Disseminated nocardiosis diagnosed by fine needle aspiration biopsy: quick and accurate diagnostic approach.

Nocardia is an uncommon pathogen in immunocompetent patients; however, it has been increasingly recognized as a significant opportunistic pathogen in organ transplant patients. Diagnosis of Nocardiosis is usually made by microbiologic culture or cytologic examination of pulmonary specimens including, sputum, and brushing/washings or by histologic evaluation of tissue biopsy material. We report a case of subcutaneous Nocardiosis diagnosed by Fine-needle aspiration biopsy (FNA). The patient is a 66-year-old man with a history of lung transplantation and posttransplant lymphoproliferative disorder who presented with subcutaneous masses in the right upper arm and the left shoulder. FNA was performed in an outpatient clinic setting, with immediate morphologic assessment revealing filamentous branching organisms suspicious for Nocardiosis. Subsequent examination with special stains and microbiologic culture confirmed the diagnosis. The quick and accurate diagnosis by FNA led to emergent and appropriate treatment.

Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension.

OBJECTIVE: Lung transplantation is a viable, life-saving intervention for several primary pulmonary disorders complicated by severe lung dysfunction. This study was undertaken to evaluate whether patients with systemic sclerosis (scleroderma), a systemic autoimmune rheumatic disorder, would receive similar benefit from this intervention. METHODS: Survival following lung transplantation was examined at 2 university medical centers among 29 patients with scleroderma as compared with 70 patients with idiopathic pulmonary fibrosis (IPF) and 38 with idiopathic pulmonary arterial hypertension (IPAH), the latter groups representing pathologically related primary pulmonary disorders. The end point was death from any cause. Risk of mortality in patients with scleroderma was compared with that in patients with IPF or IPAH, with adjustment for demographic and clinical parameters. RESULTS: During 2 years of followup, 11 patients with scleroderma (38%), 23 with IPF (33%), and 14 with IPAH (37%) died. Cumulative survival at 6 months posttransplantation was 69% in the scleroderma group compared with 80% in the IPF group (log-rank P = 0.21) and 79% in the IPAH group (P = 0.38). The estimated risk of mortality at 6 months was increased in patients with scleroderma compared with those with IPF (relative risk [RR] 1.70, 95% confidence interval [95% CI] 0.74-3.93) and those with IPAH (RR 1.52, 95% CI 0.59-3.96), but the differences were not statistically significant. Over the following 18 months, there was convergence in the survival rates such that cumulative survival at 2 years was comparable, at approximately 64%, among all 3 groups. CONCLUSION: Patients with scleroderma who are recipients of lung transplantation experience similar rates of survival 2 years after the procedure compared with those with IPF or IPAH. Lung transplantation may represent a viable therapeutic option to consider for patients with end-stage lung disease due to scleroderma.

Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts.

Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M. fermentans and immune-modulating cytokine release was assessed with and without known inducers of cytokine production. M. fermentans increased IL-6, IL-8/CXCL8, MCP-1/CCL2, and Gro-alpha/CXCL1 production. M. fermentans interacted with TNF-beta to release more IL-6, CXCL8, and CXCL1 than predicted by the responses to either stimulus alone. The effects of live infection were recapitulated by exposure to M. fermentans-derived macrophage-activating lipopeptide-2 (MALP-2), a Toll-like receptor-2- and receptor-6-specific ligand. The synergistic effect of combined stimuli was more pronounced with prolonged incubations. Preexposure to TNF-beta sensitized the cells to subsequent MALP-2 challenge, but preexposure to MALP-2 did not alter the IL-6 response to TNF-beta. Exposure to M. fermentans or MALP-2 did not enhance nuclear localization, DNA binding, or transcriptional activity of NF-kappaB and did not modulate early NF-kappaB activation in response to TNF-beta. Application of specific inhibitors of various MAPKs suggested that p38 and JNK/stress-activated protein kinase were involved in early IL-6 release after exposure to TNF-beta and M. fermentans, respectively. The combined response to M. fermentans and TNF-beta, however, was uniquely sensitive to delayed application of SP-600125, suggesting that JNK/stress-activated protein kinase contributes to the amplification of IL-6 release. Thus M. fermentans interacts with stimuli such as TNF-beta to amplify lung cell production of immune-modulating cytokines. The mechanisms accounting for this interaction can now be dissected with the use of this in vitro model.

A randomized trial of inhaled cyclosporine in lung-transplant recipients.

BACKGROUND: Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. RESULTS: The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. CONCLUSIONS: Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).

Psychomotor performance in lung transplant recipients: simple reaction time.

BACKGROUND: Many transplant recipients report difficulty completing fine motor activities such as eating, writing and manipulating buttons. These impairments are thought to stem from the immunosuppressive medications being taken by these patients. The purpose of this study was to examine central and peripheral processes and the force regulation involved in producing appropriate and quality movement in lung transplant recipients. METHODS: Fifty-one right-handed subjects were recruited from 3 study groups (17 in each group): Group 1, lung transplant recipients (LTR); Group 2, subjects with advanced emphysema; and Group 3, healthy adult controls. Each subject completed a fine motor and gross motor simple reaction time task. Central processing was examined by measuring pre-motor time, peripheral processing was measured by motor time, and force regulation was measured using movement time. A 3 x 5 multivariate analysis of co-variance (MANCOVA) was utilized to examine group differences, with the performance on the 6-minute walk test serving as co-variant. Correlation analyses were conducted to examine the relationship between medication and psychomotor performance. RESULTS: The lung transplant recipient group exhibited a longer movement time and a trend toward longer pre-motor times. There was also a significant relationship between medication and movement time. CONCLUSIONS: The results support the hypothesis that lung transplant recipients have deficits in psychomotor performance, which is consistent with the literature showing that immunosuppressive medications and hypoxia have adverse effects on skeletal muscle. This line of research is relevant to the restoration of function and improvement in quality of life of LTR.

HLA-specific antibodies are risk factors for lymphocytic bronchiolitis and chronic lung allograft dysfunction.

Bronchiolitis obliterans syndrome (BOS) represents a major limitation in lung transplantation. While acute rejection is widely considered the most important risk factor for BOS, the impact of HLA-specific antibodies is less understood. Of 51 lung recipients who were prospectively tested during a 4.2 +/- 1.6-year period, 14 patients developed HLA-specific antibodies. A multi-factorial analysis was performed to correlate the prevalence of BOS with HLA antibodies, persistent-recurrent acute rejection (ACR-PR), lymphocytic bronchiolitis, and HLA-A, -B, and -DR mismatches. HLA-specific antibodies were associated with ACR-PR (10/14 vs. 11/37 with no antibodies, p < 0.05), lymphocytic bronchiolitis (8/14 vs. 10/37, p < 0.05), and BOS (10/14, vs. 9/37, p < 0.005). Other risk factors for BOS were: lymphocytic bronchiolitis (13/18 vs. 6/33 with no lymphocytic bronchiolitis, p < 0.0001), ACR-PR (12/21 vs. 7/30 with no ACR-PR, p < 0.05), and the number of HLA-DR mismatches (1.7 +/- 0.48 in BOS vs. 1.2 +/- 0.63 without BOS, p < 0.05). The presence of antibodies exhibited a cumulative effect on BOS when it was associated with either lymphocytic bronchiolitis or ACR-PR. The complex relationship between the development of HLA antibodies and acute and chronic lung allograft rejection determines the importance of post-transplant screening for HLA-specific antibodies as a prognostic element for lung allograft outcome.

Are symptom reports useful for differentiating between acute rejection and pulmonary infection after lung transplantation?

BACKGROUND: Prompt treatment of acute rejection and pulmonary infection reduces morbidity and mortality in lung transplant recipients. Symptoms, spirometry, and bronchoscopy are used to detect these complications. Of these, symptom reporting is the least invasive, yet has received little critical examination. OBJECTIVE: To examine the potential for using reports of symptoms, such as cough and shortness of breath, to recognize clinically significant acute rejection and pulmonary infection after lung transplantation. METHODS: Symptoms reported during routine follow-up visits were compared between lung transplant recipients (LTR) with clinically significant acute rejection (grade >or= A2) and those without (grade A0 or A1) and between LTR with rejection (grade >or= A2) and those with pulmonary infection. RESULTS: LTR with rejection (grade >or= A2) reported more symptoms (P < .01) than did those without (grade A0, A1); however, the magnitude of difference was minimal. LTR with clinically significant acute rejection (grade >or= A2) reported symptoms at a rate comparable with those having pulmonary infection. CONCLUSIONS: Although symptoms may alert LTR to changes in their condition, no symptoms (respiratory, general, or activities of daily living [ADL]) differentiate between grades of rejection or pulmonary infection.

HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection.

BACKGROUND: The impact of HLA-specific antibodies is not well established in the acute rejection of lung allografts. Acute rejection represents the most important risk factor for the development of chronic lung allograft dysfunction. METHODS: We analyzed the pattern of HLA antibodies before and after transplantation in 54 patients, and correlated our data with the presence and frequency of high-grade and persistent-recurrent acute rejection, during the first 18 post-operative months. The diagnosis of acute rejection was based on histologic International Society for Heart and Lung Transplantation (ISHLT)-published criteria. RESULTS: Ten of 54 patients had a positive enzyme-linked immunoassay (ELISA) post-transplantation. In 90% of ELISA-positive patients, the presence of HLA antibodies was associated with persistent-recurrent acute rejections, compared with 34% in the ELISA-negative group (p < 0.005). There were 28 high-grade acute rejection episodes in the ELISA-positive group, compared with 36 in the ELISA-negative group (p < 0.0001). The ELISA-positive patients required a greater intensity of immunosuppressive therapy. The patients with ELISA-detected anti-HLA antibodies were at least 3-fold more likely to develop high-grade acute rejection and persistent-recurrent acute rejection, and 7-fold more likely to develop multiple episodes of persistent-recurrent acute rejection, compared with ELISA-negative patients. CONCLUSIONS: ELISA-based screening for the development of HLA antibodies is a reliable method that can identify lung transplant recipients at increased risk for high-grade and persistent-recurrent acute rejection. Although bronchiolitis obliterans appears as a point of no return in the evolution of lung-transplanted patients, early detection of risk factors for acute rejection could indirectly decrease the incidence of bronchiolitis obliterans. These lung-transplanted patients may benefit from an altered strategy of immunosuppression.

Striving for normalcy: symptoms and the threat of rejection after lung transplantation.

The purpose of this paper is to describe the psychosocial process of the symptom experience associated with the threat of organ rejection after lung transplantation. A grounded theory approach, including theoretical sampling and constant comparative analyses, was used in a sample of 14 lung transplant recipients who varied in age, gender, underlying lung disease, experience with rejection, and time since transplantation. 'Striving for normalcy' was the core process linking each of the four stages of the symptom experience and interpretation: naïveté, vulnerability, discovery, and insight. Each stage was marked by an initiating event, a predictable symptom response, and a dialectic (an internal struggle between recipients' personal perceptions of the situation and the juxtaposed understandings of the situation that they gleaned from transplant clinicians). Each stage was also labeled with a descriptor of the aspect of striving for normalcy that accounted for the variation in the symptom responses that recipients exhibited, the dialectics they faced, and the exemplars for each stage of the process. During the stage of naïveté, recipients were elated at improvements after transplantation, and often denied or delayed reporting symptoms. Once they experienced a rejection episode they entered the stage of vulnerability and became more vigilant about symptoms. The discovery stage was marked by the realization that rejection lacked characteristic symptoms; therefore, it was important to recognize any changes from their baseline condition. Recipients who achieved the insight stage realized that until they gave up some independence in exchange for interdependence, extended periods of normalcy eluded them, and embraced a reciprocal relationship with the transplant team. Knowledge that recipients' experience evolves over time from furtive hope during the stage of naïveté to qualified hope during the insight stage, directs us to intervene using stage-specific interventions to promote better symptom recognition and reporting.

Using conceptual triangulation to develop an integrated model of the symptom experience of acute rejection after lung transplantation.

The aim of this study was to develop a comprehensive model of the symptom experience associated with the development of acute rejection after lung transplantation by integrating the findings from a theory-testing quantitative study that explored the physiologic aspects and a theory-generating qualitative study that explored the interpretive aspects. Findings from the multimethod studies were integrated using conceptual triangulation methods described by Foster (Adv Nurs Sci. 1997;20:1-12). The integrated model will guide the development of interventions to promote effective patterns of symptom recognition and reporting of acute rejection.

Pattern and predictors of early rejection after lung transplantation.

BACKGROUND: Most lung transplant recipients experience improvement in their underlying pulmonary condition but are faced with the threat of allograft rejection, the primary determinant of long-term survival. Several studies examined predictors of rejection, but few focused on the early period after transplantation. OBJECTIVES: To describe the pattern and predictors of early rejection during the first year after transplantation to guide the development of interventions to facilitate earlier detection and treatment of rejection. METHODS: Data for donor, recipient, and posttransplant variables were retrieved retrospectively for 250 recipients of single or double lung transplants. RESULTS: Most recipients (85%) had at least 1 episode of acute rejection; 33% had a single episode; 23% had recurrent rejection; 3% had persistent rejection; 13% had refractory rejection; and 14% had clinicopathological evidence of chronic rejection. Serious rejection (refractory acute rejection or chronic rejection) developed in 27% of recipients. Compared with other recipients, recipients who had serious rejection had more episodes of acute rejection (P = .004), and the first acute episodes occurred sooner after transplantation (P = .01) and were of a higher grade (P = .002). CONCLUSIONS: Recipients who experienced higher grades for their first episode of acute rejection (P = .03) and higher cumulative rejection scores (P = .004) were significantly more likely than other recipients to have serious rejection during the first year after transplantation.

Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects.

Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1alpha and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation.

Evaluating the reliability and validity of the Questionnaire for Lung Transplant Patients.

CONTEXT: The Questionnaire for Lung Transplant Patients was designed for clinical use by the pulmonary transplant team in the routine evaluation of lung transplant recipients. Using the self-administered questionnaire, recipients check symptoms that they have had since their last evaluation and rate their shortness of breath, cough, and activity tolerance. OBJECTIVE: To determine whether the questionnaire meets reliability and validity standards for empirical measurement. METHODS: Demographics and disease-severity characteristics were examined in a cross-sectional survey of 37 recipients. Test-retest and intraclass correlation methods were used to estimate stability, and the Cronbach alpha was used to estimate internal consistency. Criterion validity was examined by using The Modified Symptom Frequency/Symptom Distress Scale, Functional Performance Inventory, and visual analog scales for cough and shortness of breath as criterion measures. Construct validity was examined to assess the predicted negative correlation between symptoms and functional performance. RESULTS: The questionnaire and its subscales were internally consistent (Cronbach alpha = 0.82, 0.76, 0.80, and 0.96), and the questionnaire was stable (r = 0.70) and reliable (intraclass correlations = 0.80 and 0.90). Significant correlations were found between the questionnaire and all criterion measures (r = 0.50-0.93). Significant correlations in the predicted negative direction were found between the respiratory subscale and functional performance (r = -0.51) and between cough (r = -0.51) and shortness of breath (r = -0.68) ratings and functional performance. CONCLUSIONS: The Questionnaire for Lung Transplant Patients is reliable and valid, and it provides scientifically sound information for clinical and empirical evaluation of symptoms and their effects on activity tolerance after lung transplantation.

Endobronchial metallic stent placement for airway complications after lung transplantation: longitudinal results.

BACKGROUND: In lung transplant recipients, bronchial stenosis (SB) and bronchomalacia (MB) result in obstructive airway disease and allograft dysfunction due to pulmonary infection. We hypothesized that endobronchial metallic stent placement for SB and MB would result in long-term improvement in respiratory function and rates of pulmonary infection. METHODS: We studied symptomatic lung transplant recipients with bronchoscopic evidence of proximal airway complications (SB or MB) and a synchronous decline in forced expiratory volume in 1 second (FEV1) of at least 10% in the 6-month period before intervention. Stent placement was the primary intervention for SB and all focal MB lesions and for recurrent or refractory SB lesions failing a single initial attempt at balloon dilation. FEV1 and rates of pulmonary infection were assessed in the 12-month interval before and after stent placement. Spirometric evaluation was performed at 3-month intervals and compared with spirometry at the time of stent placement. The rates of pulmonary infection, determined by the number of antibiotics prescribed, was determined before and after endobronchial correction. RESULTS: Thirty recipients underwent a total of 75 procedures (50 stent insertions and 25 balloon dilations). FEV1 improved significantly after stent placement compared with base line (1.29 +/- 0.43 L) as follows: 3 months, 1.45 +/- 0.50 L, p = 0.014; 6 months, 1.59 +/- 0.57 L, p = 0.002; 12 months 1.59 +/- 0.53 L, p = 0.006. The infection rate decreased from the 12-month period preceding stent insertion to the corresponding period after stent insertion (6.97/100 days +/- 6.33 versus 5.74/100 days +/- 7.76, p = 0.018). Recurrent SB occurred in 17.3%. No life-threatening complications occurred after stent placement and no deaths were attributed to stent malfunction or malposition. CONCLUSIONS: In lung transplant recipients with SB and MB, maintenance of airway patency by stent placement is safe and resulted in improvements in lung function and reduced pulmonary infection rates for up to 1 year after their insertion.

Lung and heart-lung transplantation at the University of Pittsburgh: 1982-2002.

The University of Pittsburgh lung transplantation program began in 1982 and through 2002 we have performed 576 lung and 101 heart-lung transplants. One-, 3- and 5-year survival rates over the past decade have been 77%, 62% and 55%, respectively, comparing favorably to ISHLT registry outcomes of 73%, 57% and 46%. We continue to utilize a very thorough evaluation process but have been flexible and aggressive with potential recipients with regard to age, coronary artery disease and disease state (eg., scleroderma). Despite worldwide progress in the field of lung transplantation, many difficulties remain. The limited number of lungs deemed acceptable for transplantation continues to hinder application to a greater number of patients. Our efforts in this regard have focused on cooperation with our OPO in education and detailed donor management protocols. Chronic rejection also remains a major difficulty frequently leading to death. Recent work utilizing aerosol cyclosporine in patients with established chronic rejection suggests that this therapy may prolong life. We are also hopeful that recently initiated therapies utilizing T-cell induction strategies may contribute to further improvement in outcomes.