W. van der Bij

Cytomegalovirus antigenemia as a useful marker of symptomatic cytomegalovirus-infection after renal-transplantation - a report of 130 consecutive patients

In earlier work we demonstrated that CMV immediate early antigens can be detected in peripheral blood leukocytes of patients with active CMV infection. We now report a comparison of the antigenemia assay and an anti-CMV ELISA in a prospective longitudinal study of 130 renal transplant recipients who were monitored for active CMV infection during the first 3 months after transplantation. Active CMV infection developed in 56 patients. The antigenemia assay had a sensitivity of 89% and a specificity of 93% in the diagnosis of active CMV infection; for the ELISA these figures were 95 and 100%, respectively. In 22 of the 56 patients a CMV syndrome occurred. Antigenemia was demonstrated in all 22 patients while an antibody response occurred in 21 of them. The antigenemia assay became positive 8 +/- 7 days before the onset of symptoms while the antibody response was observed 4 +/- 9 days after the onset of symptoms. The pattern of antigenemia was helpful for monitoring the course of the infection. The maximum level of antigenemia was significantly higher and its duration significantly longer in symptomatic than asymptomatic infection. We conclude that CMV antigenemia is a sensitive, specific, and early marker of CMV infection. The antigenemia assay is of great value in monitoring patients with a high risk of CMV infection.

Long-term outcome of lung transplantation is predicted by the number of HLA-DR mismatches

Background. The importance of HLA mismatch in determining long-term outcome in lung transplantation remains largely uncertain. Methods. A retrospective analysis of 102 consecutive primary lung transplants was performed to identify risk factors for poor long-term outcome after lung transplantation defined as graft survival and bronchiolitis obliterans syndrome (BOS) stage I and II. Variables included were patient characteristics (age, sex, prior diagnosis), the number of HLA mismatches between donor and recipient, cold ischemic time, cytomegalovirus serologic concordance, number of acute rejections, and time to first rejection. Variables carrying significance in a univariate analysis were subjected to a proportional hazard regression analysis. Results. In the multivariate analysis, an increased number of acute rejections correlated positively with decreased graft survival (risk ratio [RR]=1.25; 95% confidence interval [CI], 1.05–1.5;P =0.011), development of BOS stage I (RR=1.36/episode; 95% CI, 1.16–1.58;P <0.001), and BOS stage II (RR=1.42/episode; 95% CI, 1.2–1.67;P <0.001). An increased time to rejection correlated positively with reduced graft survival (RR=1.03/day; 95% CI, 1.01–1.06;P =0.02), and BOS stage I and II (both RR=1.04/day; 95% CI, 1.01–1.07;P <0.005). Compared with 2 HLA-DR mismatches, 0 or 1 mismatch was associated with improved graft survival (RR=0.43; 95% CI, 0.19–0.98;P =0.045) and protected against development of BOS stage I (RR=0.47; 95% CI, 0.23–0.98;P =0.044) and BOS stage II (RR=0.35; 95% CI, 0.15–0.83;P =0.017). Conclusions. HLA-DR mismatching appears to be a risk factor for the development of BOS and graft loss. Improved outcome after lung transplantation might be achieved with prospective matching for HLA-DR. Alternatively, the amount and type of immunosuppressive drugs may be guided by the degree of HLA-DR (mis)matching.

Quantitative measurement of cytomegalovirus-specific IgG and IgM antibodies in relation to cytomegalovirus antigenaemia and disease activity in kidney recipients with an active cytomegalovirus infection.

In a longitudinal investigation 103 kidney recipients were studied with respect to the development of cytomegalovirus (CMV) specific antibodies of the IgG and IgM class, in relation to the detection of CMV antigenaemia (immediate early antigen. IEA), in weekly obtained blood samples during the first 3 months after transplantation. In 15 out of 49 (31%) seronegative patients a primary infection occurred, which was characterized by a quick rise in IgM antibody followed by a slower production of IgG antibody, high maximum numbers of IEA+ cells, and a CMV syndrome in 11 patients, ln 35 out of 54 (65%) seropositive patients a secondary infection occurred. After a post‐operative fall in the IgG antibody, which was also found in patients without an active infection and which was accompanied by a similar drop in scrum albumin and IgG, a second dip in IgG antibody was found 6 days before the first IEA+ leucocyte appeared in the blood. This was followed by a significant increase, indicative of an active immune response in consequence of the infection. 18 days later. In 31 of these 35 patients an IgM response was found. This could be ascribed to the presence of rheumatoid factor activity in 20 of them. Eight patients who showed a transient rise in IgG antibody between the two dips could be distinguished from the remaining ones by a lower maximum number of IEA+ cells and less severe disease symptoms. The described results suggest that (i) an adequate humoral immune system may prevent symptomatic CMV disease in secondary infections; and (ii) CMV‐specific antibodies may be removed from the circulation by antigens present in infected tissues before CMV antigenaemia becomes detectable.

Quantitation of immunosuppression by flow cytometric measurement of the capacity of T cells for interleukin-2 production

BACKGROUND Methods to quantitate the effects of immunosuppressive drugs on immune reactivity might be helpful for monitoring immunosuppressive treatment. Cyclosporine (CsA) inhibits the induction of cytokine synthesis in T cells, and measurement of interleukin (IL)-2 production might constitute a parameter of this drugs effect. METHODS We determined the percentages of CD4+ and CD8+ lymphocytes producing IL-2 upon stimulation by phorbol myristate acetate and calcium ionophore in whole blood culture, using immunostaining of intracytoplasmatic and membrane markers, followed by multiparameter flow cytometry. A total of 38 clinically stable transplant patients on various immunosuppressive protocols were studied. RESULTS The percentage of CD4+ T cells producing IL-2 was strongly reduced in patients compared with healthy controls (23% [range, 3-68%] vs. 59.0% [range, 41-70%]; P=0.000035). The percentage of CD4+ T cells producing IL-2 was negatively correlated with the CsA level (Rc=-0.0821, P=0.00002297) but not with prednisolone or azathioprine doses. Fewer CD8+ T cells produced IL-2 in transplant patients compared with controls, but the difference failed to reach statistical significance. The percentage of CD8+ T cells capable of producing IL-2 was inversely correlated to CsA levels (Rc=-0.0375, P=0.0011). CONCLUSIONS These data suggest that the functional effects of CsA in transplant recipients can be quantitatively determined and that the capacity of CD4+ T cells to produce IL-2 upon stimulation constitutes a functional parameter of CsA effects on the immune system. Prospective studies are required to determine whether this method is useful for clinical monitoring.

Size matching in lung transplantation using predicted total lung capacity

Height is used in allocation of donor lungs as an indirect estimate of thoracic size. Total lung capacity (TLC), determined by both height and sex, could be a more accurate functional estimation of thoracic size. Size-matching criteria based on height versus predicted TLC was retrospectively evaluated, and, furthermore, whether a TLC mismatch was related to clinical and functional complications. The ratio of donor and recipient height, as well as the ratio of predicted TLC in donors and recipients, were calculated in 80 patients after bilateral lung transplantation. Complications evaluated included persistent atelectasis, persistent pneumothorax and increased number of days in intensive care, occurrence of bronchiolitis obliterans syndrome and limitation of exercise capacity. Median height donor/recipient ratio was 1.01 (0.93–1.12). Median predicted TLC donor/recipient ratio was 1.01 (with a clearly broader range 0.72–1.41). Neither sex mismatch nor TLC mismatch were related to clinical or functional complications. Allocation of donor lungs based upon height alone leads to a substantial mismatch in total lung capacity caused by sex mismatch. The absence of complications suggests that a greater height donor/recipient discrepancy can be accepted for allocation than previously assumed.

Creatinine-based estimation of rate of long term renal function loss in lung transplant recipients. Which method is preferable?

BACKGROUND Progressive renal function loss during long-term follow up is common after lung transplantation and close monitoring is warranted. Since changes in creatinine generation and excretion may occur after lung transplantation, the reliability of creatinine-based methods of renal function assessment to serial measurements of glomerular filtration rate (GFR) were compared in this population. METHODS Renal function with serial measurements of GFR by iothalamate clearance every 6 months after transplantation was studied in a cohort of 40 lung transplant recipients with at least 24 months of follow up, transplanted between November 1990 and October 1995 in this center. The correlation between the rate of renal function loss calculated from the slope of GFR and the following creatinine-based indices: 1/S-creatinine, Cockcroft clearance and Levey estimation were analyzed. The absolute difference between GFR and Cockcroft clearance and Levey estimation pre- post-transplantation at several points was also studied. RESULTS The slopes of 1/S-creatinine (r = 0.85), Cockcroft clearance (r = 0.86), and the Levey estimation (r = 0.84) correlated significantly with the slope of GFR as measured by iothalamate clearance. However, all creatinine-based slopes underestimate the rate of GFR loss. Cockcroft clearance and the reciprocal value of serum creatinine do not detect small GFR losses. During long-term follow up a time-dependent discrepancy between Cockcroft clearance, Levey estimation and GFR was observed which may partially explain the observations for this population. CONCLUSION Creatinine-based slopes correlate with GFR slopes after lung transplantation, but consistently underestimate the rate of GFR decline. The Levey estimation is the most sensitive method used to detect small GFR losses and may be preferable when no GFR measurement is available. In special conditions when an accurate renal function assessment is needed true GFR may be necessary.

Cost-effectiveness of lung transplantation in relation to type of end-stage pulmonary disease

The purpose of this study was to explore the relationship between diagnosis and the cost‐effectiveness and cost‐utility of lung transplantation.

Quality of life before and after lung transplantation in patients with emphysema versus other indications.

Whether lung transplantation improves Health-related Quality of Life in patients with emphysema and other end-stage lung diseases before and after lung transplantation was examined. Berween 1992 and 1999, 23 patients with emphysema and 19 patients with other indications completed self-administered questionnaires before lung transplantation, and at 4, 7, 13, and 25 mo. after transplantation. The questionnaire included the Nottingham Health Profile, the State-Trait Anxiety Inventory, the Self-rating Depression Scale, the Index of Well-being, the self-report Karnofsky Index, and four respiratory-specific questions. Neither before nor after transplantation were significant differences found on most dimensions of Health-related Quality of Life between patients with emphysema and other indications. Before transplantation, both groups report major restrictions on the dimensions Energy and Mobility of the Nottingham Health Profile, low experienced well-being, depressive symptoms, and high dyspnea. About 4 mo. after transplantation, most Health-related Quality of Life measures improved significantly in both groups. These improvements were maintained in the following 21 mo.

Renal hemodynamics after lung transplantation : A prospective study

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.

Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy

After solid organ transplantation, signs and symptoms of the central nervous system may present a diagnostic challenge. A 43‐year‐old patient developed a decrease in vision 15 months after bilateral lung transplantation. The initial diagnosis was a left posterior cataract, but left eye cataract extraction did not improve his vision. Seizures led to investigation of a broader differential diagnosis (cyclosporine intoxication, post‐transplant lymphoproliferative disorder, infectious disease, chronic lymphatic leukemia). The clinical diagnosis of progressive multifocal leukoencephalopathy (PML) was confirmed by demonstration of JC virus in the cerebrospinal fluid and by autopsy findings. Modulation of the immunosuppressive regimen was unsuccessful. This case illustrates that decreased vision in immunocompromised patients may be the first manifestation of PML.