Amy Pope-Harman

The Role of Microvascular Injury in the Evolution of Idiopathic Pulmonary Fibrosis

Interstitial lung disease compatible with idiopathic pulmonary fibrosis (IPF) developed in 19 previously healthy patients. Although interstitial and/or honeycomb parenchymal fibrosis was present in all, there were patchy areas of paucicellular septal capillary injury along with corroborative direct immunofluorescent evidence of a humorally mediated microvascular injury syndrome. Significantly elevated factor VIII levels were seen in 17 of 18 patients tested. Antiphospholipids were present in all 18 patients tested, comprising antibodies of phosphatidylethanolamine, beta-2 glycoprotein, phosphatidylcholine, and/or phosphatidylserine. Anti-Ro and/or anti-ribonucleoprotein (RNP) antibodies were seen in 4 patients. Serologic evidence of infection with cytomegalovirus (CMV) was found in 9 patients and parvovirus B19 (B19) in 9 patients; 1 patient was not tested. Molecular studies revealed B19 DNA in 6 of 6 B19-seropositive patients. In situ hybridization studies revealed CMV RNA in pulmonary cells in patients with serologic evidence of active CMV infection despite the absence of cytopathic changes typical of CMV infection. Antiphospholipid antibodies, antiendothelial cell antibodies, and/or endotheliotropic viral infections related to B19 and CMV may be of pathogenetic importance to the evolution of IPF. This report underscores the potential importance of microvascular injury in the evolution of IPF.

Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen‐Related

We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor‐specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel‐reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor‐specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

Association of Humoral Immunity and Bronchiolitis Obliterans Syndrome

Animal studies have shown that blockade of complement may reduce the severity of and/or prevent the development of bronchiolitis obliterans syndrome (BOS), suggesting a role for complement activation. We explored the hypothesis that humoral immunity plays a role in the evolution of BOS. Thirteen unilateral lung transplant patients with BOS defined the patient population. Fresh frozen tissue was analyzed for deposition of C1q, C4d, C5b‐9 and immunoglobulin (IgG, IgM, IgA). An indirect immunofluorescent assay was also conducted with patient serum against cytospins of the pulmonary endothelium. In each case the biopsies showed a microvascular injury syndrome involving the bronchial wall characterized by one or more of hemorrhage, fibrin deposition, and endothelial cell necrosis. Other features included bronchial epithelial and chondrocyte necrosis. The end‐stage lesion was a thinned bronchial epithelial lining mural fibrosis. Immunofluorescent analysis showed deposition of C1q, C3, C4d, C5b‐9, and immunoglobulin in the bronchial epithelium, chondrocytes, basement membrane zone of the bronchial epithelium, and bronchial wall microvasculature. The indirect antiendothelial cell antibody assay was positive in all tested. Humoral immunity may play a role in the pathogenesis of BOS; the antigenic targets include the bronchial wall microvasculature, bronchial epithelium, and chondrocytes.

Multidrug-resistant Acinetobacter baumannii Pneumonia in Lung Transplant Recipients

We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study.

To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival

The impact of induction immunosuppression on long‐term survival in lung transplant recipients remains unclear. We sought to evaluate the effect of contemporary induction immunosuppression agents in lung transplant recipients’ survival, utilizing national registry data.

Direct and indirect immunofluorescence as a diagnostic adjunct in the interpretation of nonneoplastic medical lung disease.

Fresh open lung biopsy material from 57 patients was incubated with fluoresceinated complement and immunoglobulin antisera. An indirect immunofluorescent assay using neonatal lung as substrate was conducted as well. Direct immunofluorescent patterns could be categorized into interalveolar septal capillary deposition, large vessel wall localization, alveolar basement membrane localization, or a pauci-immune immunofluorescence pattern. With respect to the septal capillary pattern, endothelial cell decoration was seen with scleroderma, mixed connective tissue disease, anti-Ro-associated lupus erythematosus, dermatomyositis, humoral allograft rejection, and patients with isolated pulmonary fibrosis in whom autoantibodies were established, including antiphospholipid antibodies. A similar pattern of endothelial cell staining was seen in these cases via the indirect assay. Granular mural septal capillary deposition was seen in the aforesaid settings along with rheumatoid factor-positive rheumatoid arthritis, type II cryofibrinogenemia, and mixed cryoglobulinemia and, in some cases, light microscopically corresponded to a neutrophilic capillaritis. Isolated vascular IgA corresponded with rheumatoid arthritis corresponding to IgA-specific antiendothelial cell antibodies, celiac disease-associated pulmonary hemorrhage, Schönlein-Henoch purpura and with IgA antiphospholipid antibodies. Alveolar wall deposition was seen with anti-glomerular basement membrane disease.

Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens

BackgroundAfter the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications.MethodsA laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications.ResultsThe incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns.ConclusionsOur study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary toxicity but may be beneficial in cases of posttransplant neoplasia.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3320012126569395.

Successful Management of Immunosuppression in a Patient With Severe Hyperammonemia After Lung Transplantation

Hyperammonemia after lung transplantation is a rare complication of unknown etiology. Its management is largely supportive and outcomes have been variable. More disconcerting is its immunosuppressive management because the precipitating factors leading to this potentially lethal entity are unknown, but are suspected to be drug-related. We describe the successful management of a lung transplant recipient with severe hyperammonemia.

Ultrastructure as a diagnostic adjunct in the evaluation of lung allograft biopsies.

Humoral immunity contributes significantly to lung graft dysfunction. Recognizing a role of ultrastructural studies in the evaluation and diagnosis of chronic humoral allograft rejection in the kidney, the authors sought to explore its utility as a diagnostic adjunct in lung allograft biopsies. Ultrastructural studies were conducted on 44 biopsies from 26 lung transplant recipients. Endothelial cell activation and necrosis were seen in the setting of acute humoral allograft rejection. Septal chronic vasculopathic changes of thickening and lamellation of the basement membrane zone (BMZ) and BMZ collagen deposition were correlated with greater numbers of humoral allograft rejection episodes and with the development of chronic graft dysfunction/bronchiolitis obliterans syndrome. There was a positive correlation between the extent of septal fibrosis and certain chronic vasculopathic changes, namely collagen deposition in the BMZ and BMZ wrinkling. Patients with chronic graft dysfunction and multiple rejection episodes manifested low diffusion capacities (less than 50% predicted). The results indicate that ultrastructural analysis is useful in identification of septal fibrosis and chronic vasculopathy of the septal microvasculature, correlating with chronic graft dysfunction, encompassing not only fibrotic sequelae of the bronchial wall but also irreversible terminal lung parenchymal changes, the latter associated with repeated episodes of humoral rejection.

Alpha-1 anti-trypsin deficiency and Henoch-Schönlein purpura associated with anti-neutrophil cytoplasmic and anti-endothelial cell antibodies of immunoglobulin-A isotype

Abstract:  Alpha‐1 anti‐trypsin (A1AT) deficiency is an inherited enzyme deficiency that manifests with fatal lung and liver complications. In addition to pulmonary and hepatic involvement, the disease has also been linked to an increased incidence of vasculitic syndromes and autoimmune diseases, including Wegeners granulomatosis, microscopic polyarteritis nodosa and Henoch‐Schönlein purpura (HSP). HSP, a systemic, small‐vessel vasculitis syndrome, is characterized by a non‐thrombocytopaenic purpuric rash, arthralgia, abdominal pain and nephritis. Both A1AT deficiency and HSP have been associated with anti‐neutrophil cytoplasmic antibodies (ANCA) and anti‐endothelial cell antibodies (AECA). We report a case of a 40‐year‐old man with severe A1AT deficiency, who developed HSP associated with AECA, ANCA and anti‐phospholipid antibodies of the immunoglobulin‐A isotype.