Optical coherence tomography (OCT) and OCT angiography allow early identification of sickle cell maculopathy in children and correlate it with systemic risk factors.

PURPOSE: To determine the presence of sickle cell retinopathy and maculopathy and to identify associations between markers of hemolysis and systemic and ocular manifestations in children affected by sickle cell disease. METHODS: Eighteen children with sickle cell disease, aged 5-16 years, underwent complete eye examination including best-corrected visual acuity, slit-lamp biomicroscopy, ophthalmoscopy after pharmacological mydriasis, spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA). Blood test results and clinical history information were collected for each child, including fetal hemoglobin (HbF), hemoglobin (Hb), hematocrit (Htc), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), reticulocytes percentage (%ret), lactic dehydrogenase (LDH), total and direct bilirubin, glomerular filtration rate, number of painful crises, acute chest syndromes, and splenic sequestration. Therapeutic regimen and transfusion therapy were also evaluated. RESULTS: Sixteen of 36 eyes (44.4%) had non-proliferative sickle cell retinopathy on ophthalmoscopic evaluation. No patients had proliferative sickle cell retinopathy. In 13 of 36 eyes (36.1%), SD-OCT and OCTA detected signs of sickle cell maculopathy. Nine eyes (25%) presented sickle cell retinopathy and maculopathy, 7 eyes (19.4%) sickle cell retinopathy alone, and 4 eyes (11.1%) sickle cell maculopathy alone. A statistically significant association was found between sickle cell retinopathy; lower levels of HbF, Hb, and Htc; and higher MCV and percentage of reticulocytes. Sickle cell maculopathy was associated with lower values of H and Htc and higher levels of reticulocytes and total bilirubin. CONCLUSIONS: We identified early signs of sickle cell retinopathy and maculopathy in a pediatric population with SD-OCT and OCTA. These two retinal complications were more frequent in children with higher hemolytic rates.

De novo cancers in paediatric renal transplant recipients: a multicentre analysis within the North Italy Transplant programme (NITp), Italy.

The purpose of this study was to determine the frequency and the outcome of de novo malignancies in a cohort of renal transplant paediatric patients. The records of 493 kidney transplants, carried out in 454 paediatric recipients at the three paediatric transplant centres of the North Italy Transplant programme (NITp, Italy) were reviewed. 10 cases of malignancies (2.2%) comprising both PTLD (post-transplant lymphoproliferative disorders) (6 cases, 1.3%) and non-PTLD malignancies (4 cases, 0.88%) were reported. Non-PTLD included one urothelial carcinoma and one Wilms' tumour of the recipient's left native kidney, one abdominal dysgerminoma and one optic nerve glioma of the left eye. The PTLD consisted of localised or disseminated Epstein-Barr virus (EBV)--associated B-lymphocyte monoclonal (5 cases) and polyclonal (1 case) proliferations. All patients suffering from PTLD had been EBV-negative at the time of transplantation, but developed EBV primary infection after transplantation. All PTLD patient donors were EBV-positive. In addition, all but 1 patient received, before and/or after transplantation, a range of immunosuppressive drugs in addition to the baseline prophylactic immunosuppressive regimen. Moreover, 3 patients suffered from syndromes associated with a genetic predisposition to cancer. Finally, the malignancies reported here were associated with 20% graft failure and 20% mortality rates.

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.

Prediction and treatment of recurrent focal segmental glomerulosclerosis after renal transplantation in children.

The recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation has a potentially detrimental course toward the loss of renal function. To identify prognostic markers for recurrence and efficacy of treatment, we evaluated the outcome of 32 renal allografts in 29 pediatric patients with FSGS who underwent transplantation from 1987 to 1998 in the North Italy Transplant program. Recurrence was observed in 15 of 29 patients (52%) after the first transplant and in 3 of 3 patients (100%) after the second graft. No significant differences in sex, age at FSGS onset, age at transplantation, or length of dialysis were noted between patients with recurrent and nonrecurrent FSGS. Those with recurrence originally developed end-stage renal failure faster (3.9 years) than those without recurrence (6.2 years). Pretransplantation serum samples from 25 patients were tested in an in vitro assay that evaluates glomerular permeability to albumin. FSGS recurred in 11 of 13 children who tested positive for the permeability factor and in 4 of 12 patients with a negative test result; the odds ratio for developing recurrence was 10.99 (95% confidence limit, 1.6 to 75.47) in the former group. The immediate onset of proteinuria after transplantation was a negative prognostic factor for the outcome; 6 of 9 patients in whom proteinuria appeared within 2 days of transplantation returned to dialysis in less than 24 months. In 9 of 11 patients who were treated with plasmapheresis plus cyclophosphamide after recurrence, proteinuria was successfully reversed and persistent remission was obtained in 7 patients. These data show that the glomerular permeability test has a significant predictive value for the recurrence of proteinuria in children with FSGS who have received a renal allograft. Of the clinical parameters considered, only the duration of disease was significantly different in patients with recurrent versus nonrecurrent FSGS. Treatment with plasmapheresis plus cyclophosphamide can be effective in the control of FSGS relapse after renal transplantation.

Extracorporeal photochemotherapy for the treatment of graft-versus-host disease.

Photopheresis is an extracorporeal photochemotherapy (ECP) 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; then, reinfused to the host. Because skin exposure to 8-MOP and UVA (PUVA) has been shown to improve cutaneous GVHD, we evaluated in a pilot study, if ECP might be beneficial for patients with GVHD unresponsive to conventional protocols. In this study, we enrolled 9 children or young adults, with acute (no = 1) or chronic extensive GVHD (no. = 8). A significant improvement was observed in three of the 5 patients with scleroderma-like lesions and in one patient with severe liver involvement. Karnofsky performance score improved from 30-50% to 90% in the 4 responders. The better control of GVHD in these patients allowed a reduction of the immunosuppressive therapy that was, finally, discontinued in two. No significant side effects were observed during ECP. Our results suggest that ECP is a nonaggressive treatment that may benefit patients with c-GVHD unresponsive to standard immunosuppressive therapies.

Cell membrane DNA: a new target for psoralen photoadduct formation.

The effects of 8-methoxypsoralen plus long wavelength ultraviolet radiation on cell membrane DNA were examined. Treatment of human lymphocytes with 100 ng/ml 8-methoxypsoralen and 5 J/cm2 UVA led to the formation of 7.1 +/- 3.8 photoadducts per million bases. A monoclonal antibody, specific for 8-methoxypsoralen 4',5'-monoadducts, was used to detect photoadducts in the cell membrane DNA of human lymphocytes and three lymphoblastoid cell lines. Treatment of lymphocytes with 8-MOP and UVA reduced the lymphocyte DNA binding capacity by 56%. Cell membranes of normal lymphocytes were shown to contain three high affinity DNA binding proteins of 28, 59, and 79 kDa, respectively.

Renal immunohistochemical distribution, plasma levels and urinary excretion of endothelin after kidney transplantation.

We investigated the immunohistochemical distribution of endothelin (ET) in 22 graft biopsies from kidney-transplanted patients. Like normal kidney tissue, 6/22 biopsies showed either no or only very weak ET positivity in the vascular endothelium. In the other 16 cases ET staining was marked on the vascular endothelium and wall (9/16), inflammatory infiltrates (11/16), glomeruli (7/16) and tubules (5/16). ET positivity in glomeruli and inflammatory infiltrates correlated with the degree of glomerular damage and interstitial inflammation but no correlation was found between the immunohistochemical results and the clinical variables considered. ET plasma levels (ET-PL) in patients (5.13 + 1.77 pmol/L) did not differ significantly from age-matched healthy controls (3.76 + 0.93 pmol/L), nor did ET urinary excretion (ET-U/CR-U) (33.94 + 21.89 and 24.94 + 8.5 pmol/mmol/L respectively). Neither ET-PL nor ET-U/CR-U was correlated with histological and immunohistochemical data or with the clinical variables. Our study suggests a potential role of ET as a local pro-inflammatory and growth factor in renal allografts and confirms its importance in the sequence of events involved in the progression of kidney damage.

Applications of extracorporeal photochemotherapy in "non-oncological" diseases.

Photopheresis (ECP) is a new therapy for oncological and autoimmune diseases consisting in the reinfusion of 3-9 x 10(9) leukocytes, taken from the patient by leukapheresis, and treated in an extracorporeal system with 8-methoxypsoralen and ultraviolet light A. Nine patients affected by T cell immunomediated diseases (2 scleroderma, 1 chronic GVHD, 1 polyarteritis, 1 rheumatoid arthritis and 4 heart transplant patients with numerous episodes of acute rejection) were treated with ECP. Photopheresis was performed on 2 consecutive days every 3-4 weeks. All patients affected by autoimmune diseases experienced an improvement during treatment with ECP. In 2 of the 4 patients with heart transplant, rejection was reversed by photopheresis. No major side effects were observed during the treatment. In conclusion ECP is a safe and well tolerated therapy. Although the number of patients is small, ECP seems to be an effective modality in many diseases.

Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection.

UNLABELLED: Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen and ultraviolet light. The treatment seems to induce an inhibition of both humoral and cellular rejection after transplantation. OBJECTIVE: Since recurrent rejection (RR) continues to be a severe complication after heart transplantation (HTx) and the immunosuppressive regimes used for the treatment are often associated with increased morbidity and mortality, we investigated whether ECP could have a beneficial effect on the number and severity of rejection episodes. METHODS: Eleven HTX recipients (5 M and 6 F, mean age 48.5 yrs) with RR were enrolled in the study. ECP was performed at weekly intervals during the 1st month, at 2 week intervals during the 2nd and 3rd month, and then monthly for another 3 months. RESULTS: The fraction of biopsies (EMB) with a grade 0/1A rejection increased during ECP from 46% to 72% while the EMB showing a 3A/3B rejection decreased from 42% to 18%. It is also noteworthy that out of the 78 EMB performed during ECP only one showed a 3B rejection in comparison with 13 out of 110 EMB in the pre-ECP period. Six rejection relapses were observed in a total follow-up of 60 months, two of them occurring during the tapering of oral steroid. Four relapses were reversed by ECP, one by i.v. steroids and the last by methotrexate after the failure of both i.v. steroids and ECP. The mean doses of immunosuppressive drugs resulted lower after 6 months of ECP: steroids were reduced from 13 to 8.25 mg/day, cyclosporine from 375 to 285 mg/day, azathioprine from 55 to 35 mg/day. CONCLUSIONS: ECP is a well tolerated treatment. Its administration allows better RR control and significant reduction in immunosuppressive therapy.

[The application of photopheresis in the therapy of cancerous and autoimmune diseases]. / Applicazione della fotoferesi nella terapia di malattie oncologiche ed autoimmuni.

Photopheresis is an extracorporeal form of immunotherapy, recently approved by the FDA for the treatment of cutaneous T-cell lymphoma. During photopheresis lymphocytes are collected from the patients by leukapheresis and after exposure to psoralens and UVA reinfused to the host. The reinfused cells induce an immunological reaction against the neoplastic cells that seems to be clone specific. 37 CTCL patients have been initially treated; 1/4 showed a complete remission, 1/4 did not answer to the therapy and 1/2 showed a clinical improvement without complete remission. The best responders were patients in erythrodermic stage, particularly when photopheresis had been started early. The association with methotrexate induced a complete clinical remission in the cases with a partial answer to photopheresis. The average survival of patients treated with photopheresis was around 50 weeks in comparison with the Mycosis Fungoides Study Group data reporting for the same type of patients a 30 weeks survival using conventional therapies. Photopheresis has been recently used in the rejection control after heart transplantation and in the treatment of AIDS and several autoimmune diseases as pemphigus, sclerodermia, rheumatoid arthritis, LES. The preliminary therapeutic results are very encouraging for a larger use of photopheresis in the treatment of T cell mediated diseases.

[Chronic renal failure secondary to vesicoureteral reflux: is the prevention possible?]. / Insufficienza renale cronica secondaria a reflusso vescico-ureterale: è possibile la prevenzione?

Vesicoureteral reflux (VUR) is the commonest cause of end-stage renal failure reported by the ITALKID (Italian Register of Chronic Renal Failure) (CRF) in children (0-15 years). Herein we report 131 children (53 M and 78 F) with a diagnosis of VUR made in our Centre between 1987 and 1994. Diagnosis was made in 69% of cases (85/131) during the 1st year of life and in 31% of cases (47/131) afterwards. VUR was demonstrated following a prenatal ultrasonography suspicion in 24/131 and after symptoms such as urinary tract infection (94/131) and poor growth (6/131). 75/131 of patients were treated conservatively (continuous chemoprophylaxis) while 56/131 underwent an antireflux surgery. CRF was found in 14% (19/131) of cases even though the diagnosis of VUR was performed in most of the cases (79%) during the 1st year of life. In conclusion prenatal ultrasonography has a low sensibility in the diagnosis of VUR. In addition, an early diagnosis made during the 1st year of life do not prevent CRF. The study was carried out in a Centre where patients with urological problems are referred from a large part of Northern East of Italy and this may explain the high prevalence of CRF and of children receiving a surgical treatment.

[Diagnostic and therapeutic protocol in malformative uropathies prenatally diagnosed]. / Protocollo diagnostico e terapeutico delle uropatie malformative con diagnosi prenatale.

The increased frequency of prenatal detection of urinary tract abnormalities has brought to the attention of the pediatrician a high number of neonates and infants with asymptomatic hydronephrosis, which represents the most common form of uropathy. As it becomes clear that hydronephrosis does not necessarily mean obstruction, the purpose of the evaluation is to identify those infants in whom hydronephrosis will cause progressive renal deterioration, because of an ongoing restriction to urinary outflow. In the present paper, the discussion of the post-natal diagnosis and management focuses on the embryologic background, the pathophysiology of the obstruction and the rationale to utilise the different diagnostic techniques (ultrasonography, associated with the use of the Doppler; intravenous urography; avoiding cystourethrography; renal scintigraphy).

Extracorporeal photochemotherapy for the treatment of graft-versus-host disease.

Photopheresis (extracorporeal photochemotherapy, ECP) is a new type of photochemotherapy used for the treatment of oncological and autoimmune diseases. Additionally, recent reports indicate that this therapy is promising in both pediatric and adult patients who develop graft versus host disease (GVHD) resistant to conventional protocols after bone marrow transplantation (BMT). In this paper, we review 31 studies where ECP was used in the treatment of acute and chronic GVHD. A total of 76 (32% female) acute GVHD patients have been considered in 11 series. Fifty-nine patients presented with skin involvement; 47 had liver involvement, and 28 had gastrointestinal manifestations. Treatment duration ranged from 1 to 24 months. A regression of skin manifestations was observed in 83% of the patients with a complete response in 67%. A complete regression of liver and gut manifestations was reported in 38% and 54% of the patients, respectively. The overall patient survival was 53%. Of the 43 patients alive, 8 developed chronic GVHD manifestations. The immunosuppressive therapy was discontinued in 28% of cases and reduced in 46%. A total of 204 (45% female) chronic GVHD patients treated with ECP 1 to 110 months from transplantation have been considered in 20 series. One hundred twenty-eight patients presented with skin involvement, 84 with liver, 31 with lung, and 59 with oral manifestations. Treatment duration ranged from 3 to 40 months. A regression of skin manifestations was observed in 76% of patients with a complete response in 38%. An improvement of liver and lung involvement was reported in 48% and 39% of the patients, respectively. Of the 59 patients with oral manifestations, an improvement was obtained in 63% of cases. The overall patient survival was 79%. ECP is a nonaggressive treatment that may benefit patients with both acute and chronic GVHD who do not respond to standard immunosuppressive therapy.

Percutaneous ethyl alcohol intoxication in a one-month-old infant.

A one-month-old child was referred to our hospital for unexplained lethargy. She was found to be intoxicated from ethanol-soaked gauze pads which had been applied to the umbilical stump and contiguous skin for several days for the purpose of promoting umbilical cord detachment. We emphasize the importance of considering the risk of percutaneous alcohol absorption, especially in young infants, and the necessity of toxicology screening in every child with drowsiness of unknown etiology.