Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Vascular catheterization is difficult in infants with Down syndrome.

BACKGROUND: Our aim was to compare difficulties in vascular access interventions in infants with and without Down Syndrome (DS) undergoing congenital heart surgery. METHODS: The anesthesia records of infants with DS undergoing congenital heart surgery (Group DS, n=61) were reviewed and matched with records of infants without DS (Group ND, n=61). Vascular cannulation sites, the experience of the anesthesiologists performing each procedure, the number of clinicians who attempted each procedure until it was successfully performed, and the number of attempts for each catheterization were recorded. RESULTS: The rate of unsuccessful peripheral venous cannulation in any of the four extremities was higher in Group DS (P=0.026). The success rate of radial artery cannulation was lower in Group DS (P=0.048). Although the total number of attempts for arterial cannulation was higher in Group DS, the difference was not statistically significant (P=0.058). However, in Group DS, the clinician who was able to cannulate the artery successfully required a significantly higher number of attempts at cannulation (P=0.011). For central venous catheterization, cannulation site and the number of attempts required before success was achieved were similar in both groups. The specialist-to-resident ratio was higher in Group DS (P=0.037). CONCLUSION: Our results indicate a trend toward clinicians having more difficulty performing arterial and peripheral venous catheterizations in infants with DS compared with performing the same procedure in infants without DS. Anesthesiologists should be prepared for catheterization difficulties in this patient population. In infants with DS, we recommend that catheterizations be performed by more experienced physicians.

Surgery-related complications in cardiac transplantation patients.

OBJECTIVE: The surgical techniques was first described by Lower and Shumway for cardiac transplantation have not changed for many years; they are still being commonly used worldwide despite recently presented alternatives. We sought to evaluate the surgical complications among our cardiac transplantation patients in whom we performed the standard technique. PATIENTS AND METHODS: The standard biatrial anastomosis technique was used in 13 patients who have a mean follow-up of 18.6 (1 to 38) months. During the follow-up, echocardiographic assessment was performed to evaluate left and right atrial diameters, tricuspid and mitral valve regurgitation, interatrial septum, and suture lines. Elecotrocardiograms were evaluated for arryhthmia and pacemaker requirements in the midterm. RESULTS: The mean left and right atrial diameters were measured as 40.5 (32 to 57) x 66.6 (48 to 78) and 37.9 (32 to 43) x 56.3 (48 to 69) mm, respectively. The jet area was calculated at less than 5 cm(2) for mitral and tricuspid valve regurgitation, which can be defined as "mild" regurgitation. There was no increase in the degree of regurgitation of both atrioventricular valves during the follow-up period. In one patient, a thrombus was detected in the suture line; there was a nonsignificant left to right shunt in another patient. A temporary pacemaker was indicated in two patients. Atrial fibrillation was detected in three patients, who responded to medical therapy. During the follow-up atrial fibrillation developed in one patient. CONCLUSION: The cardiac transplantation operation using the standard technique may result in atrial dysfuntion due to deformation of atrial integrity and geometry. However, when we evaluated our results, we concluded that the standard surgical technique was a safe, simple, effective, and feasible method.

The midterm results of cardiac transplantation patients.

OBJECTIVE: Cardiac transplantation is an important treatment option that increases the survival and decreases the limitations in effort capacity among patients with end-stage heart disease. In this study we have presented the midterm results of 13 patients who underwent cardiac transplantation between 2003 and 2007. PATIENTS AND METHODS: There were 10 male and three female patients of mean age of 32 +/- 13.27 years (12 to 54). In one patient, we performed combined cardiac and renal transplantation. Ischemic cardiac disease was present in six patients and cardiomyopathy in seven patients. The mean age of the donors was 23.3 +/- 11.8 years (12 to 46). Corticosteroids, cyclosporine, and mycophenolate mofetil were used for immunosuppression. Sirolimus was employed in five cases due to impaired renal function. Patients were followed by echocardiography, endomyocardial biopsy, and dobutamine stress echocardiography. RESULTS: The mean follow-up was 18.6 +/- 13.4 (1 to 38) months. In four patients, there was grade IIIA (II-R) rejection. In five patients, tacrolimus or cyclosporine was replaced with sirolimus due to elevated creatinine levels. Dobutamine stress echocardiography was positive in one patient, who displayed a severe left main coronary artery lesion. There was no operative mortality. There was only one hospital mortality (7.6%). Two patients died in the midterm. The overall mortality on follow-up was 3 (23.1%). The survival rates in the first, second, and third years were 92%, 88%, and 75%, respectively. Ejection fraction were more than 50%; all of posttransplant survivors showed good effort capacity. CONCLUSION: Cardiac transplantation is a definitive, safe, and effective treatment for patients with end-stage heart failure.

Our experience in cardiac transplantation in Baskent University.

Recently cardiac transplantation has an important place in treatment of end-stage cardiac failure. In Turkey between 2003 and 2005 at 10 centers 64 cardiac transplantations were performed including five at our facility. Herein we have presented our results. All patients were men of mean age 34.2 +/- 10.7 (17 to 44) years. Upon preoperative echocardiography their mean ejection fraction was 18% +/- 3.27% (17% to 23%). Pulmonary vascular resistance was 4.47 wood unit in one patient and in one case, there was Rh incompatibility between donor and recipient. We used HTK solution for protection of donor hearts. Mean ischemia time was 251.2 +/- 62.7 minutes (155 to 314). Mean aortic clamping time was 84 +/- 4.7 minutes (80 to 90). In all patients we performed a biatrial anastomosis technique. Hemofiltration was used to prevent hemodilution during operation. In the postoperative period four patients had acute renal dysfunction; one, a minor cerebrovascular accident; two, reoperated because of bleeding; one, cholestasis; one, temporary atrio-ventricular block; and one, mediastinitis. Mean follow-up time was 15.6 +/- 19.7 months (2 to 50). Neither early nor late mortality has occurred. All patients are in New York Heart Association class I. In all cases we used triple immunosuppressive therapy. In the follow-up period the mean number of cardiac biopsies per patient was 4.2 +/- 3.03 (2 to 8). Two cases had cardiac catheterization. As a complication of cardiac biopsy, pericardial tamponade developed in one patient; in another one we observed a right ventricular aneursym after cardiac biopsy. Cardiac transplantation was performed with low mortality and morbidity rates in end-stage cardiac failure patients with longer life expectancy and higher life quality. Unfortunately in our country, because of difficulties to find donor hearts, cardiac transplantations were small in number. For better results, we need a larger series.

Pulse contour cardiac output system use in pediatric orthotopic liver transplantation: preliminary report of nine patients.

Anesthetic management of orthotopic liver transplantation (OLT) in pediatric patients is challenging in terms of intraoperative bleeding, fluid management, and hemodynamic monitoring. The pulse contour cardiac output (PiCCO) system, a relatively new device based on the single-indicator transaortic thermodilution technique, may be useful for intraoperative hemodynamic monitoring in pediatric patients. This is a preliminary report of PiCCO use in nine children (aged 9.8 +/- 4.7 years) undergoing OLT. Hemodynamic volumetric parameters monitored by the PiCCO system were mean arterial pressure (MAP), cardiac index (CI), intrathoracic blood volume index (ITBVI), extravascular lung water index (EVLWI), systemic vascular resistance index (SVRI), and stroke volume variability (SVV). All parameters were recorded at anesthesia induction (T0), at the end of the anhepatic phase (Tanhepatic), and at the end of operation (Tend). The PiCCO system revealed similar MAP, CI, EVLWI, SVV, and SVRI values at all measurement intervals. Despite similar central venous pressure measurements, ITBVI values indicated significantly lower values at Tanhepatic than at T0 (627 +/- 160 mL/m2 and 751 +/- 151 mL/m2, respectively, P = .013). There were no PiCCO catheter-related complications in any patient. These findings demonstrate that the PiCCO system is a safe, continuous, multiparameter invasive monitoring device for use in pediatric patients undergoing OLT. This system may provide valuable data during pediatric OLT and appears to be a promising monitoring tool in these patients.

Topical ciclosporin in the treatment of ocular surface disorders.

Mounting evidence suggests that inflammation is the key factor in the pathogenesis of various ocular surface diseases, with a complex interplay of genetic, environmental, and psychosocial factors. Management of these conditions is often challenging. Topical corticosteroids, with their associated side effects, are the mainstay of current treatments for patients with vision threatening disease. Ciclosporin A is an immunomodulator that specifically inhibits T lymphocyte proliferation. Recently, a topical ciclosporin preparation was approved by the US Food and Drug Administration and became available for use in ophthalmology. Given the increasing use of ciclosporin eye drops, the goal of this article is to provide the reader with an overview of the well established uses of ciclosporin and to help refine the questions that should be addressed by future investigations.

The effect of anesthetic technique on early postoperative renal function after donor nephrectomy: a preliminary report.

General and regional anesthesia may both be used successfully in donor nephrectomy although the use of regional anesthesia is rare. We compared the remaining kidney function during general (n = 10) versus combined spinal-epidural (n = 10) anesthesia for donor surgery. Blood biochemistry data were collected preoperatively and postoperatively, while renal function was assessed by scintigraphy and urine levels of microalbumin, creatinine, Na, K, Ca and creatinine clearance rate were measured/calculated in 24-hour urine samples collected preoperatively and on postoperative day 2. There were no differences preoperatively and on postoperative day 2 with respect to glomerular filtration rate, microalbuminuria, or creatinine clearance rate (P > .05 for all). There were also no differences between the groups with respect to other scintigraphic findings preoperatively and on postoperative day 2 (P > .05 for all). The results suggest that general or combined spinal-epidural anesthesia for donor nephrectomy have similar effects on the remaining donor kidney function.

Regional versus general anesthesia for donor nephrectomy: effects on graft function.

Various general and regional anesthesia methods are used successfully in living-donor kidney transplantation. This study compared kidney graft function after general versus combined spinal-epidural anesthesia for donor nephrectomy. The study groups included recipients who received grafts from donors who had undergone nephrectomy under general anesthesia (GA group; n=10), and recipients who received grafts from donors who had combined spinal-epidural anesthesia (CSE group, n=10). Standard continuous epidural anesthesia was administered during all transplantations. Graft function was assessed using scintigraphy and Doppler ultrasonography on days 3 and 7. Urine levels of microalbumin, creatinine, and creatinine clearance rate were measured/calculated in 24-hour urine samples collected on postoperative days 3 and 7. There were no differences on either day 3 or day 7 with respect to glomerular filtration rate, microalbuminuria, or creatinine clearance rate (P >.05 for all). There were also no differences between the groups with respect to other scintigraphic findings on day 3 or day 7 (P >.05 for all). Ultrasonography on day 7 showed significantly higher mean peak systolic flow in the main renal artery in the CSE group than in the GA group (P=.035). The results suggest that GA and CSE for donor nephrectomy have similar effects on kidney graft function in recipients.

Immune defense at the ocular surface.

The ocular surface is constantly exposed to a wide array of microorganisms. The ability of the outer ocular system to recognize pathogens as foreign and eliminate them is critical to retain corneal transparency, hence preservation of sight. Therefore, a combination of mechanical, anatomical, and immunological defense mechanisms has evolved to protect the outer eye. These host defense mechanisms are classified as either a native, nonspecific defense or a specifically acquired immunological defense requiring previous exposure to an antigen and the development of specific immunity. Sight-threatening immunopathology with autologous cell damage also can take place after these reactions. This article discusses the innate and acquired corneal elements of the immune defense at the ocular surface. The relative roles of the various factors contributing to prevention of eye infection remain to be fully defined.

Clinical and ultrastructural features of a novel hereditary anterior segment dysgenesis.

OBJECTIVE: To describe the clinical, histopathologic, and hereditary features of a novel familial anterior segment dysgenesis. DESIGN: Prospective, observational case series and interventional case report. PARTICIPANTS: Ten individuals from three generations of a single family with iris and corneal abnormalities associated with congenital cataracts. MAIN OUTCOME MEASURES: An ophthalmic evaluation including slit-lamp examination, corneal topography, pachymetry, and specular biomicroscopy of all family members, and histopathologic and ultrastructural evaluation of one excised corneal button. RESULTS: The proband was an 81-year-old man with bilateral aphakia and diffuse corneal haze, and thinning associated with corneal guttae. His pupils were small, mildly eccentric, and difficult to dilate. Pachymeter readings were 335 microm (right eye) and 330 microm (left eye). Topography confirmed advanced steepening of both corneas. Light microscopic and transmission electron microscopic examinations of the corneal button revealed an attenuated endothelium with prominent intracellular random aggregates of small-diameter filaments staining positively for cytokeratin. Descemet's membrane was thickened and had marked posterior nodularity. Various-sized polymorphic vacuoles containing layered electron-dense material were present within and between collagen lamellae and within keratocytes throughout the stroma and Bowman's membrane. Secondary bullous changes of the epithelium with thickening of the basement membrane were also observed. The family pedigree demonstrated an autosomal dominant inheritance pattern. CONCLUSIONS: This constellation of autosomal dominantly inherited corneal endothelial and stromal disorder, with congenital cataracts and iris abnormalities, represents a novel anterior segment disorder. Its etiology may involve an abnormal migration of the secondary mesenchyme.

Spontaneous corneal perforation in a patient with unusual unilateral pellucid marginal degeneration.

A 56-year-old man presented with acute loss of vision and tearing in his left eye. Slitlamp examination demonstrated peripheral corneal edema extending between the 2 and 6 o'clock positions as well as a perforation located inferiorly. The right eye was unremarkable. An emergent crescentic lamellar keratoplasty was performed. The patch graft remained clear during the 30-month follow-up, and visual acuity improved significantly. No changes occurred in the right eye. This case represents an unusual, unilateral corneal ectatic disorder, most likely pellucid marginal degeneration.

Long-term immunosuppressive treatment of serpiginous choroiditis.

OBJECTIVE: To determine the efficacy of immunosuppressive treatment in serpiginous choroiditis. DESIGN: The clinical courses were reviewed of six consecutive patients (12 eyes) with vision-threatening, steroid-dependent/resistant serpiginous choroiditis treated with a combination of immunosuppressive agents including azathioprine, cyclosporine, and cyclophosphamide. All patients underwent treatment for at least 12 months. RESULTS: The follow-up period ranged from 17 to 105 months (mean 57, median 43). All patients were able to taper oral steroids. Five patients discontinued all immunosuppressive medications after a treatment period of 12 to 69 months (mean 39 months). Immunosuppressive treatment was continued in one patient at a "low" maintenance dose. Ten eyes had improved visual acuities, while vision remained impaired in two due to macular scars. Recurrence was noted in two patients when an attempt was made to decrease the dose of immunosuppressive medication. Two patients experienced side effects which were reversed by decreasing the dose of the medications. CONCLUSION: Long-term immunosuppressive treatment appears to prolong remission and preserve vision in patients with serpiginous choroiditis.

Induction of experimental autoimmune keratitis by adoptive transfer of human corneal antigen-specific T-cell line.

PURPOSE: To establish a permanent human corneal antigen (HuCOAg)-specific T-cell line and to determine whether line cells are capable of inducing inflammatory keratitis by adoptive transfer. METHODS: Lymphoid cells harvested from HuCOAg-immunized Lewis rats were expanded to a permanent T-cell line by repetitive cycles of restimulation with HuCOAg and irradiated antigen-presenting cells and propagation in interleukin 2-containing medium. The phenotype and epitope specificity of the line cells were determined. Adoptive transfer was performed after seven cycles by intraperitoneal injection of activated T cells into irradiated recipient rats. RESULTS: A panel of 11 overlapping synthetic HuCOAg peptides to identify T-cell epitopes recognized by the line cells was used. The cells responded selectively to a synthetic peptide containing an immunodominant epitope of HuCOAg (peptides 69-83). Line cells bore the surface phenotype of the T-helper/inducer marker (W 3/25(+) or CD4(+)). Intraperitoneal inoculation of naive rats with 5 x 10(7) activated line cells led to maximal clinical signs of stromal keratitis 7 to 9 days after transfer, characterized by corneal haze, conjunctival and episcleral injection, corneal infiltrates, and neovascularization. Histopathologic examination of the tissues revealed numerous lymphocytes and macrophages and some polymorphonuclear leukocytes along with neovascularization. The pathologic lesions were confined to the peripheral corneal stroma. Immunohistochemical studies demonstrated that the overwhelming majority of the inflammatory cells were CD4(+) T lymphocytes and macrophages; an upregulation of major histocompatibility complex class II antigen expression was also noted. CONCLUSIONS: A long-term, rat T-cell line of CD4(+) phenotype specific for HuCOAg that can induce autoimmune keratitis by adoptive transfer of the line cells to naive syngeneic recipients is described. With the development of this cell line, the mechanisms by which T cells exert their immunopathologic effects in experimental autoimmune keratitis models can be studied.

Peripheral ulcerative keratitis after clear corneal cataract extraction(1).

A previously healthy 80-year-old man had uneventful clear corneal cataract extraction. An extensive peripheral corneal infiltrate with overlying epithelial defect at the incision site was noted at the regular follow-up visit 1 week after surgery. Corneal cultures showed no evidence of infectious keratitis. A systemic evaluation uncovered early-stage, active rheumatoid arthritis. This case illustrates that peripheral ulcerative keratitis may occur with a small clear corneal incision and may be the presenting sign of a previously undiagnosed rheumatoid disease.

Herpes zoster sine herpete presenting with hyphema.

PURPOSE: To report a case of herpes zoster sine herpete presenting with hyphema. METHODS: A 69-year-old man was referred for traumatic hyphema and corneal edema in his left eye after a sandblast exposure three weeks previously. Slit-lamp examination demonstrated hyphema, anterior chamber inflammation, mid-dilated pupil, impaired corneal sensation, and high intraocular pressure, without any facial skin lesions. Iris fluorescein angiography revealed tortuosity and extensive occlusion of iris vessels. The patient was treated with oral acyclovir and intensive topical steroids with a presumed diagnosis of severe herpes zoster uveitis. RESULTS: Clinical findings improved dramatically within several days. Typical sectorial iris atrophy with pupillary sphincter dysfunction and complete loss of corneal sensation developed after the resolution of intraocular inflammation. CONCLUSION: Herpes zoster should be considered in patients with uveitis and hyphema even in the absence of typical skin rash.