In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.

Revision of the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart Rejection

Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

http://www.jsht.jp/uploads/ISHLT_GL_TaskForce2_110810.pdf

The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients

https://journal.chestnet.org/article/S0012-3692(12)60137-8/pdf

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1600-6143.2003.00072.x

Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection.

http://icnapedia.org/guidelines/open/Chest-2008-Monagle-887S-968S.pdf

Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Background Acute cellular rejection is the mechanism of most immune-related injury in cardiac transplant recipients. However, antibody-mediated humoral rejection (HR) has also been implicated as an important clinical entity following orthotopic heart transplantation. Humoral rejection has been reported to play a role in graft dysfunction in the early post-transplant period, and to be a risk factor for the development of transplant coronary artery disease. Some involved in transplantation pathology doubt the existence of clinically significant humoral rejection in cardiac allografts. Those who recognize its existence disagree on its possible role in graft dysfunction or graft coronary artery disease. In this study, we report clinical features of patients with the pathologic diagnosis of HR at our institution since July 1997, when we began systematic surveillance for humoral rejection. Methods We reviewed medical records of patients with the pathologic diagnosis of HR without concurrent cellular rejection between July 1997 and January 2001. Diagnosis was based on routine histology (“swollen cells” distending capillaries, interstitial edema and hemorrhage) and immunofluorescence (capillary deposition of immunoglobulin and complement with HLA-DR positivity), or immunoperoxidase staining of paraffin-embedded tissue (numerous CD68-positive macrophages and fewer swollen endothelial cells distending capillaries). Results A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent cellular rejection at autopsy or on one or more biopsies. Although females comprised only 26% of our transplant population, 23 patients (52%) with HR were female. A positive peri-operative flow cytometry T-cell crossmatch was observed in 32% of HR patients compared with 12% of controls ( p = 0.02). Hemodynamic compromise consisting of shock, hypotension, decreased cardiac output/index and/or a rise in capillary wedge or pulmonary artery pressure was observed in 47% of patients at the time of diagnosis of HR. Six patients (5 females) died (14% mortality) with evidence of HR at or just before autopsy, 6 days to 16 months after transplantation. The incidence of transplant coronary artery disease was 10% greater at 1 year, and 36% greater at 5 years, in patients with HR when compared with non-HR patients. Conclusion Humoral rejection was associated with acute hemodynamic compromise in 47% of patients, and was the direct cause of death in 6 patients (13%). Humoral rejection is a clinicopathologic entity with a high incidence in women and is associated with acute hemodynamic compromise, accelerated transplant coronary artery disease and death.

Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease.

Background: Pulsatile ventricular assist devices (VADs) are used to bridge adults with end-stage heart disease to transplantation. A combination of external implantable pulsatile and continuous-flow external mechanical support now can be used to bridge pediatric patients with end-stage cardiomyopathy to orthotopic heart transplantation (OHT). Methods: We reviewed consecutive pediatric patients with cardiomyopathy ( n = 28) who required mechanical cardiac support from July 1995 to February 2001. All were OHT candidates with severe hemodynamic compromise despite maximal medical support. We excluded from this series patients who had undergone cardiotomy. Results: Nineteen patients received support from external continuous-flow devices, either with extracorporeal membrane oxygenation or with centrifugal VADs, and 9 patients received pulsatile support. Nineteen of 28 (68%) patients were successfully bridged to transplant (17) or weaned (2) from their devices after recovery. Of the patients successfully bridged to transplant or recovery, 89% are alive to date. Univariate analysis revealed that a lower bilirubin concentration after 2 days of support was associated with a favorable outcome ( p = 0.006). As expected, the patients with pulsatile VADs had significantly higher rates of extubation and oral feeding. Conclusion: Pulsatile and continuous-flow devices can complement each other to significantly extend the lives of a wide range of pediatric patients with severe cardiomyopathies.

Use of assist devices and ECMO to bridge pediatric patients with cardiomyopathy to transplantation.

Background The normal B-type natriuretic peptide (BNP) concentration and the significance of increased BNP concentration in children after orthotopic heart transplant (OHT) remain unknown. We sought to determine plasma BNP concentrations in relation to post-transplant time and to explore factors associated with increased BNP in pediatric OHT recipients. Methods We obtained plasma BNP concentrations in 44 pediatric patients at 1 to 171 months after OHT. All patients underwent endomyocardial biopsies and echocardiography. We analyzed the association between BNP and post-transplant time , as well as the association between BNP concentration and left ventricular end-diastolic dimension (LVEDD) after transplantation. Results The age of study patients ranged from 0.9 to 21.2 years (mean, 11.4 ± 6.2 years; median, 10.5 years). We evaluated BNP concentrations immediately after transplantation. The mean BNP concentration decreased exponentially to 100 pg/ml by 14 weeks after OHT. Although BNP concentration relative to time after OHT varied among individuals, all patients with multiple measurements showed predictable rates of decrease. This decrease in BNP concentration was not associated with changes in LVEDD. Conclusions Plasma BNP concentration was elevated in children after OHT and decreased exponentially in time to 100 pg/ml by 14 weeks after OHT. The decrease in BNP concentration was unrelated to left ventricular dimension.

B-type natriuretic peptide in children after cardiac transplantation.

Endomyocardial biopsy is commonly used to screen for cellular rejection in pediatric heart transplant patients. The yield of EMBs when combined with newly developed immunohistochemical techniques and modern immunosuppression in pediatric heart transplant patients is unknown. After OHT, surveillance biopsies were performed on a routine basis on all pediatric patients. EMBs were also performed on symptomatic OHT patients suspected to have rejection. All positive results (greater than ISHLT grade 1B) were confirmed with immunohistochemical staining. A retrospective review of consecutive EMBs performed in this institution from January 1995 to January 2003 was performed. The echocardiographic results, clinical history and treatment changes at the time of every biopsy were also catalogued. Of the 1093 EMB results from 136 pediatric heart transplant grafts (127 patients, 64 male) reviewed, 825 biopsies were performed on patients managed with tacrolimus and 268 were performed on patients managed with cyclosporine. The patients managed with tacrolimus had an incidence of 0.85% (7/825) for significant rejection (greater than ISHLT grade 1B rejection) vs. an incidence of 4.1% (11/268) for the patients on cyclosporine (p < 0.0005). In the asymptomatic tacrolimus patients, only two screening biopsies (0.26%) manifest significant rejection, and both of these were performed within the first month after transplantation. Of the symptomatic tacrolimus patients, 9.1% (n = 5) had findings on biopsy consistent with significant cellular rejection. There were 25 patients with grade 1B rejection. Twenty-two of these patients were not treated, and all cases of grade 1B rejection resolved without clinical sequelae. For pediatric patients more than 30 days after OHT, EMB has failed to reveal significant episodes of cellular rejection in asymptomatic patients managed with tacrolimus.

The yield of surveillance endomyocardial biopsies as a screen for cellular rejection in pediatric heart transplant patients

Acute viral myocarditis triggers an autoimmune phenomenon that aggressive immunosuppressive therapy with monoclonal OKT3 may suppress. We treated 5 patients, aged 15 months to 16.5 years, who had acute viral myocarditis and left ventricular ejection fraction (LVEF) of 5% to 20%, with a combination immunosuppressive regimen that included OKT3, intravenous immunoglobulin, methylprednisone, cyclosporine, and azathioprine. Within 2 weeks of therapy, all patients demonstrated normalization of LVEF to 50% to 74%, and on mid-term follow-up, we have found no recurrence of heart failure or progression to dilated cardiomyopathy. In patients with severe acute myocarditis, aggressive immunosuppressive regimen based on OKT3 is safe and may inhibit or reverse the immune response, resulting in dramatic improvement in myocardial function.

C. Burch

Papers

Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease.

Use of assist devices and ECMO to bridge pediatric patients with cardiomyopathy to transplantation.

B-type natriuretic peptide in children after cardiac transplantation.

The yield of surveillance endomyocardial biopsies as a screen for cellular rejection in pediatric heart transplant patients

Use of OKT3 for Acute Myocarditis in Infants and Children