[Cytomegalovirus infection in patients after lung transplantation].
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Biomedical subjects
Publications and source records attributed to J Cerrina.
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The functional status of immune cells within human transplanted lungs was analyzed during cytomegalovirus (CMV) pneumonia complicating lung and heart-lung transplantations. The expression of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) genes is a marker for the activation of macrophages as is that of serine esterase B (SE-B) gene for cytotoxic cells. The levels of expression of these genes by bronchoalveolar lavage (BAL) cells were determined by in situ hybridization. Eight cases of CMV pneumonia were included in this study. BAL cells from either rejection episodes (eight cases) or control transplanted patients experiencing neither infection nor allograft rejection (eight cases) were analyzed in parallel. In the control patients, virtually no cells expressed the IL-1 beta, the IL-6, or the SE-B genes. In contrast, these three genes were all expressed in samples from patients with CMV pneumonia. IL-1 beta gene-expressing cells were abundant in all infected patients (mean +/- SEM: 898 +/- 449 positive cells per 10(4) cells, p less than 0.001, compared with those in control patients). IL-6 gene-expressing cells were less numerous (92 +/- 74 positive cells per 10(4) cells) and present in five of the eight cases of CMV pneumonia. Activated cytotoxic cells were detected in seven of the eight cases of CMV pneumonia (36.5 +/- 19 SE-B gene-expressing cells per 10(4) cells, p less than 0.001). During allograft rejections (eight cases) IL-1 beta gene-expressing cells were present in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)
To investigate whether survivors of heart/lung and double-lung transplantations have normal or increased nonspecific bronchial responsiveness, nine heart/lung and four double-lung transplant recipients with normal lung histology underwent methacholine challenge and voluntary isocapnic dry air hyperventilation (VIH) in a randomized order at a mean time of 14.8 +/- 12.1 months after surgery. Transplant recipients were compared with 10 normal subjects and 11 patients with mild asthma. Asthmatic patients had a mean provocative concentration of methacholine inducing a 20% fall (PC20) in FEV1 of 3.4 +/- 3.6 mg/ml (SD). Seventy seven percent of the transplant recipients and 70% of the normal subjects had PC20 superior to 32 mg/ml. The percentage fall from baseline FEV1 after VIH was 12.6 +/- 10.4% in asthmatic patients as compared with 1.9 +/- 2.9% in transplant recipients (p = 0.002) and 0.45 +/- 1.2% in normal subjects (p = 0.001). The decrease in FEV1 after VIH was similar in transplant recipients and normal subjects (p = 0.14). These results show that heart/lung or double-lung transplant recipients with normal lung histology have a normal response to nonspecific bronchial stimulation.
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In 10 patients who received a heart lung transplant, TNF-alpha generation by cells collected during bronchioloalveolar lavages (n = 30) and by circulating mononuclear cells was measured. Basal and recombinant IL-2-stimulated productions (50 U/ml) were measured. TNF-alpha concentration was determined by an immunoradiometric assay (IRMA). Circulating mononuclear cells produced at least 4 times less TNF-alpha than BAL cells. Rejection episodes or CMV diseases were not associated with significant changes in TNF-alpha generation. Recombinant IL-2 increased this production in both cell populations but the magnitude of this effect was smaller in BAL cells, suggesting an in vivo preactivation.
Between June 1986 and October 1989, 29 heart lung transplantations and 4 double lung transplantations were performed at the Marie Lannelongue Hospital, Paris. The early and later course of these patients was studied. The actuarial survival rates at one and two years were 65 percent and 55 percent respectively. Bacterial infection was the main cause of early death. Late morbidity was predominantly due to cytomegalovirus infection and episodes of rejection. Respiratory function, evaluated in 19 long-term survivors, was usually normal. Only 3 patients developed a functional pattern of severe obliterative bronchiolitis probably related to uncontrolled rejections. The indications of the different types of lung transplantation are discussed: in cases of primary pulmonary hypertension or Eisenmenger's complex, heart lung transplantation is the only possible procedure. In patients with respiratory failure without cardiac dysfunction, double lung transplantation gives good functional results and makes an extra heart available for transplantation in another patient. Single lung transplantation, which gives worse functional results with a similar mortality rate, must be reserved for patients who are unable to undergo double lung transplantation.
Since Shumway carried out the first successful heart-lung transplant (HLT) in Stanford in 1981, HLT has become a new therapeutic means for patients with end-stage pulmonary disease or arterial hypertension. However, it is still rarely carried out because of a lack of donors and the complexity of the surgery and postoperative course. This review described the criteria for proper donor and recipient selection, as well as the anaesthetic and postoperative management of HLT patients at Marie Lannelongue Hospital. The lack of suitable organ grafts results, at least in part, from improper donor management. Pulmonary oedema by fluid overloading and excessive haemodilution should be carefully prevented. Low doses of catecholamines and vasopressin maintain circulatory stability and convenient organ function. The indications for HLT (primary pulmonary hypertension, Eisenmenger's complex, and end-stage bronchopulmonary disease) are all characterized by severe pulmonary hypertension, hypoxaemia and cardiac failure. Careful anaesthetic induction is required to avoid circulatory collapse. Cardiopulmonary bypass (CPB) should be started early, so that mediastinal dissection may be carried out in satisfactory haemodynamic conditions. After unclamping the aorta, circulatory support with fluid and catecholamine infusion is often required. High inspired oxygen fraction and end-expiratory positive pressure may be required because of reperfusion pulmonary oedema. Blood transfusion is often needed as there are major blood losses due to dissection of the posterior mediastinum during CPB. Postoperative catecholamine administration is prolonged over several days. Negative fluid balance is often necessary to reduce pulmonary oedema. Improvement in surgical technique, early extubation, and late prescription of steroids have reduced the incidence of tracheal complications. Acute renal failure often occurs as a result of prolonged CPB, hypovolaemia, drug nephrotoxicity and sepsis. Bacterial complications (pneumonia, mediastinitis) are the main causes of early death. After the 15th postoperative day, opportunistic infections and allograft rejection are the main complications. Since 1981, major advances in HLT recipient management resulted in improved survival rates (70-80% at 1 year, and 60-70% at 2 years for the best teams). Despite the complexity of management, and the longterm threat of obliterative bronchiolitis, HLT is, at present time, the only possibility for these young patients to recover a normal quality of life.
To investigate whether lung 99mTc-DTPA clearance is altered during allograft lung rejection, a group of four double lung and 24 heart-lung transplant patients was studied using serial measurement of the clearance rate of aerosolized 99mTc-DTPA (DTPA-Cl), in association with pulmonary function tests, bronchoalveolar lavage, and transbronchial lung biopsies. Using histologic diagnosis as a standard, we compared 56 episodes with normal lung histology to 32 episodes with allograft lung rejection. A control group of 20 healthy nonsmokers was used to define normal DTPA-Cl. In patients with normal lung histology, DTPA-Cl was higher than in control subjects (2.62 +/- 0.25 versus 1.20 +/- 0.12 %/min; p less than 0.001). In the episodes of allograft lung rejection, DTPA-Cl increased to 3.65 +/- 0.41 %/min (p less than 0.02) as compared with episodes of normal lung histology. The change in DTPA-Cl during allograft lung rejection was correlated (r = 0.3, p less than 0.01) with the increased percentage of lymphocytes in bronchoalveolar lavage (27.8 +/- 3.5% in rejection versus 19.9 +/- 2.2% in normal histology; p less than 0.02). Sensitivity and specificity of DTPA-Cl measurement in detecting lung rejection were 69 and 82%, respectively, versus 45 and 85% for FEV1 measurement. These results suggest that DTPA-Cl monitoring could be used in conjunction with pulmonary function testing as a noninvasive approach for the detection of lung rejection.
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The contraindication to curative excision of mediastinal and pulmonary cancers because of invasion of the superior vena cava is now challenged by the existence of vascular prostheses that are suitable for venous replacement. Between 1979 and 1990 22 patients underwent resection of lung cancer (n = 6) or malignant mediastinal tumors (n = 16) involving the superior vena cava. Resection was done with concomitant venous reconstruction, and polytetrafluorethylene grafts were used. All bronchogenic carcinomas necessitated right pneumonectomy, whereas the excision of mediastinal tumors had to include pulmonary resections in nine patients (five lobectomies and four sublobar resections) and the right phrenic nerve in 12 patients. Venous reconstruction was performed by interposition of a large polytetrafluoroethylene graft between the proximal and cardiac ends of the superior vena cava (n = 8), or between one (n = 10) or both brachiocephalic veins (n = 4) and the right atrium. One patient died postoperatively (4.5%), and another had mediastinitis that was successfully treated by omentopexy. Chemotherapy was administered preoperatively to five patients and postoperatively to seven patients; radiotherapy was administered to two and 10 patients, respectively. The overall actuarial survival rate is 48% at 5 years, with 11 patients presently alive. The survival rate of patients with mediastinal tumors is 60% at 5 years. Among the patients with lung cancer, two with N1 disease are alive at 16 and 51 months, and one died at 38 months; the two patients with N2 disease died at 6 and 8 months. Only one graft occlusion occurred in the postoperative period; another occurred 14 months after operation and was precipitated by insertion of a central venous catheter. The patency of all remaining grafts was demonstrated after an average time of 23 (1 to 98) months. On the basis of these results, polytetrafluoroethylene graft replacement of the superior vena cava should be part of the planning and execution of radical excision with curative intent of mediastinal and right pulmonary malignant tumors that are not present with other contraindications, such as pleural or distant metastasis and severe systemic disease.
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Lung transplantation has been made possible by the advent of cyclosporin, and it can be divided into three categories: single lung, double lung and heart-lung transplantations. Heart-lung transplantation is the only one that can be performed in case of primary pulmonary arterial hypertension, but the respective indications of these three types of transplantation in patients with respiratory failure have not yet been clearly determined. Heart-lung transplantation is also the one that gives the best results in terms of survival and respiratory function. In the post-operative period, graft rejection and bacterial, viral, fungal or parasitic infections are responsible for a 35 per cent death rate. Later in life, transplant recipients are prone to respiratory impairment caused by obliterating bronchiolitis, itself due to insufficiently treated chronic rejection. The development of lung transplantation is considerably limited by the scarcity of donors with procurable lungs and by the frequency of heart procurement at the expense of the heart-lung block.
Airway reactivity to histamine was determined in a group of non-asthmatic and asthmatic patients prior to thoracotomy. The latter group was more reactive to histamine provocation than the former (PC40: 28.40 +/- 6.27 mg/ml and 1.15 +/- 0.19 mg/ml, respectively). Subsequent to the surgical intervention, isolated human bronchial muscle preparations were obtained from both groups (15 non-asthmatic and 5 asthmatic subjects). Histamine concentration-effect curves were generated both in the absence and in the presence of indomethacin (1.7 microM; 30 min). Neither the basal tone nor the histamine response and sensitivity of the preparations were altered by the antiinflammatory drug. In bronchial preparations from one asthmatic subject, indomethacin significantly reduced the prostaglandin production during histamine contraction. Prostaglandin E2 and F2 alpha contracted isolated human bronchial muscle preparations from these asthmatic individuals. These data suggest that endogenous prostaglandins may not regulate the contractile response to histamine in vitro.
A bolus injection of methylene blue (1 mg), a guanylate cyclase inhibitor, or aspirin (3 mg) in the isolated rat lung preparation had little or no effect on resting perfusion pressure under normoxic condition. In contrast, methylene blue markedly potentiated hypoxic vasopressor response (4-fold) when injected before or during the alveolar hypoxic stimulation. Hemoglobin also potentiated the hypoxic pressor response. Similarly, methylene blue or aspirin augmented the pressor responses to angiotensin II (0.1-1 microgram). The increased hypoxic response induced by methylene blue was immediate and sustained. Methylene blue, when added during hypoxia in the presence of aspirin, further augmented the response to hypoxia compared with the enhanced hypoxic response observed with aspirin alone. Our results suggest that, in addition to the role of cyclooxygenase products, the pulmonary vascular bed may be regulated by endothelium-dependent factors that can be antagonized directly or indirectly by methylene blue.
In human bronchial muscle preparations contracted with histamine, the rank order potency for the relaxant effect of various antagonists was: thiazinamium chloride less than tripelennamine less than atropine (pD2 values: 7.78, 6.16 and greater than 4 for each antagonist, respectively). These antagonists also relaxed human isolated bronchial muscle preparations contracted with acetylcholine. The rank order potency was: atropine less than thiazinamium chloride less than tripelennamine (pD2 values: 7.76, 6.94 and 4.05, respectively). Tripelennamine and thiazinamium chloride displaced histamine concentration-effect curves and atropine and thiazinamium chloride antagonized acetylcholine curves in human isolated bronchial muscle preparations. These results suggest that thiazinamium chloride may have important therapeutic value in airways disease since this drug not only relaxed human isolated airway muscle preparations but also antagonized contractile responses in these tissues to both histamine and acetylcholine.
From 1966 to 1986, a total of 55 patients underwent a tracheal sleeve pneumonectomy (53 right and 2 left) for bronchogenic carcinoma. Preoperative radiotherapy was given in only 5 patients. The overall operative death rate was 10.9%, but no patient has died since 1975 (32 survivors). Seven patients had a postoperative empyema (12.7%); 4 of these patients had a bronchopleural fistula. Twenty-five patients had postoperative radiotherapy, 5 of whom also had chemotherapy. The actuarial survival rate, after exclusion of the 6 operative deaths, was 38% at 3 years and 23% at 5 years. Survival was correlated to regional lymph node involvement. The actuarial survival rate among patients with tumoral spread to bronchial lymph nodes was 43% at 3 years. Among the 13 patients with only subcarinal involvement, the actuarial survival rate was 34% at 3 years. None of the 8 patients with paratracheal lymph node involvement survived more than 30 months. These results indicate that tracheal sleeve pneumonectomy for bronchogenic carcinoma with extension to the carina is now fully justified considering the low operative mortality and the good results observed when lateral tracheal lymph nodes were not involved.
Three different ways of pulmonary transplants are feasible: heart and lungs together, one single lung or both lungs. While concerning the primitive or secondary pulmonary arterial hypertension, only the cardio-pulmonary transplant is possible, concerning the respiratory deficiency; the respective indications of each of these transplants are not yet clearly defined. During the postoperative period, rejection and bacteriological, viral, fungal or parasitical infections are responsible for a mortality of about 30%. In the long term, the transplant patients are in danger of respiratory insufficiency by obliterating bronchiolitis due to untreated chronic rejection. The development of these transplants is considerably limited by the rarity of donors whose lungs are usable and by the frequency of isolated heart removals to the prejudice of the cardiopulmonary bloc transplants.