Cyclosporine A drives a Th17- and Th2-mediated posttransplant obliterative airway disease.

Calcineurin-inhibitor refractory bronchiolitis obliterans (BO) represents the leading cause of late graft failure after lung transplantation. T helper (Th)2 and Th17 lymphocytes have been associated with BO development. Taking advantage of a fully allogeneic trachea transplantation model in mice, we addressed the pathogenicity of Th cells in obliterative airway disease (OAD) occurring in cyclosporine A (CsA)-treated recipients. We found that CsA prevented CD8(+) T cell infiltration into the graft and downregulated the Th1 response but affected neither Th2 nor Th17 responses in vivo. In secondary mixed lymphocyte cultures, CsA dramatically decreased donor-specific IFN-γ production, enhanced IL-17 production and did not affect IL-13. As CD4(+) depletion efficiently prevented OAD in CsA-treated recipients, we further explored the role of Th2 and Th17 immunity in vivo. Although IL-4 and IL-17 deficient untreated mice developed an OAD comparable to wild-type recipients, a single cytokine deficiency afforded significant protection in CsA-treated recipients. In conclusion, CsA treatment unbalances T helper alloreactivity and favors Th2 and Th17 as coexisting pathways mediating chronic rejection of heterotopic tracheal allografts.

Percutaneous endoscopic jejunostomy in patients with gastroparesis following lung transplantation: feasibility and clinical outcome.

The aim of the present study was to describe success rates, complications, and outcome in patients who underwent percutaneous endoscopic jejunostomy (PEJ) because of gastroparesis due to previous lung transplantation. Between October 2008 and May 2011, 14 attempts at PEJ placement were made in 12 patients in our center. Of the 14 attempts, 11 were successful, giving a technical success rate of 78.6 %. Median duration of followup was8.5 months (2­15 months). No immediate complications were reported. Two severe complications occurred during follow up (one volvulus and one jejunocolic fistula). Jejunal nutrition was well tolerated in most of patients (9 /10). PEJ insertion is a feasible technique, which could help to provide nutritional support for patients with gastroparesis and previous lung transplantation.

[Complications of lung transplantation: perioperative complications, acute and chronic rejection]. / Complications de la transplantation pulmonaire: complications péri-opératoires, rejet aigu et chronique.

In 2009 lung transplantation is a valuable therapeutic option for a spectrum of end-stage pulmonary diseases. To many patients who are dying, lung transplantation offers a new and normal life for several years. However, lung transplantation is a major surgical intervention associated with a significant early mortality. Moreover, matching according to the major human histocompatibilty antigens is impossible, exposing the recipient to an increased risk of acute and chronic rejection. Chronic rejection and its clinical corollary the bronchiolitis obliterans syndrome, is the main cause of death medium and long term. The immunosuppressive treatment administered in order to prevent or stabilize this complication induces a number of potentially severe complications including infection, malignancies, and cardio-vascular, metabolic and renal complications which not only limit autonomy and quality of life, but also cause death in a number of long term survivors. A better understanding of the precise mechanisms underlying the development of the bronchiolitis obliterans syndrome and the development of specific preventive or therapeutic strategies will be key elements for the improvement of long term survival. The control of this main cause of death will allow individual tailoring of the immunosuppressive therapy and decrease the incidence of infectious and metabolic complications.

Clostridium difficile colitis in cystic fibrosis patients with and without lung transplantation.

BACKGROUND: Despite a large carriage rate of Clostridium difficile among cystic fibrosis (CF) patients, C. difficile-associated disease (CDAD) is rather rare. In case of lung transplantation, the incidence and clinical aspects of CDAD in this patient population are not well known. METHODS: We reviewed the medical files of all CF patients who presented with symptomatic C. difficile infection from January 1998 to December 2004 and compared the incidence, clinical aspects, severity of disease, and clinical outcome between non-transplanted and transplanted CF patients. RESULTS: Between 1998 and 2004, 106 adult CF patients were followed at our clinic. Forty-nine patients underwent lung transplantation; 15 before 1998 and 34 after 1998. The incidence density of CDAD was higher in transplanted CF patients as compared with non-transplanted CF patients (24.2 vs. 9.5 episodes/100,000 patient-days; risk ratio: 2.93 [1.41-6.08]; P=0.0044). Diarrhea was a very frequent feature, but was notably absent in 20% of the cases. Rates of moderate and severe colitis were similar in both groups. However, only transplanted patients developed complicated colitis. CT scan and endoscopy were performed more frequently in the transplant group. Two transplant recipients died because of CDAD. CONCLUSION: CF patients who undergo lung transplantation are at a higher risk of developing CDAD and seem to present more often atypical and/or complicated disease. CDAD should be part of the differential diagnosis in case of digestive symptoms, even in the absence of diarrhea, and requires early treatment.

Mechanism of relief of dyspnea after thoracocentesis in patients with large pleural effusions.

In an attempt to understand the mechanism underlying the relief of dyspnea that follows thoracocentesis in patients with large pleural effusions, we measured respiratory mechanics in nine patients before and two hours after removal of 600 to 2,750 ml (mean = 1,818 ml) of pleural fluid. Thoracocentesis resulted in only small changes in pulmonary mechanics: Mean vital capacity and functional residual capacity increased by 300 and 460 ml, respectively, lung recoil pressure slightly decreased, and mean static expiratory compliance increased by 0.021 liter/cm H2O. These changes were inconsistent and could not explain the immediate and remarkable relief of dyspnea noted by the patients. By contrast, thoracocentesis invariably resulted in a shift of the minimal (inspiratory) pleural pressure-volume curve so that the pressures generated by the inspiratory muscles were markedly more negative at any comparable lung volume. This shift was entirely due to the decrease in thoracic cage volume. We suggest that the relief of dyspnea following thoracocentesis results primarily from reduction in size of the thoracic cage, which allows the inspiratory muscles to operate on a more advantageous portion of their length-tension curve.

Disturbance of respiratory muscle function in patients with mitral valve disease.

A reduced total lung capacity associated with a normal or decreased lung recoil pressure at full inflation (Pel max) has been noted in patients with valvular heart lesions. In order to investigate the mechanism underlying this inappropriately low Pel max, we measured respiratory mechanics in a group of 15 patients with mitral valve disease uncomplicated by other illness. The total lung capacity was 81 percent of control. The static pressure-volume curve of the long intersected the normal one in the vicinity of functional residual capacity (i.e., the recoil pressure was increased at large lung volumes and diminished at low lung volumes), and both expiratory compliance and Pel max were significantly decreased. In 13 of the 15 patients, the minimal (inspiratory) pleural pressure-volume curve was shifted so that the pressures generated by the inspiratory muscles were less negative than normal at any given lung volume. The decrease in Pel max was proportional to the alteration in muscle pressures. These findings indicate (1) that patients with mitral valve disease have compromised function of the inspiratory muscles, and (2) that this alteration is responsible for the low Pel max. Respiratory muscle weakness contributes to the restriction of lung volume in patients with pulmonary vascular congestion and is probably implicated in cardiac dyspnea.

Lung rejection occurs in lung transplant recipients with blood chimerism.

BACKGROUND: It has been postulated that chimerism after transplantation might promote graft acceptance. In the present study, we prospectively assessed blood chimerism in 10 lung transplant recipients during the first posttransplant year and investigated whether chimerism was associated with an immunologically stable situation of the graft. METHODS: The recipients' peripheral blood mononuclear cells were obtained before transplantation and at various time points during the first postoperative year. Donor cells were detected using nested polymerase chain reaction amplification of a donor-specific HLA-DRB1 allele. Clinical graft acceptance was determined by the number of rejection episodes. RESULTS: The incidence of blood chimerism was high during the first 3 postoperative months and then decreased over time. All patients experienced at least one acute rejection episode, and three patients developed chronic rejection. CONCLUSION: We, thus, conclude that rejection of the lung allograft may occur in the presence of blood chimerism.

Impaired antigen-presenting cell function contributes to T-cell hyporesponsiveness in stable lung transplant recipients.

BACKGROUND: Peripheral blood mononuclear cells (PBMC) of stable renal or cardiac transplant recipients were previously shown to respond to allogeneic cells but not to soluble protein antigens. The aim of the present study was to assess the T-cell and antigen-presenting cell (APC) functions of stable lung transplant (LT) recipients. METHODS: We obtained PBMC from 38 stable LT recipients. PBMC from healthy volunteers served as controls. PBMC were stimulated with either anti-CD3 monoclonal antibody, allogeneic PBMC, or tetanus toxoid (TT). T-cell activation was assessed by determination of interleukin (IL)-2 levels in culture supernatants; in some experiments, interferon-y levels were also determined. Patients' APC function was tested in a mixed leukocyte reaction using patients' PBMC as stimulators. The expression of class II MHC, B7.2, and CD40 molecules on patients' APC was determined by flow cytometry, and their production of IL-10 and IL-12 at the basal state and upon CD40 ligation was also measured. RESULTS: Patients' T cells produced normal amounts of IL-2 in response to anti-CD3 monoclonal antibody and allogeneic PBMC. In contrast, the response of memory T cells to TT was severely blunted both in terms of IL-2 and interferon-y production. Patients' PBMC were poor stimulators in mixed leukocyte reaction, and class II MHC expression on patients' monocytes was significantly reduced. Patients' APC presented a modest but significant increase in basal IL-10 production and produced significantly less IL-12 upon CD40 ligation than control APC. CONCLUSIONS: T cells from stable LT recipients respond normally to stimuli that do not depend on autologous APC. The major impairment in the T-cell response to TT is caused by APC dysfunction, which involves decreased class II MHC expression and deficient IL-12 synthesis.

Detection of blood chimerism after lung and heart-lung transplantation. The superiority of nested as compared with standard polymerase chain reaction amplification.

Migration of donor cells from the graft to various tissues of the recipient has been demonstrated after different types of solid organ transplants. Currently, the detection of donor cells in the recipient's tissues is most simply performed by polymerase chain reaction (PCR) amplification of a donor-specific gene. In the present study, we first determined in vitro the sensitivity of standard and nested PCR amplification with sequence-specific primers (PCR-SSP) of a donor-specific allele of the HLA-DRB1 gene and then used this technique to assess prospectively blood chimerism in two single-lung (SLT) and one heart-lung (HLT) transplant recipients. Standard PCR-SSP consisted in a single amplification round with sequence-specific primers for the donor-specific DRB1 allele. Nested PCR-SSP consisted in a first round of generic amplification of exon 2 of the DRB1 gene, followed by a second amplification round with primers specific for the donor allele. In vitro, nested PCR-SSP of the donor-specific allele was 1000-fold more sensitive than standard PCR-SSP and allowed the detection of 1 donor cell in 10(5) recipient cells. In vivo, standard PCR-SSP detected donor cells among the recipients' peripheral blood mononuclear cells (PBMCs) only during the first postoperative days, whereas nested PCR-SSP demonstrated their presence until the end of the first postoperative month in patients 1 and 2 and until 3 months after transplantation in patient 3. We conclude that donor cells can be detected in the peripheral blood of SLT and HLT recipients during the first postoperative months and that nested PCR-SSP amplification of a donor-specific HLA-DRB1 allele is much more sensitive than standard PCR-SSP to demonstrate such chimerism.

Gastric perforation due to mucormycosis after heart-lung and heart transplantation.

BACKGROUND: Gastrointestinal complications are a well-documented source of morbidity and mortality after heart and lung transplantation. METHODS: We report on two patients who presented with gastric perforation caused by mucormycosis during the first 2 months after heart-lung and heart transplantation. RESULTS: In the first patient, the clinical presentation was insidious and the diagnosis was made at an advanced stage of the disease. Despite surgery and aggressive antifungal treatment, the patient died. In the second patient, the diagnosis was made promptly, but despite antifungal treatment, he presented with gastric perforation within a week. CONCLUSIONS: These cases illustrate that fungal invasive disease may be a cause of early gastrointestinal perforation after solid organ transplantation.

The mechanism of CO2 retention in cardiac pulmonary edema.

We studied a 58-year-old woman during an acute episode of cardiac pulmonary edema complicated by carbon dioxide (CO2) retention. As pulmonary wedge pressure became greater, metabolic production of CO2 increased by 38 ml/min and minute ventilation by 1.53 L; by contrast, alveolar ventilation remained unchanged due to a concomitant rise in physiologic dead space and, as a result, arterial CO2 tension increased up to 61 mm Hg. With treatment, all these variables returned to baseline values. Subsequent measurement of mouth occlusion pressure (p 0.1) during a CO2 rebreathing trial showed that neuromuscular inspiratory drive response to CO2 was preserved, but that ventilatory response was markedly reduced, presumably because of the severe restrictive and obstructive ventilatory defect and of the loss of inspiratory muscle force demonstrated in the patient. We conclude that CO2 retention in cardiac pulmonary edema involves a combination of: (1) increased CO2 production, (2) rise in physiologic dead space, and (3) severe respiratory mechanical impairment.

Combined heart-lung transplantation for terminal pulmonary lymphangioleiomyomatosis.

Combined heart-lung transplantation with cyclosporine is reported in a 26-year-old patient who presented with end-stage pulmonary lymphangioleiomyomatosis. The operation was successful and the patient's rehabilitation excellent over the first 7 postoperative months. She then developed obliterative bronchiolitis of unknown origin. To our knowledge, this is the first published report of an out-hospital survival after heart-lung transplantation for terminal nonvascular lung disease.

Dextroposition of the left lower lobe after heart-lung transplantation.

Immediately after heart-lung transplantation for cystic fibrosis, a patient had development of a right lower lobe retrocardiac density that persisted on all postoperative chest radiographs. A computed tomographic examination of the thorax performed 3 weeks after surgery showed that there was partial collapse of the left lower lobe in the right hemithorax. The patient required a posterolateral thoracotomy for cure.

Radiation-induced pulmonary veno-occlusive disease.

Late occurrence of radiation-induced pulmonary pneumonitis and fibrosis is well documented. We report an unusual case of radiation induced veno-occlusive disease (VOD) occurring six years following mantle irradiation for Hodgkin's lymphoma. The patient developed severe pulmonary hypertension and cor pulmonale. A left lung transplantation was performed successfully and pathologic examination of the explanted lung showed severe changes compatible with VOD. In the absence of exposure to alternate therapeutic or toxic agents that may cause VOD, it is likely that radiation caused damage to the venular endothelium and caused progressive obliteration of the pulmonary vessels. Review of the literature reveals only a few similar reports of VOD mostly following radiation for bone marrow transplantation. We conclude that previous irradiation (even several years earlier) should be considered as a possible cause of pulmonary VOD.

Action of the diaphragm during cough in tetraplegic subjects.

Subjects with traumatic tetraplegia use the pectoralis major to compress the upper rib cage and increase intrathoracic pressure during cough. It is not known, however, whether they also contact the diaphragm during the expiratory phase of cough, as normal subjects do. We have investigated the action of the diaphragm during single voluntary coughing efforts in subjects with complete transection of the lower cervical (n = 5) or midthoracic (n = 2) cord. All subjects showed at least one peak of transdiaphragmatic pressure during the expiratory phase of the effort, and simultaneous bursts of electrical activity were recorded from the diaphragm. Coughing also resulted in an outward (paradoxical) motion of the abdomen during the compressive phase. We conclude that antagonistic contraction of the diaphragm is present during the expiratory phase of cough in spinal cord-injured subjects with paralysis of the abdominal muscles; this contraction, therefore, does not occur in response to activation of these muscles. The present results also indicate that the cough-induced paradoxical expansion of the abdomen is due to contraction of the pectoralis major and not of the diaphragm.

Action of intercostal muscles on the lung in dogs.

The action on the lung of interosseous intercostal muscles located in the third and the seventh interspaces was studied in 15 anesthetized-curarized supine dogs. Changes in pleural pressure, airflow rate, and lung volume produced by maximal stimulation of both intercostal muscle layers were measured at and above functional residual capacity (FRC). In five animals measurements were also obtained during isolated stimulation of the internal layer. At FRC, intercostal stimulation in the upper interspaces had invariably an inspiratory effect on the lung but no effect was detectable in the lower interspaces. Qualitatively similar results were obtained during isolated stimulation of the internal layer. Increasing lung volume reduced the inspiratory action of the upper intercostals and conferred an expiratory action to the lower intercostals. These results indicate the following: 1) when contracting in a single interspace, the external and internal intercostals have a qualitatively similar action on the lung; and 2) this action, however, depends critically on their location along the cephalocaudal axis of the rib cage: in the upper portion of the rib cage, both muscle layers have an inspiratory effect at and above FRC; in the lower portion of the rib cage, they have no respiratory action at FRC and act in the expiratory direction at higher lung volumes.

Three-dimensional reconstruction of human diaphragm with the use of spiral computed tomography.

We developed a technique of diaphragm imaging by using spiral computed tomography, and we studied four normal subjects who had been previously investigated with magnetic resonance imaging (A. P. Gauthier, S. Verbanck, M. Estenne, C. Segebarth, P. T. Macklem, and M. Paiva. J. Appl. Physiol. 76: 495-506, 1994). One acquisition of 15- to 25-s duration was performed at residual volume, functional residual capacity, functional residual capacity plus one-half inspiratory capacity, and total lung capacity with the subject holding his breath and relaxing. From these acquisitions, 20 coronal and 30 sagittal images were reconstructed at each lung volume; on each image, diaphragm contour in the zone of apposition and in the dome was digitized with the software Osiris, and the digitized silhouettes were used for three-dimensional reconstruction with Matlab. Values of length and surface area for the diaphragm, the dome, and the zone of apposition were very similar to those obtained with magnetic resonance imaging. We conclude that satisfactory three-dimensional reconstruction of the in vivo diaphragm may be obtained with spiral computed tomography, allowing accurate measurements of muscle length, surface area, and shape.

Rib cage and diaphragm-abdomen compliance in humans: effects of age and posture.

The influence of age and posture on compliance of the rib cage (Crc) and diaphragm-abdomen (Cab) compartments of the chest wall was studied in 61 healthy adults (33 men, 28 women) aged 24-75 yr. Chest wall compliance (Cw) was measured by the weighted spirometer technique; Crc and Cab were derived from the slope of the relaxation line of the thoracoabdominal system obtained with two pairs of linearized magnetometers. While Cw was being measured, we monitored electrical activity of the abdominal external oblique muscle with a concentric needle electrode and thoracoabdominal configuration. In 52 subjects, the electromyogram did not show any abdominal muscle activity and the end-expiratory level never departed from the relaxed thoracoabdominal configuration, thus suggesting adequate respiratory muscle relaxation. Aging was associated with significant decreases in Crc and Cab. In the upright posture Crc decreased from 0.164 +/- 0.041 (mean +/- SD) l/cmH2O in the younger subjects (24-39 yr) to 0.114 +/- 0.027 l/cmH2O in the older subjects (55-75 yr). Cab concomitantly fell from 0.032 +/- 0.012 l/cmH2O to 0.020 +/- 0.007 l/cmH2O. These reductions were statistically significant (P less than 0.05-0.01) and were also present in the supine posture. Shifting from the seated to the supine posture did not cause any significant change in Cw but was invariably associated with a decrease in Crc and an increase in Cab.(ABSTRACT TRUNCATED AT 250 WORDS)

Expiratory muscle contribution to tidal volume in head-up dogs.

A change from the supine to the head-up posture in anesthetized dogs elicits increased phasic expiratory activation of the rib cage and abdominal expiratory muscles. However, when this postural change is produced over a 4- to 5-s period, there is an initial apnea during which all the muscles are silent. In the present studies, we have taken advantage of this initial silence to determine functional residual capacity (FRC) and measure the subsequent change in end-expiratory lung volume. Eight animals were studied, and in all of them end-expiratory lung volume in the head-up posture decreased relative to FRC [329 +/- 70 (SE) ml]. Because this decrease also represents the increase in lung volume as a result of expiratory muscle relaxation at the end of the expiratory pause, it can be used to determine the expiratory muscle contribution to tidal volume (VT). The average contribution was 62 +/- 6% VT. After denervation of the rib cage expiratory muscles, the reduction in end-expiratory lung volume still amounted to 273 +/- 84 ml (49 +/- 10% VT). Thus, in head-up dogs, about two-thirds of VT result from the action of the expiratory muscles, and most of it (83%) is due to the action of the abdominal rather than the rib cage expiratory muscles.

Lung volumes, chest wall configuration, and pattern of breathing in microgravity.

We studied the changes in functional residual capacity (FRC), thoracoabdominal volume (Vw), and chest wall configuration in five normal subjects seated in an aircraft flying parabolic trajectories resulting in 20-s periods of microgravity. We measured vital capacity (VC), inspiratory capacity, and tidal volume by integrating airflow at the mouth and changes in rib cage and abdominal volume (delta Vrc and delta Vab, respectively, where delta Vrc + delta Vab = delta Vw) using induction plethysmography. During microgravity (0 Gz) FRC decreased by 413 +/- 70 (SE) ml and VC by 0.37 liter. The decrease in Vw did not differ from that in FRC and was entirely the result of reduction of Vab, the Vrc showing no significant change. During tidal breathing the abdominal contribution (delta Vab/delta Vw) increased from 0.39 +/- 0.08 at 1 Gz to 0.57 +/- 0.08 at 0 Gz. During brief periods of hypergravity (approximately 1.8 Gz) all changes were opposite in sign and relatively smaller. Limited data during "roller coaster" flight patterns suggested that, in contrast to configurational changes, the temporal pattern of breathing was uninfluenced by changes in Gz. We conclude that at the onset of weightlessness there are substantial changes in lung volume and thoracoabdominal configuration. Abdominal contribution to tidal excursions increases but the temporal pattern of breathing is unchanged.