In situ production of interleukin-6 within human lung allografts displaying rejection or cytomegalovirus pneumonia.

Interleukin-6 (IL-6) is a pleiotropic cytokine that is a regulator of inflammation and immunity. As production of IL-6 may be an important mechanism by which local and systemic inflammatory processes are regulated during lung transplantation, we measured this cytokine concentration in the serum and bronchoalveolar lavage fluid (BALF) collected in 27 lung recipients. IL-6 bioactivity was analyzed using a B cell hybridoma proliferation assay (B9 cell line). Three groups of clinical situations were analyzed: control lung recipients, rejections, and CMV pneumonia. Serum IL-6 concentrations (mean +/- SEM) were 24.2 +/- 3.3 U/ml in the 26 control samples. In 20 allograft rejection episodes, the serum IL-6 concentration was higher than in control samples but the difference was not significant (59.3 +/- 20.5 U/ml, P > 0.05). IL-6 serum levels were significantly increased during the 14 CMV pneumonias (61.2 +/- 11.5 U/ml, P < 0.01). In BALF, IL-6 levels were increased during CMV pneumonia (52.4 +/- 21.9 U/ml BALF), and to a lesser extent during rejection events (14.1 +/- 3.7 U/ml BALF), as compared with controls (5.6 +/- 1.6 U/ml BALF, P < 0.005, and P < 0.05, respectively). Similar results were observed when IL-6/albumin and IL-6/urea ratios were determined so as to compensate for possible dilution effects in BALF. IL-6 in BALF was produced in situ during CMV pneumonia as shown by in situ hybridization experiments that revealed a significant number of IL-6 gene-expressing alveolar cells in this condition. IL-6 concentrations in the serum and in the BALF were compared. There was no correlation between serum and BALF IL-6 concentrations, showing that serum IL-6 levels do not accurately reflect intrapulmonary IL-6 levels do not accurately reflect intrapulmonary IL-6 production. Thus IL-6 is produced within lung transplants during CMV pneumonia, and to a lesser extent during allograft rejection.

Emergence of inflammatory alveolar macrophages during rejection or infection after lung transplantation.

Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.

Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.

RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation.

[Nodular regenerative hyperplasia and pulmonary arterial hypertension]. / Hyperplasie nodulaire régénérative et hypertension artérielle pulmonaire.

Two cases of nodular regenerative hyperplasia of the liver coexisting with pulmonary hypertension are described. Regarding its low frequency, nodular regenerative hyperplasia has been found more often than expected in our series of coexisting porto-pulmonary hypertension (2 out of 14 cases, 14 percent). In our 2 cases, pulmonary symptoms occurred before or simultaneously with hepatic symptoms. The high prevalence of this association and the unusual onset setting of symptoms suggest that this association is unfortuitous. A common pathogenesis for pulmonary and hepatic lesions is discussed.

[Acute lipid pneumopathy]. / Pneumopathie aiguë lipidique.

BACKGROUND: Lipid pneumonia in children has rarely been described in Europe. In some countries, due to local customs, the course is chronic. This study describes an acute lipid pneumonia in a young boy. CASE REPORT: A 12 year-old boy, previously treated for a rhabdomyosarcoma, developed acute fever with thoracic pain. A chest radiograph revealed heterogenous consolidation. The patient was given oral antibiotics, although no improvement was observed. The diagnosis of lipid pneumonia was made by a bronchoscopy with bronchoalveolar lavage. Treatment with corticosteroids was started. Clinical manifestations improved rapidly. One month later, chest radiograph and biological findings were normal. CONCLUSION: Diagnosis of lipid pneumonia should be considered in children with an acute febrile pneumonitis non resolving with antibiotic treatment. Examination of the fluid obtained by bronchoalveolar lavage confirms the diagnosis.

[Pulmonary arterial hypertension of chronic thrombo-embolic origin. 70 patients]. / Hypertension artérielle pulmonaire d'origine thrombo-embolique chronique. 70 malades.

OBJECTIVES: Chronic thrombo-embolic pulmonary hypertension is a rare and aberrant outcome of acute pulmonary embolism. Because it has become a potentially curable form of pulmonary hypertension, the frequency of recognized cases has increased. We report a case series of 70 patients with chronic thromboembolic pulmonary hypertension evaluated in our institution between 1984 and 1993, and discuss diagnostic clues and therapeutic approaches. RESULTS: All patients complained of dyspnoea on exertion. A history of acute thrombo-embolic events and lung murmurs were found in 60% and 17% of patients respectively. Coagulation disorders were found in 30% of the patients tested; the most common abnormality was lupus anticoagulant. The key non-invasive study for diagnosis was the lung perfusion scan which showed at least one segmental or wider perfusion defects in all patients. Pulmonary angiography confirmed the diagnosis in all cases and, sometimes associated with intravascular ultrasound imaging, established the feasibility of thromboendarterectomy. Medical therapy included the use of long-term oral anticoagulant, and in case of lower limb venous thrombosis, inferior vena cava filtration. Finally two surgical procedures were discussed in selected patients: thromboendarterectomy and lung transplantation. Since 1988, eight patients have benefited from lung transplantation (six patients are still alive) and 11 patients underwent thromboendarterectomy which was successful in 9 patients leading to dramatic functional and haemodynamic improvement. CONCLUSION: Chronic thrombo-embolic pulmonary hypertension is a severe, sometimes fatal, disease which can be successfully treated by pulmonary thromboendartectomy and lung transplantation.

[Mediastino-pulmonary sarcoidosis in Ivory Coast. Epidemiological and clinical significance of sixteen new cases observed in Abidjan (author's transl)]. / La sarcoidose mediastino-pulmonaire en Côte-d'Ivoire. Intérêt épidémiologique et clinique de seize nouveaux cas observés à Abidjan.

Sixteen cases of mediastion-pulmonary sarcoïdosis are reported, half of them presenting extra-thoracic associated lesions. The clinical and epidemiological study of these cases, compared to the previously published ones, demonstrates that the clinical features are similar in Africans and Black Americans and that the disease in coming out in Africa South of the Sahara.

[Primary pulmonary artery hypertension (data of the literature and personal experience with 25 cases in 10 years)]. / Hypertension artérielle pulmonaire primitive (données de la littérature et expérience personnelle sur 125 cas en 10 ans).

Primary pulmonary hypertension (PPH) is an uncommon disease, of unknown cause. Patients are usually young with a slight predominance in females. We report our experience of 125 patients over 10 years and it is compared to the data of the literature. Epidemiology, physiopathology, clinical and hemodynamic features are reported. Therapeutic aspects are discussed, pointing out on more recent approaches like vasodilating drugs, lung and heart-lung transplantation. Prognosis and survival are presented.

Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma.

Hepatitis B virus (HBV) may be one of the agents involved in the aetiology of human primary liver cancer. This hypothesis is supported by (1) the similarity between the geographical distribution of chronic carriers of the viral surface antigen (HBsAg) and that of hepatocellular carcinoma (HCC); (2) the increase in the prevalence of HBV markers in serum of patients with primary liver cancer when compared with the general population; (3) the observation that HBV infection precedes the development of the tumour. Moreover, these epidemiological indications of an association between HBV infecton and hepatocellular carcinoma are supported by the detection of HBV markers such as HBsAg or viral DNA sequences, although in a non-integrated form in tumour tissue. To study the relationship between HBV and primary liver cancer further, we looked for the presence of free or integrated viral DNA in tumour tissue of human hepatocellular carcinomas and in a HBsAg-producing human hepatoma cell line. Using the blot-transfer hybridization technique and cloned HBV DNA as a probe, we have now demonstrated that the viral DNA is integrated in the cellular genome both in tumour tissue and in a hepatoma cell line.

Pulmonary hypertension in patients with human immunodeficiency virus infection. Comparison with primary pulmonary hypertension.

BACKGROUND: Previously reported cases of patients with pulmonary hypertension (PH) and human immunodeficiency virus (HIV) infection are poorly documented regarding baseline hemodynamics and potential for pulmonary vasodilatation. The purpose of this report was to compare HIV-infected patients who had PH with non-HIV-infected patients who had primary pulmonary hypertension (PPH) in terms of (1) clinical characteristics, (2) hemodynamics in baseline conditions and during a short-term vasodilator trial with epoprostenol, and (3) survival. METHODS AND RESULTS: Between April 1987 and August 1992, 20 HIV-infected patients with PH and 93 non-HIV-infected patients with PPH were referred to our department. At the time of referral, baseline right-side heart hemodynamics were obtained in addition to demographic variables and medical history. A short-term vasodilator trial with epoprostenol was performed in 19 of 20 HIV-infected and 86 of 93 non-HIV-infected patients. Outcome and survival were analyzed and compared for both groups (22 transplant recipients were excluded from the group of patients with PPH). At the time of diagnosis of PH, HIV-infected patients significantly differed from non-HIV-infected patients in age (32 +/- 5 versus 42 +/- 13 years; P < .05) and degree of disability (New York Heart Association functional class III or IV, 50% versus 75%; P < .01). The proportion of disease states known to be associated with PPH (Raynaud's phenomenon, migraine, collagen disease without overt symptoms and signs, or a positive family history of PPH) was similar in the two groups. HIV-infected patients had a severe but significantly lower level of PH than patients with PPH. The percentage of responders to epoprostenol and the level achieved in pulmonary vasodilatation were similar in the two groups. PH was the cause of death in 8 of the 10 HIV-infected patients who died within 1 year after the diagnosis of PH. Overall survival was poor and not significantly different between the two groups. Pathological findings in lung tissue obtained from 3 HIV-infected patients were close to those seen in most of the lung specimens available from 27 patients with PPH and resembled plexogenic pulmonary arteriopathy. CONCLUSIONS: These results support the view that HIV infection may now be regarded as another common disease state that can be associated with PPH development. The lower initial severity in HIV-infected patients may be due to the close medical attention usually devoted to such patients, who may account for an earlier diagnosis. However, the overall survival rate of HIV-infected patients with PH appeared to be as poor as in non-HIV-infected patients with PPH.

Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis.

Continuous intravenous epoprostenol (prostacyclin) produces hemodynamic and symptomatic responses and improves survival in patients with severe primary pulmonary hypertension refractory to conventional medical therapy. However, it has been recently shown that short-term infusion of epoprostenol can produce pulmonary edema in pulmonary veno-occlusive disease, presumably because of increased pulmonary perfusion in the presence of downstream vascular obstruction. We describe two additional cases of pulmonary edema complicating continuous intravenous epoprostenol in patients displaying severe pulmonary hypertension and pulmonary capillary hemangiomatosis, a rare condition characterized by the proliferation of thin-walled microvessels in the alveolar walls. This report indicates that epoprostenol therapy should not be used in patients with severe pulmonary hypertension secondary to pulmonary capillary hemangiomatosis.

Early neutrophil alveolitis after rechallenge in drug induced alveolitis.

A patient with drug induced alveolitis due to an antidepressant drug, nomifensine, is described. After an inadvertent rechallenge by the patient sequential bronchoalveolar lavage was carried out. Twenty four hours after the rechallenge the lavage fluid contained a high cell count with neutrophils predominating. Seven days after challenge the cells were predominantly lymphocytes.