal 2008-9 influenza vaccine containing either 6 µg (intradermal) or 15 µg (intramuscular) of hemagglutinin per viral strain. Immunogenicity was assessed by measurement of geometric mean titer of antibodies using the hemagglutination-inhibition (HI) assay. Vaccine response was defined as a 4-fold or higher increase of antibody titers to at least one vaccine antigen. RESULTS: Eighty-five patients received either the intradermal (n = 41) or intramuscular (n = 44) vaccine. Vaccine response was seen in 6 of 41 patients (14.6%) in the intradermal vs 8 of 43 (18.6%) in the intramuscular group (p = 0.77). Seroprotection (HI ≥ 1:32) was 39% for H1N1, 83% for H3N2 and 29% for B strain in the intradermal group vs 28% for H1N1, 98% for H3N2 and 58% for B strain in the intramuscular group (p = 0.36 for H1N1, p = 0.02 for H3N2, p < 0.01 for B). Mild adverse events were seen in 44% of patients in the intradermal group and 34% in the intramuscular group (p = 0.38). CONCLUSIONS: Immunogenicity of the 2008-9 influenza vaccine given intradermally or intramuscularly was overall poor in lung transplant recipients. Novel strategies for influenza vaccination in this population are needed.

The use of patient-reported outcomes becomes standard practice in the routine clinical care of lung-heart transplant patients.

OBJECTIVE: To assess the use of patient-reported outcome (PROs) measures in the routine clinical care of lung-heart transplant patients. We assessed whether the addition of PROs in routine clinical care affected the duration of the consultation and patient's and clinician's views. METHOD: Consecutive lung-heart transplant patients visiting the outpatient clinic, University of Alberta Hospital, completed the Chronic Respiratory Questionnaire (CRQ) and the Health Utilities Index (HUI) on touchscreen computers. Information on the patient's responses was made available to the members of the transplant team prior to the encounter with the patient. The duration of clinical encounters was noted. At the end of every visit, clinicians completed a questionnaire on the usefulness of having PRO information available. After 6 months patients completed a survey of their experiences. RESULTS: The final patient sample consisted of 172 patients with a mean (SD) age of 52 (13.3) years old; 47% were female; 68% were organ recipients and 32% candidates. The transplant team, comprising four pulmunologists, two nurses, and one pharmacist had an average of 9 years of practical experience in pulmunology. The mean duration of patient-clinician encounters in minutes was 15.15 (4.52). Ninety-eight percent of patients indicated that they would be happy to complete the CRQ and HUI at every clinic visit. Ninety-one percent of the assessments completed by clinicians showed complete satisfaction with the use of PROs in routine practice. Further, the clinicians developed guidelines for the use of PRO information in clinical practice. CONCLUSIONS: The incorporation of PRO measures in the routine clinical care of lung-heart transplant patients resulted in a reduction of the duration of patient-clinician encounters. The experience was well accepted by patients and clinicians. We conclude that the routine use of PROs in lung-heart transplant patients has become standard practice.

Lung and heart lung transplantation at the University of Alberta 1986-2010.

The lung transplantation program at the University of Alberta has been in existence for 25 years. The current volume is 35-40 new lung transplants per year. We offer single-lung, bilateral lung, heart/lung and bilateral living lobar transplantation as options. Experience has allowed for widening of the indications and acceptance of patients with more risk. Donor evaluation and management has allowed for extended donors to be included in the donor pool. Results will likely continue to improve with increased understanding of the mechanisms and management of bronchiolitis obliterans syndrome. Our research interests have been in the areas of risk analysis, outcome assessment, and quality of life changes from transplantation.

An international survey of cytomegalovirus management practices in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is an important infection in lung transplant recipients. Center-to-center variation in preventive and treatment strategies is unknown. METHODS: An electronic survey was sent to 102 lung transplant programs registered with the International Society of Heart and Lung Transplantation and United Network for Organ Sharing. RESULTS: Fifty-nine (58%) programs responded to the survey. For CMV prevention (D+/R-), 56 of the 59 (94.9%) programs used prophylaxis and two (3.4%) of them used preemptive therapy. For R+ patients, 86.4% used prophylaxis and 13.6% used preemptive strategy. Duration of prophylaxis was extremely variable ranging from 3 months to indefinite. Adjunctive prophylactic strategies included routine viral monitoring (51% D+/R-; 44% R+) and CMV immunoglobulin (32% D+/R-; 14% R+). The medication used for prophylaxis was valganciclovir with approximately half starting with intravenous ganciclovir. 9 of the 59 (15.2%) centers reported using specific CMV prophylaxis in D-/R- patients. Methods for viral monitoring included peripheral blood polymerase chain reaction, antigenemia, bronchoalveolar lavage viral culture, and bronchoalveolar lavage polymerase chain reaction. For treatment of CMV viremia, valganciclovir or intravenous ganciclovir were used. A total of 47.5% of centers routinely decreased immunosuppression at the time of viremia. Secondary antiviral prophylaxis was used routinely by 36 of the 59 (61%) centers. CONCLUSIONS: Although prophylaxis is the most commonly used preventive strategy, significant variation exists in the way it is implemented. Specifically, duration of prophylaxis is extremely variable. Uniform international guidelines would be of value in this population.