Effect of Lung Transplantation on Health-Related Quality of Life in the Era of the Lung Allocation Score: A U.S. Prospective Cohort Study.

Under the U.S. Lung Allocation Score (LAS) system, older and sicker patients are prioritized for lung transplantation (LT). The impact of these changes on health-related quality of life (HRQL) after transplant has not been determined. In a single-center prospective cohort study from 2010 to 2016, we assessed HRQL before and repeatedly after LT for up to 3 years using the SF12-Physical and Mental Health, the respiratory-specific Airway Questionnaire 20-Revised, and the Euroqol 5D/Visual Analog Scale utility measures by multivariate linear mixed models jointly modeled with death. We also tested changes in LT-Valued Life Activities disability, BMI, allograft function, and 6-min walk test exercise capacity as predictors of HRQL change. Among 211 initial participants (92% of those eligible), LT improved HRQL by all 5 measures (p < 0.05) and all but SF12-Mental Health improved by threefold or greater than the minimally clinically important difference. Compared to younger participants, those aged ≥65 improved less in SF12-Physical and Mental Health (p < 0.01). Improvements in disability accounted for much of the HRQL improvement. In the LAS era, LT affords meaningful and durable HRQL improvements, mediated by amelioration of disability. Identifying factors limiting HRQL improvement in selected subgroups, especially those aged ≥65, are needed to maximize the net benefits of LT.

Defective interleukin 2 production and responsiveness in human pulmonary tuberculosis.

Patients with newly diagnosed, pulmonary tuberculosis had a tuberculin-specific defect in IL-2 production. Mean PPD-induced IL-2 activity was 81.2% lower in patients as compared with healthy tuberculin reactors. PPD-induced expression of T cell IL-2 receptors was 5.9 times less in peripheral blood mononuclear cells of patients with tuberculosis as compared with healthy tuberculin reactors. Furthermore, purified IL-2 failed to correct PPD-induced blastogenesis in patients. Suppression by adherent cells was operative in one group of patients; adherent cell depletion increased their T cell production of IL-2 7.2-fold. A second group of patients with low IL-2 production did not have suppressor adherent cells and were clinically distinct, with more extensive disease on chest x ray. The basis for low IL-2 production in such individuals is unknown. Disordered regulation of IL-2 metabolism may be a key feature in the depressed cellular immune response of tuberculosis.

Antireflux surgery for patients with end-stage lung disease before and after lung transplantation.

BACKGROUND: Gastroesophageal reflux disease (GERD) is prevalent among patients with end-stage lung disease (ESLD). This disease can lead to microaspiration and may be a risk factor for lung damage before and after transplantation. A fundoplication is the best way to stop reflux, but little is known about the safety of elective antireflux surgery for patients with ESLD. This study aimed to report the safety of laparoscopic fundoplication for patients with ESLD and GERD before or after lung transplantation. METHODS: Between January 1997 and January 2007, 305 patients were listed for lung transplantation, and 189 patients underwent the procedure. In 2003, routine esophageal studies were added to the pretransplantation evaluation. After the authors' initial experience, gastric emptying studies were added as well. RESULTS: A total of 35 patients with GERD or delayed gastric emptying were referred for surgical intervention. A laparoscopic fundoplication was performed for 32 patients (27 total and 5 partial). For three patients, a pyloroplasty also was performed. Two patients had a pyloroplasty without fundoplication. Of the 35 operations, 15 were performed before and 20 after transplantation. Gastric emptying of solids or liquids was delayed in 12 (92%) of 13 posttransplantation studies and 3 (60%) of 5 pretransplantation studies. All operations were completed laparoscopically, and 33 patients recovered uneventfully (94%). The median hospital length of stay was 2 days (range, 1-34 days) for the patients admitted to undergo elective operations. Hospitalization was not prolonged for the three patients who had fundoplications immediately after transplantation. CONCLUSIONS: The results of this study show that laparoscopic antireflux surgery can be performed safely by an experienced multidisciplinary team for selected patients with ESLD before or after lung transplantation, and that gastric emptying is frequently abnormal and should be objectively measured in ESLD patients.

Suppression of lymphocyte responses by tuberculous plasma and mycobacterial arabinogalactan. Monocyte dependence and indomethacin reversibility.

During tuberculosis, exposure of monocytes to circulating factors may induce the suppressor activity observed in some anergic patients. To explore this possibility, we examined the effects of plasma pooled from 28 untreated tuberculosis (TB) patients and the mycobacterial cell wall polysaccharide D-arabino-D-galactan (AG) on the in vitro function of peripheral blood mononuclear cells (PBMC) from healthy donors. In the [3H] thymidine incorporation assay, stimulated responses of PBMC incubated in culture medium supplemented with TB plasma or co-cultured with 3.0 microgram/ml AG were depressed significantly when compared with control responses. Cytotoxicity and altered kinetics of stimulated DNA synthesis did not contribute to the observed suppression. TB plasma and AG-induced suppression of the PBMC response to purified protein derivative was monocyte dependent and indomethacin reversible. In addition, TB plasma and AG directly inhibited the phytohemagglutinin-stimulated responses of T lymphocytes. In a quantitative assay of monocyte attachment to plastic, both TB plasma and AG significantly increased monocyte adherence from basal levels. These effects on monocyte adherence were reversed with indomethacin or antibody to mycobacterial polysaccharide. In addition, TB plasma passed over an immunoabsorbent column of Sepharose-linked antibody to mycobacterial polysaccharide was depleted of the suppressive and monocyte-adherence augmenting factors. 3.0 microgram/ml AG stimulated a fivefold increase in prostaglandin E2 production by cultured mononuclear cells. Our data suggest that AG circulating alone or bound in immune complexes may account for the observed effects of TB plasma. Similar in vivo exposure may contribute to the cell-mediated suppression of lymphocyte responses in tuberculosis.

Destruction of the multicellular parasite Schistosoma mansoni by T lymphocytes.

The role of cytotoxic T lymphocytes in host defenses against infectious agents is unknown as these cells have not previously been demonstrated to kill microorganisms directly. We studied the cytotoxicity of T lymphocytes purified from peripheral blood mononuclear cells of healthy subjects for the multicellular schistosomula of Schistosoma mansoni. Unstimulated and phytohemagglutinin (PHA)-stimulated T cells were cultured with schistosomula at a 5,000:1 effector/target (E:T) ratio for 18 h at 37 degrees C. Unstimulated T cells killed 2.1 +/- 0.6% of schistosomula as judged by dye uptake and did not change their infectivity for mice. In contrast, PHA-stimulated T cells killed 41.3 +/- 3.1% of schistosomula by dye uptake and 56.7 +/- 7.7% of these organisms could not mature to adult worms in vivo. Killing was associated with and dependent on increased binding of PHA-stimulated T lymphocytes to schistosomula. Significant schistosomula killing first was noted after 2 h of exposure to T cells to PHA and peaked at 24; enhanced killing by PHA-stimulated cells was observed at an E:T ratio of 500:1 and was maximal at 5,000:1. Exposure of T lymphocytes to oxidative mitogens, soluble antigens, and alloantigens also resulted in enhanced killing of schistomula. These studies show that T lymphocytes activated by a variety of stimuli develop the capacity to kill schistosomula of Schistoma mansoni. Direct killing of infectious agents by cytotoxic T cells may contribute to host resistance to infections.

Bovine aortic endothelial cells elaborate an inhibitor of the generation of lipopolysaccharide-stimulated human blood monocyte procoagulant activity.

We examined the effect of bovine aortic endothelial cell culture supernatants upon the generation of procoagulant activity by human blood monocytes. Confluent endothelial monolayers were cultured for up to 96 h. At timed intervals, culture supernatants were collected and incubated for 5 h with lipopolysaccharide-stimulated human peripheral blood mononuclear cells. The procoagulant activity of mononuclear cell lysates was determined in a one-stage clotting assay. In five experiments, procoagulant activity with culture supernatant (time 0) was 2,294 +/- 761 U/ml (mean +/- SEM). Culture supernatants from endothelial cells incubated for 24-96 h strongly inhibited mononuclear cell generation of procoagulant activity. Indomethacin (10 microM) added to endothelial cells delayed the appearance of procoagulant inhibitor for 72 h. Bovine aortic smooth muscle cell culture supernatants did not inhibit procoagulant activity. The inhibitor was heat stable, effective at 1:50 dilution, soluble, and acid sensitive, with a molecular weight of less than 1,500. Further studies on subpopulations of mononuclear cells demonstrated that endothelial inhibitor selectively decreased the generation of monocyte procoagulant activity and interfered with T lymphocyte amplification of monocyte production of procoagulant activity. Thus, we have demonstrated that endothelial cells elaborate a potent inhibitor of monocyte procoagulant activity.

Augmentation of natural killer cell activity by lipopolysaccharide through separable effects on the binding of nonadherent lymphocytes to tumor targets and tumor killing.

A single-cell assay was utilized to study the augmentation by Escherichia coli lipopolysaccharide (LPS) of the cytotoxicity of human lymphocytes for the human myeloid tumor K562. Preincubation with LPS at 20 micrograms/ml for 30 min at 37 degrees increased the binding of all nonadherent (NA) lymphocyte populations to K562 tumors [unseparated NA lymphocytes from 13.1 to 25.1%, immunoglobulin G Fc receptor-enriched lymphocytes from 27.6 to 42.9%, and immunoglobulin G Fc receptor-depleted lymphocytes from 14.0 to 23.7%, at p less than 0.001]. In contrast, interferon (IFN) at 10 units/ml had no effect on the overall binding of lymphocytes to K562 tumors. When lymphocyte-tumor conjugates were dispersed in agarose, cytotoxic activity of unseparated NA lymphocytes at 1 to 3 hr was markedly increased by preincubation with LPS (p less than 0.001). However, LPS did not enhance cytotoxicity if conjugates were formed in its absence. IFN, likewise, increased cytotoxic activity in unseparated NA lymphocytes at 1 to 3 hr (p less than 0.001). No synergistic cytotoxicity was seen with concurrent exposure to LPS and IFN. LPS increased cytotoxicity in the Fc receptor-enriched:tumor conjugates at 1 to 3 hr (p less than 0.001) and appeared to promote more efficient killing in individual conjugates over time. Cytotoxicity in the Fc receptor-depleted:tumor conjugates was not enhanced by LPS. Thus, LPS may enhance natural killer cell-like activity by increasing the binding of human lymphocytes to K562 tumors and by rearranging the population of binding cells to include more efficient killer cells. While the effects of LPS on binding appear independent of IFN, selective recruitment of more efficient killer cells could be through an IFN mechanism.

Prolonged Barium-Impaction Ileus in Two Lung Transplant Recipients With Systemic Sclerosis: Case Report.

Lung transplantation can be a life-saving measure for people with end-stage lung disease from systemic sclerosis. However, outcomes of lung transplantation may be compromised by gastrointestinal manifestations of systemic sclerosis, which can involve any part of the gastrointestinal tract. Esophageal and gastric disease can be managed by enteral feeding with the use of a gastrojejunal feeding tube. In this report, we describe the clinical courses of 2 lung transplant recipients with systemic sclerosis who experienced severe and prolonged barium-impaction ileus after insertion of a percutaneous gastrojejunal feeding tube.

Immunohistologic identification of antigen-presenting cells in cutaneous sarcoidosis.

Considerable evidence exists to show that activated T lymphocytes preferentially accumulate at sites of disease activity in sarcoidosis. Langerhans cells, which can be recognized by reactivity with an antibody to the T6 antigen are thought to play a primary role in T-lymphocyte activation by the skin, a tissue frequently involved in sarcoidosis. This immunohistologic study examined the distribution of OKT6-positive cells and surface expression of HLA-DR antigen in cutaneous sarcoid lesions. Skin specimens stained with an anti-HLA-DR antibody demonstrated diffuse staining of the granulomas. In addition, keratinocytes, which do not normally express HLA-DR antigens, were found to stain with monoclonal antibody to HLA-DR in an intercellular pattern. Examination of specimens for OKT6-reactive Langerhans cells revealed significantly greater concentrations in the epidermis overlying sarcoidal granulomas (33 +/- 7 cells/mm) than in the epidermis of age-, sex-, and race-matched controls (11 +/- 3 cells/mm, p less than 0.001). Of greater importance was the demonstration that significant numbers of OKT6-positive cells were present within the dermal sarcoid granulomas (19-208/mm2) in a distribution that paralleled that of Leu-3a-positive T lymphocytes. These data suggest that the epidermis may participate in activation of lymphocytes in cutaneous sarcoidosis, and implicate OKT6-positive cells in granuloma formation.

Paradoxical embolization in an adult patient with cystic fibrosis.

To our knowledge, we describe the first reported case of paradoxical embolization via a patent foramen ovale (PFO) in an adult with moderately severe cystic fibrosis (CF) and advanced lung disease. Fluctuating neurologic symptoms and signs suggestive of cerebrovascular disease in an adult patient with advanced CF may be due to paradoxical embolization via a PFO. The possibility of a PFO should be considered before placement of a totally implantable venous access device to avert unnecessary risk of stroke in CF patients. Further study is needed to determine whether the use of a totally implantable venous access device increases the risk of paradoxical embolization in adult CF patients with a PFO.

Validity of three clinical performance assessments of internal medicine clerks.

PURPOSE: To analyze the construct validity of three methods to assess the clinical performances of internal medicine clerks. METHOD: A multitrait-multimethod (MTMM) study was conducted at the Case Western Reserve University School of Medicine to determine the convergent and divergent validity of a clinical evaluation form (CEF) completed by faculty and residents, an objective structured clinical examination (OSCE), and the medicine subject test of the National Board of Medical Examiners. Three traits were involved in the analysis: clinical skills, knowledge, and personal characteristics. A correlation matrix was computed for 410 third-year students who completed the clerkship between August 1988 and July 1991. RESULTS: There was a significant (p < .01) convergence of the four correlations that assessed the same traits by using different methods. However, the four convergent correlations were of moderate magnitude (ranging from .29 to .47). Divergent validity was assessed by comparing the magnitudes of the convergence correlations with the magnitudes of correlations among unrelated assessments (i.e., different traits by different methods). Seven of nine possible coefficients were smaller than the convergent coefficients, suggesting evidence of divergent validity. A significant CEF method effect was identified. CONCLUSION: There was convergent validity and some evidence of divergent validity with a significant method effect. The findings were similar for correlations corrected for attenuation. Four conclusions were reached: (1) the reliability of the OSCE must be improved, (2) the CEF ratings must be redesigned to further discriminate among the specific traits assessed, (3) additional methods to assess personal characteristics must be instituted, and (4) several assessment methods should be used to evaluate individual student performances.

The diffusing capacity in adult cystic fibrosis.

The value of adjusting the diffusing capacity for the lung volume has been demonstrated in a large number of patients with other lung diseases but has not been validated in patients with cystic fibrosis (CF). Pulmonary function test results on a cohort of 52 adult CF patients were analyzed to determine whether the diffusing capacity of carbon monoxide by single breath method (DLCO(SB)) when adjusted for alveolar volume (V(A)%), correlated with the severity of pulmonary dysfunction. The DLCO(SB) remained within the reference range except in those with severe lung impairment (61.88 +/- 15.48%). DLCO(SB) has a significant (P < 0.05) positive correlation (0.70, 0.67, 048, 0.69 and 0.31, respectively) with measures of airflow limitation (FVC%, FEV1%, FEV1/FVC%, MVV%, and sGaw) and negative correlation (-0.36 and -0.21, respectively) with measures of air trapping (RV% and RV/TLC%). DLCO(SB)/V(A) remained above 100% of predicted despite worsening lung disease and did not correlate with other measures of lung function. On the other hand, the DLCO(SB) and DLCO(SB)/V(A), when adjusted for V(A)%, decreased and were significantly correlated with worsening airflow limitation and, to a lesser extent, air trapping. The relatively preserved adjusted DLCO(SB) and DLCO(SB)/V(A) values in CF patients up until late in its course may be explained the predominant airway involvement, minimal loss of alveolar-capillary units, and enhanced V/Q relationship due to claustration in CF.

Chronic ventilator dependence in elderly patients.

Long-term ventilator dependence is the need for mechanical ventilation for more than 6 h/d for more than 21 days. Long-term ventilator dependence complicates 9% to 20% of the episodes of mechanical ventilation treated in the intensive care units of acute care hospitals; it is associated with an average mortality rate of 40%. Unlike acute respiratory failure, the risk for which does not increase with age, long-term ventilator dependence falls disproportionately to patients aged 70 years or older. During the past 2 decades, a profusion of care sites for patients with long-term ventilator dependence has evolved, largely as the product of the prospective payment system for health services introduced by the Health Care Financing Administration in 1983. The outcome of long-term ventilator dependence in elderly patients across this health care continuum is addressed.

Psychological factors in sarcoidosis: the relationship between life stress and pulmonary function.

Seventeen patients with diagnosed sarcoidosis were administered a number of psychological instruments to assess anxiety, depression, life stress, and symptoms of agoraphobia and/or panic. These patients were then followed medically for a period of nine months. Scores on the various psychological tests were then compared with results obtained from repeated pulmonary function tests. Results showed a consistent relationship between increased life stress at time one and impairment in lung function throughout the study period. In addition, no consistent set of psychiatric symptoms were associated with the disease. Sarcoid patients did, however, report many symptoms similar to patients with agoraphobia. These results are discussed in terms of the potential benefits of stress reduction treatment as an adjunctive therapy for patients with sarcoidosis.

Antigen responsiveness during tuberculosis: regulatory interactions of T cell subpopulations and adherent cells.

Previous studies from this laboratory demonstrated that adherent mononuclear cells selectively decreased in vitro tuberculin responses in some anergic patients with tuberculosis; subsequently this adherent suppressor cell was characterized as a monocyte. The current study of 41 patients with active pulmonary tuberculosis examined whether T cell subpopulations also acquired antigen-specific suppressor function during Mycobacterium tuberculosis infection, contributed to monocyte-mediated suppression of tuberculin responses, or both. Alteration in the numbers of circulating T-helper (Leu 3a) and T-suppressor (Leu 2a) cells was not observed in patients with tuberculosis, nor did Leu 2a cells selectively modulate in vitro tuberculin responses. The numbers of circulating T gamma cells, a subset of T cells identified by surface receptors for the Fc portion of IgG (Fc gamma R), was increased twofold in patients with active pulmonary tuberculosis. Depletion of T gamma cells from in vitro cell culture consistently and selectively increased tuberculin responsiveness of T cells from patients with tuberculosis. In addition, in the absence of T gamma cells, monocyte-mediated suppression of tuberculin responses was demonstrated in each patient observed. These studies demonstrate that during M. tuberculosis infection T gamma cells acquire antigen-specific suppressor cell activity and suggest that T gamma cells also contribution to immunoregulation modulating the expression of tuberculin-specific suppression by monocytes.

Divergent T gamma cell functions in antigen-induced blastogenesis: facilitory interactions with Tnon gamma cells and participation in monocyte- and prostaglandin-mediated suppression.

The contribution of T gamma cells, i.e., T cells bearing surface receptors for the Fc portion of IgG, to the immunologic response to antigen has not been assessed in health or disease. We examined the role of T gamma cells in antigen-induced blastogenesis of T cells from healthy subjects and characterized their participation in monocyte- and prostaglandin-mediated suppression. Cell fractions enriched in the depleted of T gamma cells were prepared from nonadherent T cells by preparative rosetting with IgG-sensitized ox erythrocytes; antigen-induced blastogenesis was assayed as 3H-thymidine incorporation (3H-TdR), by microculture techniques. Removal of T gamma cells resulted in a Tnon gamma cell fraction whose in vitro response to soluble antigen was a mean 40% +/- 8 less than the response of the unseparated T cells from the same donors. Antigen did not induce 3H-TdR in cultures of T gamma cells; however, in cell-mixing experiments, addition of autologous T gamma cells reconstituted the antigen responsiveness of the Tnon gamma cell fraction. Monocytes (MN) added to cell cultures at a ratio known to be suppressive in vitro (MN to T = 1:4) significantly decreased antigen-induced 3H-TdR of unseparated T cells but did not alter the antigen responses of Tnon gamma cells. MN-dependent suppression was abrogated by co-culture with indomethacin. Exogenous prostaglandin E2, an immunosuppressive cyclooxygenase product of MN, selectively decreased antigen-induced 3H-TdR of cell cultures containing T gamma cells but did not affect antigen responses of Tnon gamma cell fraction. Thus these studies show that MN and their cyclooxygenase products modulate T gamma cells to function in a suppressive mode. This demonstration of divergent T gamma cell functions indicates that the contribution of an expanded T gamma cell population to altered antigen reactivity in disease can be determined only by careful functional studies.

Immunoregulatory adherent cells in human tuberculosis: radiation-sensitive antigen-specific suppression by monocytes.

In human tuberculosis, adherent mononuclear cells (AMC) selectively depress in vitro responses to the mycobacterial antigen tuberculin purified protein derivative (PPD). The phenotype of this antigen-specific adherent suppressor cell was characterized by examining the functional activity of adherent cells after selective depletion of sheep erythrocyte-rosetting T cells or OKM1-reactive monocytes. Adherent cell suppression was studied in the [3H]thymidine-incorporation microculture assay by using T cells rigorously depleted of T cells with surface receptors for the Fc portion of IgG (T gamma cells) as antigen-responsive cells. PPD-induced [3H]thymidine incorporation by these non gamma T cells was uniformly reduced (mean, 42% +/- 10% [SD]) when autologous AMC were added to non gamma T cells at a ratio of 1:2. Antigen-specific suppression by AMC was not altered by depletion of sheep erythrocyte-rosetting T cells or treatment with indomethacin. However, AMC treated with OKM1 and complement or gamma irradiation (1,500 rads) no longer suppressed tuberculin responses in vitro. These studies identify the antigen-specific adherent suppressor cell in tuberculosis as an OKM1-reactive, non-erythrocyte-rosetting monocyte. The radiosensitivity of this monocyte immunoregulatory function may facilitate its further definition.