Roberto Dall'Amico

Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial.

OBJECTIVES. Febrile urinary tract infections are common in children and associated with the risk for renal scarring and long-term complications. Antimicrobial prophylaxis has been used to reduce the risk for recurrence. We performed a study to determine whether no prophylaxis is similar to antimicrobial prophylaxis for 12 months in reducing the recurrence of febrile urinary tract infections in children after a first febrile urinary tract infection. METHODS. The study was a controlled, randomized, open-label, 2-armed, noninferiority trial comparing no prophylaxis with prophylaxis (co-trimoxazole 15 mg/kg per day or co-amoxiclav 15 mg/kg per day) for 12 months. A total of 338 children who were aged 2 months to <7 years and had a first episode of febrile urinary tract infection were enrolled: 309 with a confirmed pyelonephritis on a technetium 99m dimercaptosuccinic acid scan with or without reflux and 27 with a clinical pyelonephritis and reflux. The primary end point was recurrence rate of febrile urinary tract infections during 12 months. Secondary end point was the rate of renal scarring produced by recurrent urinary tract infections on technetium 99m dimercaptosuccinic acid scan after 12 months. RESULTS. Intention-to-treat analysis showed no significant differences in the primary outcome between no prophylaxis and prophylaxis: 12 (9.45%) of 127 vs 15 (7.11%) of 211. In the subgroup of children with reflux, the recurrence of febrile urinary tract infections was 9 (19.6%) of 46 on no prophylaxis and 10 (12.1%) of 82 on prophylaxis. No significant difference was found in the secondary outcome: 2 (1.9%) of 108 on no prophylaxis versus 2 (1.1%) of 187 on prophylaxis. Bivariate analysis and Cox proportional hazard model showed that grade III reflux was a risk factor for recurrent febrile urinary tract infections. Whereas increasing age was protective, use of no prophylaxis was not a risk factor. CONCLUSIONS. For children with or without primary nonsevere reflux, prophylaxis does not reduce the rate of recurrent febrile urinary tract infections after the first episode.

Photopheresis for the Prevention of Rejection in Cardiac Transplantation

BACKGROUND Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts. METHODS A total of 60 consecutive eligible recipients of primary cardiac transplants were randomly assigned to standard triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) alone or in conjunction with photopheresis. The photopheresis group received a total of 24 photopheresis treatments, each pair of treatments given on two consecutive days, during the first six months after transplantation. The regimen for maintenance immunosuppression, the definition and treatment of rejection episodes, the use of prophylactic antibiotics, and the schedule for cardiac biopsies were standardized among all 12 study centers. All the cardiac-biopsy samples were graded in a blinded manner at a central pathology laboratory. Plasma from the subgroup of 34 patients (57 percent) who were enrolled at the nine U.S. centers was analyzed by polymerase-chain-reaction amplification for cytomegalovirus DNA. RESULTS After six months of follow-up, the mean (+/-SD) number of episodes of acute rejection per patient was 1.44+/-1.0 in the standard-therapy group, as compared with 0.91+/-1.0 in the photopheresis group (P=0.04). Significantly more patients in the photopheresis group had one rejection episode or none (27 of 33) than in the standard-therapy group (14 of 27), and significantly fewer patients in the photopheresis group had two or more rejection episodes (6 of 33) than in the standard-therapy group (13 of 27, P=0.02). There was no significant difference in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise, or survival at 6 and 12 months. Although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group (P=0.04). CONCLUSIONS In this pilot study, the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection.

Extracorporeal photochemotherapy for paediatric patients with graft‐versus‐host disease after haematopoietic stem cell transplantation

Summary. This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft‐versus‐host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8·6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5‐year overall survival was 69% for responding patients vs 12% for non‐responders (P = 0·001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5‐year overall survival was 96% for responders vs 58% for non‐responders (P = 0·04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.

Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial

Objective To compare the efficacy of oral antibiotic treatment alone with treatment started parenterally and completed orally in children with a first episode of acute pyelonephritis. Design Multicentre, randomised controlled, open labelled, parallel group, non-inferiority trial. Setting 28 paediatric units in north east Italy. Participants 502 children aged 1 month to <7 years with clinical pyelonephritis. Intervention Oral co-amoxiclav (50 mg/kg/day in three doses for 10 days) or parenteral ceftriaxone (50 mg/kg/day in a single parenteral dose) for three days, followed by oral co-amoxiclav (50 mg/kg/day in three divided doses for seven days). Main outcomes measures Primary outcome was the rate of renal scarring. Secondary measures of efficacy were time to defervescence (<37�C), reduction in inflammatory indices, and percentage with sterile urine after 72 hours. An exploratory subgroup analysis was conducted in the children in whom pyelonephritis was confirmed by dimercaptosuccinic acid (DMSA) scintigraphy within 10 days after study entry. Results Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), difference in risk −4%, 95% confidence interval −11.1% to 3.1%) and secondary outcomes (time to defervescence 36.9 hours (SD 19.7) v 34.3 hours (SD 20), mean difference 2.6 (−0.9 to 6.0); white cell count 9.8�109/l (SD 3.5) v 9.5�109/l (SD 3.1), mean difference 0.3 (−0.3 to 0.9); percentage with sterile urine 185/186 v 203/204, risk difference −0.05% (−1.5% to 1.4%)). Similar results were found in the subgroup of 278 children with confirmed acute pyelonephritis on scintigraphy at study entry. Conclusions Treatment with oral antibiotics is as effective as parenteral then oral treatment in the management of the first episode of clinical pyelonephritis in children. Trial registration Clinical Trials NCT00161330.

Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants.

To determine whether prophylactic treatment with recombinant human erythropoietin (rHuEPO) and iron would reduce the need for blood transfusions, we randomly assigned 22 premature infants with gestational ages less than or equal to 32 weeks and birth weights less than or equal to 1.75 kg to receive rHuEPO, 400 IU/kg three times a week, plus iron, 20 mg/wk intravenously, from the second day of life (11 infants), or no rHuEPO and no iron (11 infants). The two groups had similar birth weights and clinical variables. The treated infants required fewer blood transfusions (0.8 +/- 1.5 vs 3.1 +/- 2.1; p = 0.01) and less volume of packed erythrocytes (14.2 +/- 25.9 vs 48.4 +/- 34.0 ml/kg; p = 0.02). The amounts of blood sampled were not different (19.5 +/- 21.1 vs 27.8 +/- 19.1 ml/kg; p = 0.35). Reticulocyte and hematocrit values were higher in the treated group (4.46% +/- 0.8% vs 1.49% +/- 1.1% (p = 0.0001) and 48.1% +/- 7.3% vs 43.8% +/- 4.7% (p = 0.004), respectively). No side effects of either rHuEPO or intravenously administered iron were noted. These data indicate that rHuEPO, in combination with iron supplementation, is effective in reducing the need for blood transfusions in the premature infant. More information is needed on dosage, timing, and iron and vitamin supplementation.

Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease

Photopheresis (ECP) is a new type of photochemotherapy, used for the treatment of oncological and autoimmune diseases. Lymphocytes are drawn from the patients by leukapheresis, treated with 8‐methoxypsoralen (8‐MOP) and ultraviolet light A (UVA) in an extracorporeal system and then reinfused. Skin exposure to 8‐MOP and UVA (PUVA) has been shown to relieve cutaneous symptoms of graft‐versus‐host disease (GVHD) in bone marrow transplant (BMT) recipients. ECP, which is similar in some ways to PUVA, has been used in this study to treat four paediatric patients who developed chronic GVHD following BMT and in whom GVHD had failed to respond to conventional immunosuppressive therapy. Following ECP, skin lesions cleared almost completely and pulmonary function tests improved in two of three patients with cutaneous and lung involvement. Serum bilirubin and transaminases gradually normalized, and γGT decreased considerably in the remaining patient who had a severe cholestatic hepatopathy. The Karnofsky performance score increased to 90% in the three patients with positive responses to ECP and remained unchanged (40%) in the patient who did not respond. Immunosuppressive therapy was reduced in three patients and eventually discontinued in two. No significant side‐effects were observed during the treatment. Our results suggest that ECP is a non‐aggressive treatment that may benefit patients with chronic GVHD who do not respond to standard immunosuppressive therapy.

Value of Imaging Studies After a First Febrile Urinary Tract Infection in Young Children: Data From Italian Renal Infection Study 1

OBJECTIVE. We examined the diagnostic accuracy of routine imaging studies (ultrasonography and micturating cystography) for predicting long-term parenchymal renal damage after a first febrile urinary tract infection. METHODS. This study addressed the secondary objective of a prospective trial evaluating different antibiotic regimens for the treatment of acute pyelonephritis. Data for 300 children ≤2 years of age, with normal prenatal ultrasound results, who completed the diagnostic follow-up evaluation (ultrasonography and technetium-99m-dimercaptosuccinic acid scanning within 10 days, cystography within 2 months, and repeat technetium-99m-dimercaptosuccinic acid scanning at 12 months to detect scarring) were analyzed. Outcome measures were sensitivity, specificity, and negative and positive predictive values for ultrasonography and cystography in predicting parenchymal renal damage on the 12-month technetium-99m-dimercaptosuccinic acid scans. RESULTS. The kidneys and urinary tracts were mostly normal. The acute technetium-99m-dimercaptosuccinic acid scans showed pyelonephritis in 54% of cases. Renal scarring developed in 15% of cases. The ultrasonographic and cystographic findings were poor predictors of long-term damage, showing minor sonographic abnormalities for 12 and reflux for 23 of the 45 children who subsequently developed scarring. CONCLUSIONS. The benefit of performing ultrasonography and scintigraphy in the acute phase or cystourethrography is minimal. Our findings support (1) technetium-99m-dimercaptosuccinic acid scintigraphy 6 months after infection to detect scarring that may be related to long-term hypertension, proteinuria, and renal function impairment (although the degree of scarring was generally minor and did not impair renal function) and (2) continued surveillance to identify recurrent urinary tract infections that may warrant further investigation.

Is Serum Cystatin C a Sensitive Marker of Glomerular Filtration Rate (GFR)? A Preliminary Study on Renal Transplant Patients

Human cystatin C is a basic low molecular mass protein (13,359 Dalton) freely filtered through the glomerulus and almost completely re-absorbed and catabolized by proximal tubular cells. We measured serum cystatin C in 38 kidney transplant patients (23 males, 15 females) aged between 6 and 32 years. To assess renal function, serum and urinary creatinine were also determined in all patients, and creatinine clearance was finally calculated. Cystatin C was determined by a particle-enhanced turbidimetric assay, and creatinine was measured by gas chromatography-mass spectrometry. To compare the diagnostic efficiency of cystatin C with that of creatinine, inulin clearance was performed on 12 renal transplant patients, and receiver operating characteristic (ROC) analysis was applied. The results of this study demonstrate that serum cystatin C significantly increases in renal transplant patients with reduced creatinine clearance (< 70 mL/min per 1.73 m2) and that the diagnostic accuracy of serum cystatin C is better than of serum creatinine. Cystatin C may be utilized as a very marker of reduced GFR.

Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection

Recurrent rejection is an uncommon, severe complication after heart transplantation that is associated with a poor long-term prognosis. Photopheresis (ECP), a new form of extracorporeal photo-chemotherapy used for the treatment of cutaneous T cell lymphoma and several autoimmune diseases, has also been used for prevention and treatment of acute rejection in heart transplant recipients. It seems to induce specific suppression of both cellular and humoral rejection. In this study, we evaluated whether ECP added to standard therapies allowed better control of rejection and reduction of conventional immunosuppressive drugs in patients with repeated rejection episodes. Eight heart transplant recipients (6 men and 2 women, mean age 48 yr), with recurrent rejection were treated with ECP for 6 months. Endomyocardial biopsies (EMB) were performed monthly. As a result of treatment, 7 patients on ECP experienced a reduction of the number and severity of rejection episodes. The fraction of EMB negative for rejection increased from 13 to 41%, whereas the fraction of specimens with multifocal and/or diffuse moderate lymphocytes infiltration (grades 3A and 3B) decreased from 41 to 21%. ECP allowed reductions of daily immunosuppressive therapy: prednisone by 44% (16.9 vs. 9.4 mg), cyclosporine by 21% (366 vs. 291 mg), and azathioprine by 29% (137 vs. 97 mg). No major side effects were observed. We conclude that, although the number of patients is small, the use of ECP was safe and associated with improved control of recurrent rejection. This allowed tapering of immunosuppressive drugs, which was particularly useful in two patients with insulin-dependent diabetes and one with sternal wound osteomyelitis.

Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen (8-MOP) and ultraviolet light. The treatment seems to induce an inhibition of both umoral and cellular rejections after transplantation. More than 160 transplanted patients have been treated with ECP (107 heart, 30 kidney, 24 lung and I liver) in different studies. Indication for ECP included acute rejection, recurrent/refractory rejection, prophilaxis of rejection, need of reducing standard immunosuppression. Patient survival is satisfactory. Only one study where ECP was used as the last therapeutic resource in very compromised patients shows a high rate of mortality. On the contrary, when ECP was used earlier after the failure of a first immunosuppressive line the outcome was better with a very low mortality. An hystological resolution of acute rejection is reported in 89% of cardiac transplant patients. The rate of response is similar even in the other transplanted patients treated with ECP. A better control of alloreactivity has been also reported in both cardiac and renal transplant patients with recurrent rejection. In renal allograft the treatment induces a reduction of both lymphocytes and monocytes infiltrate and downregulates the expression of HLA-DR and integrins ICAM-1 and VCAM-1 on tubular cells. Markers of fibrogenesis such as TGFbeta1 and ASMA are only moderately reduced with a more focal pattern of distribution in the post-ECP specimens. The optimal schedule and the length of treatment are still unclear and probably a patient-tailored treatment is needed at least in responder patients. ECP is effective for patients resistant to conventional treatments, particularly when it is started early. This beneficial effect is obtained without the complications typically encountered with immunosuppressive regimens used to control rejection.