Severi Mattila

The correlation between symptomatic CMV infection and CMV antigenemia in heart allograft recipients

Previous studies have demonstrated that CMV-specific antigens detected from peripheral blood leukocytes correlate with active CMV infection in transplant patients. However, the clinical diagnosis of CMV infection is difficult, and the significance of a positive blood finding is unclear, while CMV antigenemia and viremia may also occur in asymptomatic patients. To investigate the clinical significance of CMV antigenemia after heart transplantation, 68 heart allograft recipients were monitored weekly. Altogether 501 blood specimens were analyzed. CMV was demonstrated in blood leukocytes by a monoclonal antibody and immunoperoxidase staining, and the antigenemia level was expressed as CMV positive cells/50,000 leukocytes. CMV antigenemia occurred in 28/68 patients, and 12 of them developed a symptomatic infection. Of all blood specimens 88/501 were CMV positive, and 30 of them related to the clinical manifestation of CMV. When antigenemia level exceeded >100/50,000, a significant correlation between antigenemia and CMV-related clinical manifestation was reached (P<0.001). Of the 28 antigenemia positive patients 16 never developed any clinical signs of CMV infection. Their maximal antigenemia level was low (median 23, range 30–90) compared with those with clinical manifestation (median 500, range 30–1000) (P<0.002). In conclusion, high antigenemia levels (>100/50,000) correlate with clinical manifestations of CMV infection. Patients with lower levels (<100/ 50,000) do not necessarily ever develop a symptomatic infection. Quantitative monitoring of CMV antigenemia may, thus, be helpful in the clinical diagnosis of CMV infection in heart transplant patients.

Cytomegalovirus infection accelerates cardiac allograft vasculopathy: correlation between angiographic and endomyocardial biopsy findings in heart transplant patients

In order to determine the impact of cytomegalovirus (CMV) infection on cardiac allograft vasculopathy (CAV), we quantitated angiograms and endomyocardial biopsy (EMB) specimens obtained from 53 heart transplant recipients. CMV infection was particularly associated with the development of discrete stenosis in major branch vessels (P<0.03). Also, the number of diffusely affected vessel segments was significantly higher in CMV patients than in CMV-free recipients after the 2nd post-operative year (P<0.05). The EMB histology correlated well with angiography. Significantly higher levels of arteriolar endothelial cell proliferation and intimal thickness were recorded in biopsies of CMV patients than in those of CMV-free recipients during the 1st postoperative year (P<0.02 and P<0.005, respectively). The CMV-associated vascular changes in EMB histology clearly preceded angiographically detectable CAV findings. Taken together, CMV infection accelerated heart allograft arteriosclerosis. The histological changes appeared prior to changes detected by coronary angiography. The CMV effect was particularly pronounced during the first 2 post-transplant years but leveled off thereafter. Thus, CMV-accelerated allograft arteriosclerosis may be linked in particular with early graft loss of CMV-infected heart transplant recipients.

Major surgery increases serum levels of vascular endothelial growth factor only temporarily.

BACKGROUND Vascular endothelial growth factor (VEGF) is a hypoxia-induced endothelial cell-specific mitogen, which is angiogenic in vivo and up-regulated in several malignancies. VEGF can be used as a prognostic marker, but the effect of surgical trauma on serum VEGF (S-VEGF) concentrations is unknown and might reduce the value of VEGF as a serum marker. METHODS We monitored S-VEGF levels by enzyme-linked immunosorbent assay in patients undergoing surgery. RESULTS Eighteen patients with major surgery had slightly elevated S-VEGF compared with the preoperative level (median 9.5 pg/mL) on the first (median 35 pg/mL; P = 0.0002) and third (median 19 pg/mL; P = 0.004) postoperative day, but not in later samples. The levels measured in 8 patients after minor surgery did not differ from the preoperative levels (P = 0.14). CONCLUSIONS Even major surgery is associated only with a slight and transient increase in S-VEGF levels, and, therefore, is unlikely to interfere markedly with the use of VEGF as a prognostic marker.

ASD in patients over 40 years of age.

To evaluate the benefits of operative treatment of congenital heart disease in older age groups, a clinical study on patients over 40 years of age with atrial septal defect was carried out. The series consisted of 125 consecutive patients operated on between 1966 and 1974. There were 8 cases with a primum, 12 cases with a sinus venosus type of secundum and 105 cases with a simple secundum defect. The operative mortality was 2 patients (1.6%). It was due to myocardial infarction in one case and high pulmonary vascular resistance in the other. On re-examination 3-6 months postoperatively, 107 patients were improved, 13 patients unchanged and 3 patients were worse than before operation. On re-evaluation after an average period of 6 years, 88 patients were still improved. 32 patients unchanged and 3 patients were worse compared with their pre-operative status. On the basis of the results and the previous reports on atrial septal defect without operation, the surgical correction of ASD even in older age groups can be recommended. The problem of deterioration of some patients, despite a good immediate postoperative result, is discussed.

Thoracic duct cyst: a case report and review of 29 cases.

Cysts of the thoracic duct are rare. We report a case of a cervical thoracic duct cyst and review 29 thoracic duct cysts reported previously (19 mediastinal, 9 cervical, and 1 abdominal). The mean age of the patients was 47.6 years (range 17 to 86 years). Fourteen (46.7%) of the patients were asymptomatic. When symptoms were present, they ranged from retrosternal pain, dysphagia, and dyspnea to respiratory insufficiency and superior vena cava compression. Diagnosis of the cyst can be made after computed tomography or ultrasonography. The cystic fluid contains T lymphocytes and triglycerides in excess. The symptoms in a patient with a thoracic duct cyst are related to compression of adjacent structures. The most profound symptoms are likely to be produced by mediastinal cysts above the aortic arch. Treatment consists of surgical removal of the cyst and ligation of all lymphatics connected to the cyst.

Malignancies after heart transplantation: presence of Epstein–Barr virus and cytomegalovirus

The presence of Epstein–Barr virus (EBV), human papilloma virus (HPV), and cytomegalovirus (CMV) was studied in 20 patients who developed malignancies after heart transplantation in the Helsinki University Central Hospital. The tumors were analyzed for the presence of HPV by polymerase chain reaction and for EBV by in situ hybridization. Clinical CMV infection was verified by immunochemical quantitation of CMV antigen in peripheral blood cells. HPV was detected in one of the eight epithelial malignant tumors studied. Three of the six lymphomas were positive for EBV. Two (67%) of 3 patients with EBV‐positive lymphomas and one (33%) of the other three lymphomas but only 2 (14%) of 14 patients who developed other malignancies had a history of a manifest post‐transplantation CMV infection prior to the development of malignancy. These results confirm the presence of EBV in lymphomas of heart transplant recipients and suggest that CMV might have a contributory role in the development of EBV‐associated lymphomas.

Surgery for lung cancer in the elderly.

In order to assess the appropriateness of lung cancer surgery in the elderly and determine optimal subjects and resection procedure, 75 patients operated on in 1976-1996 at age > or =75 years (including 13 > or =80) were followed up. The operations included limited resection (8), lobectomy (47), bilobectomy (10) and pneumonectomy (10) and were judged to be radical in 59 cases (79%). Perioperative mortality was 9% and morbidity 29%, including 21% major complications. Cumulative 5-year survival was 32%, in stages IA-IIB 27-41%, and cancer-related survival 61-79%. Mortality did not differ significantly between resection types, but morbidity did. Nor did mortality, morbidity or survival differ between the age groups 75-79 and > or =80 years. In stage I cancer there was no significant difference in survival or cancer-related survival after lobectomy vs limited resection. We conclude that age, even >80 years, is not incompatible with curative resection. Lobectomy is the treatment of choice, but a less radical resection may be advisable if there is comorbidity. If more extensive resection is performed, the individual surgical risk must be weighed against the potential long-term benefit.

Bronchial Artery Revascularization Improves Tracheal Anastomotic Healing after Lung Transplantation

The study aimed to clarify the role of direct bronchial artery revascularization (BAR) after en bloc double-lung (DLT) and heart-lung transplantation (HLT). Group I comprised eight patients with en bloc DLT or HLT and successful BAR, while group II included 14 DLT or HLT cases without BAR or with failed BAR. From these groups, 2 subgroups were extracted: group III, including 6 cases of en bloc DLT with successful BAR and group IV 10 HLT cases without or with failed BAR. Airway healing was evaluated at bronchoscopy and patency of BAR with angiography. Pulmonary viral, bacterial and fungal infections, rejections and bronchiolitis obliterans syndrome (BOS) were registered. Tracheal healing at 2 weeks and 3 months was better in group I than in group II (p = 0.003 and p = 0.05, respectively). Compared with group IV, tracheal anastomotic healing at 2 weeks was better in group III (p = 0.007) and tended to be better also after 3 months (p = 0.07). The incidence of infections, rejection or BOS did not differ between groups I and II. BAR thus improved healing of tracheal anastomosis.The study aimed to clarify the role of direct bronchial artery revascularization (BAR) after en bloc double-lung (DLT) and heart-lung transplantation (HLT). Group I comprised eight patients with en bloc DLT or HLT and successful BAR, while group II included 14 DLT or HLT cases without BAR or with failed BAR. From these groups, 2 subgroups were extracted: group III, including 6 cases of en bloc DLT with successful BAR and group IV 10 HLT cases without or with failed BAR. Airway healing was evaluated at bronchoscopy and patency of BAR with angiography. Pulmonary viral, bacterial and fungal infections, rejections and bronchiolitis obliterans syndrome (BOS) were registered. Tracheal healing at 2 weeks and 3 months was better in group I than in group 1 (p = 0.003 and p = 0.05, respectively). Compared with group IV, tracheal anastomotic healing at 2 weeks was better in group III (p = 0.007) and tended to be better also after 3 months (p = 0.07). The incidence of infections, rejection or BOS did not differ between groups I and II. BAR thus improved healing of tracheal anastomosis.

Cytomegalovirus infection-associated generalized immune activation in heart allograft recipients: a study of cellular events in peripheral blood and endomyocardial biopsy specimens

An association between cytomegalovirus (CMV) infection, heart allograft rejection, and arteriosclerosis has been reported. To investigate the mechanisms of this association, the cellular immune response in peripheral blood and the inflammation in heart allografts during antigenemia were studied. CMV antigenemia occurred in 13 recipients. In recipients with severe CMV infection, a significantly weaker immune response was recorded in peripheral blood: fewer lymphoid blast cells (max. 2.4%±0.4%) and large granular lymphocytes (LGL; max. 9.3%±1.4%) were seen than in patients with mild or asymptomatic CMV infection (lymphoid blast cells max. 6.5%±0.8% P<0.01 and LGLs max. 20%±2.3%, P<0.05). Thus, a strong immune response with lymphoid activation was associated with clinically good outcome of CMV infection. In heart allograft histology, subendothelial inflammation of small intramyocardial vessels was a characteristic finding during CMV antigenemia compared to CMV-free recipients (at the peak P<0.01). However, no difference in this mild and short-lived inflammatory response was observed between clinically mild or severe CMV infection. The CMV-linked generalized immune activation and inflammation of the vascular structures might contribute to the initiation of allograft vasculopathy and to the pathogenesis of chronic heart allograft rejection.

Heart transplantation in repaired transposition of the great arteries.

Cardiac transplantation was carried out in a 40-year-old man with the diagnosis of repaired transposition of the great arteries and right-sided aortic arch who had end-stage cardiac failure due to myopathy of the ventricles. Because of several previous surgical repairs and the orientation of the great vessels, the operation presented some technical problems. Therefore, modifications of operative procedures were used, including recipient hypothermia, circulatory arrest, and changes in the donor heart implantation. The removal of the donor heart was modified in such a way that the graft included the aortic arch and both pulmonary arteries. With the extra length of ascending aorta and transverse arch, the innominate, left carotid, and left subclavian vessels were excised as a button, thereby leaving the distal orifice of the aorta in the superior portion of the transverse arch. For the recipient, the operation was performed using hypothermic total circulatory arrest to dissect free the huge pulmonary artery and the short right-sided aortic arch to place the clamp. Implantation of the donor heart was modified accordingly. The technical results were confirmed one and a half months later on a control digital angiogram. Thirty-five days postoperatively the patient was discharged. Six months after operation, the patient is doing better than ever before in his life. Our findings suggest that a complicated conotruncal development does not preclude cardiac transplantation.