Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept

Steroid-resistant acute GVHD (aGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT) continues to be associated with a high mortality. We report the results of a phase II study of treatment of steroid-resistant aGVHD with the IL-2 receptor antibody daclizumab combined with the TNF-receptor fusion protein etanercept. Treatment consisted of daclizumab 1 mg/kg given i.v. on days 1, 4, 8, 15, 22 and etanercept 16 mg/m(2) s.c. on days 1, 5, 9, 13, 17. A total of 21 patients (age 15-61 years) with steroid-resistant aGVHD after alloHSCT were included in the study. Donor types were HLA-matched related (n=6), HLA-matched unrelated (n=14), and HLA-mismatched unrelated (n=1). Eight patients achieved complete, and six showed partial remission of aGVHD. Seven patients did not respond. Four of 21 patients are currently alive with a median follow-up of 586 (185-1155) days. Three patients died due to relapsed malignancy. Treatment-related mortality was due to infectious complications (n=11) or organ failure due to aGVHD (n=3). In total, 12 patients developed subsequent chronic GVHD. In conclusion, the data demonstrate an acceptable response rate of the combination of daclizumab and etanercept in the treatment of steroid-resistant aGVHD. Nevertheless, long-term mortality due to infectious complications and chronic GVHD remains high.     

Accuracy of supplementary serologic testing for human T-lymphotropic virus types I and II in US blood donors. Retrovirus Epidemiology Donor Study

Blood donations in the United States have been screened for antibody to human T-lymphotropic virus type I (HTLV-I) by HTLV-I enzyme immunoassay (EIA) since November 1988. Specimens repeatedly found to be reactive by EIA undergo confirmation by supplementary serologic tests. We assessed the accuracy of blood center testing of 994 HTLV-I EIA repeat-reactive specimens in five US blood centers between November 1988 and December 1991. Of 410 confirmed HTLV-I/II donations, 407 (99.3%) were infected with HTLV-I/II, as determined by polymerase chain reaction (PCR) (403 cases) and by repeat serologic testing (4 cases). The three false- positive results occurred in the first year of testing. Of 425 HTLV- indeterminate specimens, 6 (1.4%) were found to be infected by PCR (5 with HTLV-II and 1 with HTLV-I). None of 159 confirmatory test-negative donations was PCR positive. Of HTLV-I/II-seropositive specimens, 80.2% to 95.4% could be typed as HTLV-I or HTLV-II by type-specific serologic assays. These results support recommendations that HTLV-I/II- seropositive donors should be advised that they are infected with HTLV- I, HTLV-II, or HTLV-I/II (depending on results of type-specific assays). HTLV-indeterminate donors should be advised that their results only rarely indicate HTLV infection. HTLV confirmatory test-negative donors should be reassured that they are not infected with HTLV-I or HTLV-II.     

Kidney Function and Plasma Copeptin Levels in Healthy Kidney Donors and Autosomal Dominant Polycystic Kidney Disease Patients

Background and objectives

Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney.

Design, setting, participants, & measurements

Data were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as ¹²⁵I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging.

Results

Patients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4–15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8–6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6–6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105±17 to 66±10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (β=−0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (β=0.84, P<0.001; β=−0.51, P<0.001, respectively).

Conclusions

On the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.     

Human plasma complement C3 is independently associated with coronary heart disease, but only in heavy smokers (the CODAM study)

Background

Complement C3 is an emerging risk factor for coronary heart disease (CHD) and is particularly increased in the metabolic syndrome. A direct effect of smoking on structure and function of complement C3 has been suggested.

Hypothesis

Smoking behavior may affect the cardiovascular risk that is associated with plasma complement C3.

Methods

The association between plasma C3 and CHD was studied in the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) study population (n = 562, 61% male) with examination of effect modification by smoking.

Results

The overall prevalence of CHD was 23.3%. Higher plasma C3 levels were associated with a higher CHD prevalence, and there was a significant interaction with heavy smoking (p = 0.01). In never & light smokers, the univariate OR for CHD per 1 s.d. (0.33 g/L) increase in C3 was 1.09 [95% confidence interval (CI) 0.85-1.41] (p = 0.505) whereas in heavy smokers it was 2.05 [1.43-2.93] (p < 0.001). The association in the group of heavy smokers remained significant (OR 2.38 [1.54-3.68], p < 0.001) after adjustment for traditional risk factors for cardiovascular disease and also after further adjustment for other cardiometabolic risk factors, i.e. the metabolic syndrome, CRP and insulin resistance (HOMA2IR) (OR C3 between 2.16 and 2.29, all p ≤ 0.001).

Conclusion

Human plasma complement C3 is associated with prevalent CHD, but only in heavy smokers, and this association is independent of important metabolic cardiovascular risk factors.     

Bearing exchange in the management of pseudotumours

Introduction

Soft tissue reactions following metal-on-metal (MoM) arthroplasty of the hip have been under considerable discussion. These reactions are seen following both hip resurfacing and MoM total hip arthroplasty (THA). The phenomenon may arise owing to shedding of metal particles in high wear states, hypersensitivity with normal metal wear rates or a combination of the two.

Methods

Three patients were identified who had developed a soft tissue reaction (pseudotumour) following MoM hip resurfacing procedures. The prostheses were revised to ceramic-on-ceramic (CoC) THA with only minimal debridement of the pseudotumour. Pre and postoperative magnetic resonance imaging was performed to assess the size of the lesions.

Results

Progressive and satisfactory resolution of the associated pseudotumours was identified following revision of the prostheses to CoC THA.

Conclusions

In the early stages of pseudotumour formation following MoM hip resurfacing, this potentially devastating condition can be managed adequately with revision to a CoC bearing THA with minimal soft tissue excision.     

Performance of angiographic, electrocardiographic and MRI methods to assess the area at risk in acute myocardial infarction

Objective Validation of methods to assess the area at risk (AAR) in patients with ST elevation myocardial infarction is limited. A study was undertaken to test different AAR methods using established physiological concepts to provide a reference standard. Main outcome measured In 78 reperfused patients with first ST elevation myocardial infarction, AAR was measured by electrocardiographic (Aldrich), angiographic (Bypass Angioplasty Revascularization Investigation (BARI), APPROACH) and cardiovascular magnetic resonance methods (T2-weighted hyperintensity and delayed enhanced endocardial surface area (ESA)). The following established physiological concepts were used to evaluate the AAR METHODS: (1) AAR size is always ≥ infarct size (IS); (2) in transmural infarcts AAR size=IS; (3) correlation between AAR size and IS increases as infarct transmurality increases; and (4) myocardial salvage ((AAR-IS)/AAR×100) is inversely related to infarct transmurality. Results Overall, 65%, 87%, 76%, 87% and 97% of patients using the Aldrich, BARI, APPROACH, T2-weighted hyperintensity and ESA methods obeyed the concept that AAR size is ≥IS. In patients with transmural infarcts (n=22), Bland-Altman analysis showed poor agreement (wide 95% limits of agreement) between AAR size and IS for the BARI, Aldrich and APPROACH methods (95% CI -22.9 to 29.6, 95% CI -28.3 to 21.3 and 95% CI -16.9 to 20.0, respectively) and better agreement for T2-weighted hyperintensity and ESA (95% CI -6.9 to 16.6 and 95% CI -4.3 to 18.0, respectively). Increasing correlation between AAR size and IS with increasing infarct transmurality was observed for the APPROACH, T2-weighted hyperintensity and ESA methods, with ESA having the highest correlation (r=0.93, p<0.001). The percentage of patients within a narrow margin (±30%) of the inverse line of identity between salvage extent and infarct transmurality was 56%, 76%, 65%, 77% and 92% for the Aldrich, BARI, APPROACH, T2-weighted hyperintensity and ESA methods, respectively, where higher percentages represent better concordance with the concept that the extent of salvage should be inversely related to infarct transmurality. Conclusions For measuring AAR, cardiovascular magnetic resonance methods are better than angiographic methods, which are better than electrocardiographic methods. Overall, ESA performed best for measuring AAR in vivo.