Antibiotic prescribing for acute lower respiratory tract infections (LRTI) - guideline adherence in the German primary care setting: An analysis of routine data.

OBJECTIVES: Antibiotic overprescribing in primary care has major impacts on the development of antibiotic resistance. The objective of this study is to provide insight in antibiotics prescriptions for patients suffering from cough, acute bronchitis or community acquired pneumonia in primary care. METHODS: Data from 2009 to 2013 of electronic health records of 12,880 patients in Germany were obtained from a research database. The prescription of antibiotics for acute lower respiratory tract infections was compared to the national S3 guideline cough from the German Society of General Practitioners and Family Medicine. RESULTS: Antibiotics were prescribed in 41% of consultations. General practitioners' decision of whether or not to prescribe an antibiotic was congruent with the guideline in 52% of consultations and the antibiotic choice congruence was 51% of antibiotic prescriptions. Hence, a congruent prescribing decision and a prescription of recommendation was found in only 25% of antibiotic prescriptions. Split by diagnosis we found that around three quarters of antibiotics prescribed for cough (73%) and acute bronchitis (78%) were not congruent to the guidelines. In contrast to that around one quarter of antibiotics prescribed for community acquired pneumonia (28%) were not congruent to the guidelines. CONCLUSIONS: Our results show that there is a big gap between guideline recommendation and actual prescribing, in the decision to prescribe and the choice of antibiotic agent. This gap could be closed by periodic quality circles on antibiotic prescribing for GPs.

VEGF 936 C/T gene polymorphism in renal transplant recipients: association of the T allele with good graft outcome.

We investigated the possible impact of vascular endothelial growth factor (VEGF) 936 C/T gene polymorphism on kidney graft outcome. DNA samples of 290 first deceased donor kidney graft recipients with well-functioning grafts and no rejection treatment during the first transplant year (WFG), 265 recipients with graft failure within the first transplant year (F), and 187 healthy control subjects were tested using the polymerase chain reaction restriction fragment length polymorphism technique. Although VEGF 936 CT genotype and T allele carrier frequencies in 555 kidney graft recipients did not differ significantly from frequencies observed in healthy control subjects, significantly higher frequencies were found in WFG patients (CT: 19.0%, T: 20.7%) than in F patients (CT: 11.7%, p=0.019; T: 12.8%, p=0.017, respectively). The VEGF 936 CT genotype and T allele appear to be associated with good outcome in renal transplantation and, if confirmed, might be helpful for the pretransplant identification of recipients with low risk of graft rejection.

Evaluation of hepatocyte growth factor as a sensitive marker for early detection of acute renal allograft rejection.

BACKGROUND: It has been shown that hepatocyte growth factor (HGF), besides its well-established hepatotrophic effect in liver regeneration, is involved in the regeneration of the kidney after injury. In the present study we investigated whether HGF can serve as a marker for detection of acute rejection in the early posttransplantation period. METHODS: HGF levels were determined in pre- and posttransplant sera (up to day 21) of 26 recipients with biopsy-proven acute rejection, 30 recipients with acute tubular necrosis (ATN), and 32 recipients without posttransplant complications. RESULTS: Although no association was found between pretransplant HGF and death-censored functional graft survival, receiver operating characteristic (ROC) curves demonstrated that HGF measured during the entire posttransplant study period, and especially on days 3 to 5, was a good marker for differentiating recipients who subsequently developed acute rejection from recipients with an uncomplicated course (P<0.0001, specificity 87%, sensitivity 84%). HGF measured from day 3 until day 21 posttransplantation, and especially on days 7 to 9, was also a sensitive marker for differentiating recipients with ATN from recipients with an uncomplicated course (P<0.0001). If considered in combination with sCD30, the diagnostic value of HGF was further improved. While 73% of samples from patients with impending rejection were positive for both HGF and sCD30, 94% of samples from nonrejecting patients were double-negative and none of the samples from this group fell into the double-positive category (P<0.0001). CONCLUSIONS: Our data suggest that HGF measured during the early posttransplant period might be a useful parameter for early detection of acute renal allograft rejection.

Serum sCD30 in monitoring of alloresponse in well HLA-matched cadaveric kidney transplantations.

In kidney transplantation, pretransplant serum sCD30 testing has been proposed in immunological risk estimation together with anti-HLA antibodies. We evaluated the risks associated with high pretransplant serum sCD30 in well HLA-matched cadaveric kidney recipients recruited in a clinical study comparing different immunosuppressive regimens. Rejection rate was similar in 37 recipients with high pretransplant serum sCD30 compared to 117 recipients with low serum sCD30 (16% vs. 15%, P=NS). Compared to pretransplant levels, the posttransplant sCD30 levels generally decreased, also in patients with rejection, although on day 21 posttransplant, rejecting patients had significantly higher relative sCD30 than nonrejecting patients (P<0.01). However, steroid-resistant rejection was associated with increasing posttransplant sCD30 levels. High pretransplant sCD30 values were associated with tubulointerstitial rejection. There was no correlation of sCD30 with delayed graft function. Good HLA matching seems to be effective in neutralizing the negative effect of a high pretransplant serum sCD30.

Evaluation of T-cell receptor repertoires in patients with long-term renal allograft survival.

The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (> or = 9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vss usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR V beta families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.

ATG induction therapy: long-term effects on Th1 but not on Th2 responses.

Antithymocyte globulin (ATG) induction therapy is associated with an increased long-term risk of infection- and cancer-related death. To analyze long-term effects of ATG induction on lymphocyte function, we prospectively assessed CD4 helper function, B-cell/monocyte and cytokine responses in 84 renal transplant recipients (ATG, n = 44) up to 1 year post-transplant. A PWM-driven allogeneic coculture system was used to assess helper function of CD4+ T cells and T-cell-dependent B-cell responses. SAC I was used for T-cell-independent stimulation of B-cell cultures. In vitro cytokine secretion and serum soluble CD30 (sCD30) were determined by enzyme-linked immunosorbent assay (ELISA). ATG induced a persistent decrease of peripheral blood lymphocyte counts compared with non-ATG treatment because of a predominant decrease of CD4+ T cells (4 months, 1 year; P < 0.0005) which was associated with a decreased CD28 expression (1 year, P = 0.02) and CD4 cell interleukin 2 (IL-2) response (4 months, P < 0.0005). However, Th2 responses (CD4 help, CD4 cell IL-4 and IL-10 responses, sCD30), which proved to be predictive of graft outcome, were not affected, and neither was the secretion of the lymphoma growth factors IL-6 and IL-10 by B cells and monocytes. Our data show that ATG induction therapy in immunological high-risk patients induces a profound long-term decrease in cell counts and Th1 but not Th2 responses of CD4+ T cells which may explain long-term effects on infection and post-transplant lymphoproliferative disease (PTLD) incidence because of inadequate T-cell control.

Serial peripheral blood interleukin-18 and perforin gene expression measurements for prediction of acute kidney graft rejection.

BACKGROUND: We and others have shown that expression of the cytotoxic T-lymphocyte effector gene perforin in the peripheral blood is a strong predictor of acute rejection in the early posttransplant period. In the present study we investigated whether interleukin (IL)-18, an immunostimulatory gene that up-regulates perforin-dependent cytotoxicity and promotes tissue damage through other noncytotoxic T-lymphocyte mechanisms alone or in combination with perforin gene expression, may serve as a better predictor of renal allograft rejection in the first weeks after transplantation. METHODS: Peripheral blood was collected twice weekly, and gene expression was measured using real-time polymerase chain reaction. RESULTS: Recipients with acute rejection (n = 17) showed higher levels of perforin and IL-18 transcript on days 5 to 7, 8 to 10, and 11 to 13, compared with patients without rejection (n = 37, P < 0.01 in all cases). Rejection diagnosis using gene expression criteria was possible 1 to 32 days before traditional diagnosis (median 11 days). High specificity was associated with IL-18 expression (72%-93%), and high sensitivity was associated with perforin expression (63%-90%). Positive predictive value was optimized (78%-100%) by using combined up-regulation in both genes as a diagnostic criterion (double-positive). Using high expression in "either or both" genes as a diagnostic criterion yielded high sensitivity (82%-91%) and negative predictive value (91%-96%). CONCLUSIONS: Our data indicate that combined perforin and IL-18 gene expression measurements are useful tools for the recognition of graft rejection in its earliest stages. Serial measurements could be implemented as a monitoring system to identify patients at higher risk of rejection, making them candidates for biopsy or prophylactic increases in immunosuppression.

Strong human leukocyte antigen matching effect in nonsensitized kidney recipients with high pretransplant soluble CD30.

The influence of human leukocyte antigen (HLA) matching on graft survival is greater in patients with preformed lymphocytotoxic antibodies than in nonsensitized patients. Pretransplant serum soluble CD30 (sCD30) affects graft outcome independently of presensitization status. The impact of HLA compatibility on kidney transplant survival was analyzed in 3980 nonsensitized first cadaveric kidney recipients in relation to the pretransplant serum sCD30 content. Although HLA compatibility influenced graft outcome only marginally in nonsensitized recipients with low sCD30 (at 3 years: P=0.0095; at 5 years: P=0.1033), a strong HLA matching effect was observed in nonsensitized recipients with high sCD30 (at 3 years: P<0.0001; at 5 years: P=0.0001). Nonsensitized patients with high pretransplant sCD30 benefit from an HLA well-matched kidney. Patients should be tested for sCD30 while on the waiting list for a kidney transplant, and HLA well-matched kidneys should be allocated to patients with high sCD30.

Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection.

BACKGROUND: Posttransplantation measurement of soluble CD30 (sCD30) may be useful for identifying kidney graft recipients at risk of impending graft rejection in the early posttransplantation period. METHODS: We measured plasma sCD30 levels and evaluated the levels in relation to the diagnosis of rejection. RESULTS: Receiver operating characteristic curves demonstrated that on posttransplantation days 3 to 5, sCD30 allowed a differentiation of recipients who subsequently developed acute allograft rejection (n=25) from recipients with an uncomplicated course (n=20, P<0.0001) (area under the receiver operating characteristic curve 0.96, specificity 100%, sensitivity 88%) and recipients with acute tubular necrosis in the absence of rejection (n=11, P=0.001) (area under the receiver operating characteristic curve 0.85, specificity 91%, sensitivity 72%). CONCLUSIONS: sCD30 measured on posttransplantation days 3 to 5 offers a noninvasive means for differentiating patients with impending acute allograft rejection from patients with an uncomplicated course or with acute tubular necrosis.

Identification of highly responsive kidney transplant recipients using pretransplant soluble CD30.

The identification of high immunologic responders is desirable for the selection of appropriate immunosuppressive regimens. With the collaboration of 29 transplant centers in 15 countries, we investigated whether the pretransplant serum content of soluble CD30 (sCD30), a marker for the activation state of Th2-type cytokine producing T cells, is a useful predictor of kidney graft outcome. Pretransplant sera of 3899 cadaver kidney recipients were tested for serum sCD30 concentration using a commercially available enzyme-linked immunosorbent assay kit. Subsequent kidney graft survival was analyzed. The 5-yr graft survival rate in 901 recipients with a high pretransplant serum sCD30 (> or =100 U/ml) was 64 +/- 2%, significantly lower than the 75 +/- 1% rate in 2998 recipients with low sCD30 (<100 U/ml) (P < 0.0001). High sCD30 was associated primarily with graft loss and not with patient death. The sCD30 effect on graft survival was evident in first transplants as well as in retransplants, in presensitized patients with lymphocytotoxic antibodies as well as in nonsensitized patients, and in patients who received HLA well-matched kidneys as well as in patients who received poorly matched grafts. Recipients with a high pretransplant sCD30 needed significantly more rejection treatment after the first posttransplant year and continued to lose grafts at a higher rate during the 5-yr follow-up period, indicating that pretransplant sCD30 predicts not only the risk of acute rejection but also of chronic allograft nephropathy.

Soluble CD30 as a predictor of kidney graft outcome.

BACKGROUND: In the present study, we investigated whether the soluble form of CD30 (sCD30), a marker for T helper 2-type cytokine-producing T cells, is increased in sera of potential kidney graft recipients. We also investigated whether the pretransplantation serum sCD30 content is related to kidney graft survival. METHODS: Pretransplantation sera of 844 cadaver kidney recipients from three transplant centers in Germany were tested for serum sCD30 content using a commercially available ELISA kit. RESULTS: Kidney graft recipients showed a significantly higher serum sCD30 content than healthy controls (P<0.0001). High sCD30 serum content was associated with graft rejection. The 2-year graft survival rate in recipients with a high pretransplantation serum sCD30 was 68+/-6%, significantly lower than the 86+/-1% rate in recipients with a low sCD30 (P<0.0001). Importantly, high sCD30 was indicative of an increased risk of graft loss even in recipients without lymphocytotoxic alloantibodies. CONCLUSION: These data show that an elevated pretransplantation serum sCD30 reflects an immune state that is detrimental for kidney graft survival.