Eric Lowell Singman, M.D., Ph.D.

• Chief, Patient Access Center for the Eye
• Associate Professor of Ophthalmology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/3740277/eric-singman

Impact of intense asthma treatment guidelines medscape purchase advair diskus online now, longitudinal retreatment with praziquantel on cure rates of schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya asthma treatment without inhaler order advair diskus with visa. Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of Schistosoma mansoni asthma treatment dulera proven advair diskus 250 mcg. Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment asthma symptoms in 12 year old order advair diskus online pills. Genetic analysis of decreased praziquantel sensitivity in a laboratory strain of Schistosoma mansoni asthma definition gina 2014 cheap generic advair diskus uk. In vitro responses of praziquantel-resistant and -susceptible Schistosoma mansoni to praziquantel asthma uncommon symptoms purchase advair diskus cheap online. In vitro praziquantel test capable of detecting reduced in vivo efficacy in Schistosoma mansoni human infections. Regular treatments of praziquantel do not impact the genetic make-up of Schistosoma mansoni in northern Senegal. Furthermore, patients needing antihypertensive treatment in addition to dialysis often require combinations of antihypertensive drugs. Significant drug interactions between these antihypertensive drugs and volatile and intravenous anesthetic agents can be expected, especially during induction of general anesthesia. Oral agents should not be taken on the day of surgery because of the potential for unrecognized hypoglycemia under anesthesia. Insulindependent patients who are extremely brittle and have declining insulin levels are at risk for the development of ketosis and intraoperative acidemia. Coagulation status, as reflected by the prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, and platelet count, is routinely assessed before surgery. A helpful preoperative screen to predict bleeding is a carefully conducted history that includes family, dental, obstetric, surgical, transfusion, and drug histories. The bleeding time is not a useful screening test to predict intraoperative bleeding. This anxiety may be suitably attenuated with an orally administered benzodiazepine. Intramuscular premedication is avoided because uremic patients tend to have bleeding disorders secondary to poor platelet function. Rapid-sequence induction should be considered, especially in patients with diabetes. Phenothiazine antiemetics and metoclopramide should be administered with care because they may cause prolonged sedation and extrapyramidal side effects in patients with renal failure. Anesthetic depth and pharmacologic interventions need to be tailored to two different biological systems (the transplant recipient and the allograft) that require individual attention and may not always align when it comes to treatment options. For example, maintainance of adequate anesthetic depth to avoid intraoperative awareness may also reduce blood pressure and perfusion pressure to the newly reperfused graft. Aggressive fluid loading in order to optimize graft perfusion may be problematic in patients with a low ejection fraction and a history of congestive heart failure. Use of pulmonary artery catheter or transesophageal echocardiography is very rarely indicated. Nevertheless, there is no consensus on appropriate intraoperative monitoring, and most protocols are based on institutional preference and experience. Significant acute changes in blood pressure may occur throughout the surgical procedure, with hypotension (49. Hypertension is particularly seen during the induction phase, endotracheal intubation, emergence, and in the postoperative care unit. Patients with longstanding pre-existing hypertension that is not well controlled are at increased risk for large fluctuations in arterial blood pressure and heart rate. Several methods have been used to achieve adequate heart rate and blood pressure control during the critical periods of induction and endotracheal intubation. These include the use of moderate to large doses of opioids, such as fentanyl, that may blunt (but not reliably) the response to laryngoscopy. However, using moderate to large doses of opioids frequently results in difficulty maintaining adequate blood pressure without the use of vasoconstrictors after induction, especially since there is little surgical stimulation once the fascia is dissected. The short-acting opioid remifentanil, which is metabolized in the plasma, has been an effective drug for good heart rate control. Furthermore, the rate of remifentanil administration can be titrated to adjust anesthetic depth rapidly (Table 13-1). In patients with longstanding severe hypertension, esmolol often needs be administered at doses larger than 1 mg/ kg and is best given in increments. Other hypnotics such as thiopenthal and etomidate have also been succesfully used (Table 13-1). Several studies have demonstrated that the induction dose of propofol needed to achieve clinical hypnosis and reduction of the bispectral index to 50 was 40Ͷ0% higher in patients with end-stage kidney disease compared to normal patients. The authors found a negative correlation between intraoperative propofol dose and preoperative hemoglobin levels. Study limitations and failure to identify an exact mechanism for this correlation do not support the use of a larger bolus induction dose in patients with end-stage kidney disease. Indeed, a larger induction dose is strongly discouraged in these patients, particularly when considering that they are dialyzed immediately prior to surgery and are possibly centrally volume-depleted. Atracurium/cisatracurium or rocuronium/vecuronium is used most commonly97 to achieve muscle relaxation for endotracheal intubation and surgical relaxation. Atracurium and cisatracurium are metabolized by spontaneous Hofmann degradation and plasma cholinesterase. Therefore, their duration of action is independent of either liver or kidney function. Most commonly, an inhaled technique is used with desflurane, isoflurane, or sevoflurane. T1/2el, elimination half-life (min); Clp, systemic clearance (mL/kg/min); Vss, apparent volume of distribution at steady state (L/kg). Note: Mean values are given throughout except for oxycodone, for which medians are given. The metabolism of sevoflurane has been implicated in renal toxicity, but no controlled studies are available to identify clearly either safety concerns or harm associated with using sevoflurane in the setting of a newly transplanted kidney. There are two elements of concern with regard to renal toxicity: (1) production of fluoride ion from the metabolism of sevoflurane; and (2) generation of "compound A" from the breakdown of sevoflurane by sodium or barium hydroxide lime. It has been administered to millions of patients worldwide without conclusive evidence of renal toxicity. Two volunteer studies have found biochemical evidence of renal injury during sevoflurane anesthesia, whereas five other volunteer studies have not. As a result, hypotension is frequently encountered, especially after the fascia is dissected, and may be further aggravated after unclamping of the iliac vessels and reperfusion of the graft. Individualized 198 Kidney transPlantation: PrinCiPles and PraCtiCe fluid management is the cornerstone of intraoperative management while pharmacologic support using vasoconstrictors with strong alpha-adrenergic effects, such as phenylephrine, is discouraged for reasons that will be subsequently discussed. Indeed, a national survey of fluid choice at 49 hospitals in the United States found that >90% of patients receive normal saline or normal saline-based solutions during their kidney tranplants. Interestingly, the study demonstrated higher rates of severe hyperkalemia and metabolic acidosis in the normal saline group,85 albeit the fluid administration in this study would have been considered excessive by most centers. Plasmalyte was not associated with any changes in acid΢ase balance and electrolyes. Primary end-points were markers of allograft function within 5 postoperative days. However, several confounding factors in the study design warrant larger and bettercontrolled prospective studies. Pharmacologic blood pressure support using alphaagonist vasoconstrictors is usually discouraged based on some limited experimental animal data. Taken together, studies indicate that there is a substantial loss of renal hemodynamic responsiveness following ischemic injury when renal blood flow is attempted to be preserved using alpha-agonists. Furthermore, the studies suggest that the transplanted, denervated kidney loses its capacity for autoregulation and that the renal response to sympathomimetics is altered with a shift towards time-dependent flow reduction to the kidney. In one rat study, the hemodynamic autoregulation in the kidney graft declined following transplantation or denervation. Furthermore, the response to sympathomimetics in the transplanted kidney was shifted towards flow reduction. The authors postulated enhanced vasoconstriction via stimulation of alpha-adrenoceptors and blunted vasodilatation via stimulation of beta-adrenoceptors as a possible mechanism. Mannitol is freely filtered and not reabsorbed by the nephron, causing osmotic expansion of urine volume. It is usually administered during the warm ischemia phase; thus mannitol may protect against ischemic injury, as well as induce osmotic diuresis in the newly transplanted kidney. In most centers, relatively low doses of mannitol are administered, ranging between 0. Some data have shown that delayed graft function of the deceased donor renal allograft can be prevented by intraoperative administration of mannitol. The high-osmolarity fluid that is carried along to the distal tubule prevents the reabsorption of water, resulting in the excretion of large volumes of urine with high electrolyte content (Tables 13-3 and 13-4). Doppler ultrasound examination of newly transplanted kidneys found no significant change in blood flow with dopamine infusion rates of 1͵ g/kg/min. In contrast, opioids such as fentanyl, sufentanil, alfentanil, and remifentanil have been shown to be safe alternatives, with fentanyl being the most commonly used opioid (Table 13-3). This is mainly due to persistent risk factors such as hypertension, diabetes, and dyslipidemia as well as new onset of metabolic syndrome and secondary hyperparathyroidism. Indeed, one study found considerable progression of coronary artery calcification in renal transplant patients at least 1 year after surgery. Findings were related to ethnicity of patients, blood pressure, body mass index, renal function, and baseline coronary artery calcification. Particular attention should be paid to graft function, which is mainly evaluated by urine output over time. Over 90% of living donor kidney transplant recipients have immediate graft function, as confirmed by urine production. However the rate of immediate graft function can drop off significantly in recipients of kidney grafts from standard criteria deceased donors and especially extended criteria donors. Poor graft function may be attributable to the graft itself, the vessels, the ureter, or clotting of the Foley catheter, all of which should be considered in the differential diagnosis. The Foley catheter should be irrigated to ensure that clot or tissue has not affected its patency. Lastly, re-exploration of the wound should not be delayed if kinking of the vascular attachments or obstruction of the ureter along its course or at the site of bladder reimplantation is suspected. They will probably be maintained on some form of dialysis to manage fluid overload and accumulation of electrolytes. They may well have significant systemic hypertension for the reasons discussed in the section on cardiovascular complications, above. Accelerated atherosclerosis and autonomic nervous system dysfunction are also major cardiovascular changes present in diabetic patients. Finally, they may also have the same problems of chronic anemia and uremic coagulopathy as those with renal failure alone. Orally administered antiglycemic agents should not be taken on the day of surgery to avoid unrecognized hypoglycemia under anesthesia. Insulin-dependent patients who are extremely brittle and have declining insulin levels are at risk for ketosis and intraoperative acidemia. As noted earlier, diabetic patients, even those without renal dysfunction, have significant risk factors for cardiovascular complications during major surgery. Historically, the principal candidates for pancreas transplantation have been younger than those receiving kidney transplants, with up to 45% being in the 18ͳ5-year age range. More recently, however, increasing numbers of older diabetic patients are being considered for pancreas transplantation. These patients will be at higher risk for major cardiovascular events perioperatively. It was suggested in the early 1990s that diabetic patients should be considered more difficult to intubate tracheally because of changes in their upper-airway tissues from exposure to high serum glucose levels. In fact, one study found a 31% incidence of difficult intubation conditions in this patient population. Intraoperative Considerations Kidneyΰancreas transplantations are long and surgically tedious operations involving extensive abdominal exposure. Therefore, general endotracheal anesthesia with muscle relaxation is the best anesthetic approach for these cases. Patients may have significant postoperative pain from the extensive abdominal dissection, so placement of an epidural catheter for postoperative pain control may be warranted. However, splanchnic perfusion to the transplanted organs is a major concern, and therefore some centers defer placement of an epidural catheter. Because the pancreas seems to be a highly immunogenic organ, intensive immunosuppression is needed to prevent graft loss. The anesthesia team will need to deliver the initial dose of immunosuppressant so it is essential that the desired drugs be present and administered correctly in the operating room. Likewise, correct administration of the preoperative and intraoperative antibiotics requested by the surgical team is very important. Prophylaxis against enteric organisms introduced with transplanted bowel segments is crucial given the use of intense immunosuppression. The arterial line allows the anesthesia team to track blood pressure carefully and to draw samples for blood gas, glucose, and electrolyte determinations during these lengthy cases. The central venous catheter permits monitoring of cardiac filling pressure and central administration of drugs. Due to their high incidence of autonomic dysfunction, diabetic patients are likely to have gastroparesis and large residual gastric volumes.

Monoclonal antibodies in 1991: new potential options in clinical immunosuppressive therapy asthma machine buy advair diskus 500mcg on line. Randomized trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients asthma definition value purchase 500 mcg advair diskus visa. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebocontrolled trial cardiac asthma definition buy advair diskus 500mcg otc. Multicenter asthmatic bronchitis journal article cost of advair diskus, randomized study of the effectiveness of basiliximab in avoiding addition of steroids to cyclosporine a monotherapy in renal transplant recipients asthma symptoms chart purchase advair diskus with mastercard. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion asthmatic bronchitis japan generic advair diskus 500 mcg amex. The use of antibody to complement protein C5 for salvage treatment of severe antibodymediated rejection. Eculizumab, bortezomib and kidney paired donation facilitate transplantation of a highly sensitized patient without vascular access. The effect of anti-L3T4 monoclonal antibody treatment on first set rejection of murine cardiac allografts. The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Orthotopic liver transplantation, Epstein΂arr virus, cyclosporine, and lymphoproliferative disease: a growing concern. Antilymphocyte induction immunosuppression in the post-Minnesota antilymphocyte globulin era: incidence of renal dysfunction and delayed graft function: a single center experience. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy. Association of antibody induction with short- and long-term cause-specific mortality in renal transplant recipients. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression. Sequential protocols using basiliximab versus antithymocyte globulins in renaltransplant patients receiving mycophenolate mofetil and steroids. Persistent long-term changes in lymphocyte subsets induced by polyclonal antibodies. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular 208. A randomized, placebo-controlled trial of natalizumab for relapsing forms of multiple sclerosis. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Serum anti-rabbit and anti-horse IgG, IgA, and IgM in kidney transplant recipients. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Administration of equine anti-thymocyte globulin via peripheral vein in renal transplant recipients. A comprehensive definition of the major antibody specificities in polyclonal rabbit antithymocyte globulin. Total and active thymoglobulin levels: effects of dose and sensitization on serum concentrations. Use of intravenous immune globulin and rituximab for desensitization of highly human leukocyte antigen-sensitized patients awaiting kidney transplantation. Antithymocyte globulin for steroid resistant rejection in renal transplant recipients immunosuppressed with triple therapy. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. A pilot protocol of a calcineurin-inhibitor free regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoidfree immunosuppressive regimen. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath. Teplizumab for treatment of type 1 diabetes (Protꨩ study): 1-year results from a randomised, placebo-controlled trial. Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy. Effect of anti-lymphocyte induction therapy on renal allograft survival: a meta-analysis. The effect of antilymphocyte induction therapy on renal allograft survival: a meta-analysis of individual patient-level data. Living donor renal transplantation using alemtuzumab induction and tacrolimus monotherapy. Rapid serologic diagnosis of serum sickness from antilymphocyte globulin therapy using enzyme immunoassay. Superior renal allograft survival and decreased rejection with early high-dose and sequential multi-species antilymphocyte globulin therapy. The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal. Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation. Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy. Preliminary experience with alemtuzumab (Campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3. Low-dose maintenance prednisone and antilymphoblast globulin for the treatment of acute rejection. Management of patients with posttransplant lymphoproliferative disorder: the role of rituximab. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. A phase I trial of humanized anti-interleukin-2 receptor antibody in renal transplantation. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Biologic therapy for psoriasis: an update on the tumor necrosis factor inhibitors infliximab, etanercept, and adalimumab, and the T-cell-targeted therapies efalizumab and alefacept. Peripheral administration of thymoglobulin for induction therapy in pancreas transplantation. Of mice and men: terminal complement inhibition with anti-C5 monoclonal antibodies. Prophylactic eculizumab after renal transplantation in atypical hemolyticuremic syndrome. However, it is important to distinguish that the specificity of a response does not dictate its character; a T cell can "respond" in many ways, including evoking antigen-specific cytotoxicity, anergy, or regulation. Thus, the character of a response is shaped largely through contemporaneous binding of additional molecules to include T-cell costimulatory receptors. The paradigm of a two-signal requirement for T-cell activation is based on the necessity for immune selfdiscrimination. As such, secondary signals whose expression is regulated as part of the "danger" signal to pathogens, as termed by Matzinger,28 is necessary for driving T-cell responses directed against foreign antigens. Conversely, costimulatory signals are not only required for effective T-cell activation but their absence of inhibitory signaling is also essential for curtailing an 314 immune response and likely for generation of tolerance. The costimulatory signal is not a simple binary on/off switch but rather induces a network of signals that influences the quantitative and qualitative nature of the ensuing T-cell response. Under certain conditions, these signals also lead to the development of regulatory T-cell subsets that actively suppress the immune response. The more we understand costimulatory pathways and their fine control over adaptive immune responses, the more attractive they have become as therapeutic targets. They simply provide a "chemical blindfold" which, once removed, results in resumed graft rejection. Thus, in an elegant display of efficiency, the costimulatory pathways that initiate an immune response reflexively curtail the response as well, and in doing so, minimize the risk of unregulated or pathological immune injury. While their description is beyond the scope of this chapter, their biology has been reviewed by Sayegh et al. Cytokine and chemokine receptors form the basis for signal 3, and once specificity and character are established by signals 1 and 2, the magnitude and dispersion of their influence is defined by alterations in cytokine and chemokine receptors. In all, immune responses should be seen as nuanced controlled processes rather than binary responses used solely for cytotoxic effector functions. In the laboratory, the primary means of testing costimulatory blockers has been to measure their effectiveness in inhibiting T-cell function, preventing graft rejection and inducing durable graft tolerance. Belatacept-based therapy also generated a trend towards improved cardiovascular and metabolic profiles. The majority of the acute rejection episodes occurred early (within the first 3 months), showed no sign of recurrence, and resolved with treatment. There were also no cases of acute rejection from year 2 to year 3 in the belatacept groups, confirming that those episodes tended to occur in the immediate time period after transplantation and were subsequently unlikely to recur. At 12 months and 3 years belatacept-based immunosuppressive regimens resulted in comparable rates of acute rejection and patient and graft survival, as compared to the cyclosporine-based regimen. Additionally, belatacept use leads to better renal function and improved cardiovascular and metabolic profiles. Kidney transplantation using alemtuzumab induction and belatacept/sirolimus maintenance therapy. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Its use outside controlled trials is only now beginning, and its efficacy in generalized practice remains to be described. The theoretical benefits of modulating immune responses through signal 2 blockade are clear: preservation of antigen specificity, potential for sustained effect, and elimination of off-target side effects. However, the limited requirement for costimulation in established immune responses likely will conscribe the use of belatacept somewhat, placing a demand upon the clinician to find the ideal adjuvant therapies for use with belatacept and to identify the patient population most likely to benefit from this approach. The coming years will help shape the optimal use of belatacept in particular, and pave the way for costimulation-based approaches in general. Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Absence of host B7 expression is sufficient for long-term murine vascularized heart allograft survival. T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. The role of novel T cell costimulatory pathways in autoimmunity and transplantation. The drug enters the enterohepatic recirculation and is excreted by the intestinal and urinary systems in equal proportions. Leflunomide is insoluble in water and is suspended in 1% carboxymethylcellulose for oral administration. Mechanism of Action Leflunomide and its analogues have strong antiproliferative effects on both T lymphocytes and B lymphocytes, thus limiting the formation of antibodies. The in vivo mechanism of action of leflunomide may depend on factors such as drug levels, disposable uridine pools, and the immune activation pathway involved. Phosphorylation of the epidermal growth factor receptor of human fibroblasts has been shown to be inhibited by leflunomide. Two clinical studies reported that leflunomide was capable of stabilizing allograft function in patients with worsening allograft function due to chronic allograft dysfunction. Toxicity Although rats tolerate leflunomide well, dogs readily develop anemia and gastrointestinal ulcerations. Reportedly, the most frequent side effects in arthritis patients receiving long-term leflunomide treatment were diarrhea (17%), nausea (10%), alopecia (8%), and rash (10%), leading to a dropout rate of ѵ%. Combination with warfarin potentially increases the international normalized ratio. The volume of distribution is largely superior to the blood volume, indicating a widespread tissue penetration.

The introduction of the microemulsion formulations enhanced bioavailability and reduced variability in serum drug levels asthma symptoms from cold air cheap advair diskus 500 mcg amex. Therapeutic monitoring of cyclosporine in children commonly utilizes trough measurements as correlation of C2 levels with drug efficacy or toxicity is not well established in children or well accepted by patients and families due to the requirement of multiple asthmatic bronchitis or pneumonia buy advair diskus 500mcg mastercard, painful blood draws asthma uri advair diskus 250 mcg online. Tacrolimus therapy is typically initiated in the first few days posttransplant once serum creatinine falls by 50% of pretransplant level zyrtec asthma symptoms purchase generic advair diskus on line. However asthma symptoms pictures order advair diskus online, abbreviated sampling for area under the concentrationδime curve can be helpful in cases where low or appropriate trough levels accompany signs of toxicity asthma definition for dummies buy generic advair diskus 500mcg on line. Diarrhea, a common problem in children, can dramatically increase tacrolimus serum levels. Therefore, tacrolimus drug levels should be monitored closely during diarrheal illness (and dosage adjusted accordingly) to avoid toxicity, and rechecked as diarrhea improves to ensure continued therapeutic levels. The most common side effects seen in children treated with long-term tacrolimus therapy include impaired glucose tolerance, posttransplant diabetes, tremor, alopecia, and mild sleep disturbances. In contrast to cyclosporine, tacrolimus rarely causes the cosmetic side effects mentioned earlier. As mentioned earlier, the Pittsburgh group has reported excellent graft survival and function in 42 consecutive pediatric kidney transplant recipients over 4 years with alemtuzumab induction (or Thymoglobulin) and lowdose tacrolimus monotherapy. A shorter drug half-life for sirolimus in children, especially prepubertal children, dictates twice-daily dosing, in contrast to once-daily dosing described in adults. Furthermore, the optimal target trough level has yet to be fully defined in children. The most common side effects reported for sirolimus in pediatric patients include recurrent aphthous ulcers, impaired wound healing, and proteinuria. Adverse effects, especially aphthous ulcers, are reportedly more significant at higher trough levels (>9 ng/mL). While there was no increase in the rate of acute rejection or graft loss following conversion to sirolimus, there was a trend of increased adverse effects, including infection and nephrotic-range proteinuria. Actuarial 5-year graft survival was 91% for those patients who remained on sirolimus (78% of the patients undergoing conversion). The antiproliferative and antiangiogenic actions of sirolimus have the potential to alter growth plate function and thereby impair linear growth in children. However, retrospective investigations of the effect of sirolimus therapy on linear growth in pediatric kidney transplant recipients have resulted in conflicting conclusions. Pharmacokinetics are reported to vary based on age, with young children requiring higher doses to achieve comparable mycophenolic acid area under the curve. Renal biopsy is the gold standard to diagnose rejection and is well tolerated by children using sedation. Diagnosis of rejection based on biopsy has become standard of care in children (so-called biopsy-proven rejection). Intravenous crystalloid is also administered to eliminate prerenal azotemia as a possible etiological or confounding factor in raising the serum creatinine level. The role of protocol biopsy in pediatric kidney transplant is not well established. However, not all pediatric centers perform regularly scheduled surveillance biopsies. Historically, nearly half of pediatric kidney transplant recipients experienced acute rejection within the first 12 months following transplant. As with adults, late episodes of acute rejection and multiple episodes of acute rejection are associated with worse long-term allograft survival. Treatment of Acute Rejection There are few controlled trials in children to guide the treatment of acute allograft rejection. As with adults, high-dose corticosteroids are the first-line treatment in children with suspected or biopsy-proven acute rejection. Intravenous methylprednisolone succinate is typically administered at 10ͳ0 mg/kg/dose for 3͵ consecutive doses. A taper of oral corticosteroids back down to maintenance doses over 3͵ days is used by some, but not all, pediatric transplant centers. It is not uncommon for the serum creatinine to increase slightly during the first few days of steroid pulse. In addition, serum creatinine may not return to baseline levels for several days following completion of the pulse, but typically a trend of decreasing creatinine is suggestive of a response to therapy. Severe Rejection Severe rejection or steroid-resistant rejection has historically been treated with lymphocyte-depleting antibodies. Alemtuzumab has also been reported to be effective in some cases of refractory cellular rejection. B cells are postulated to contribute to cellular rejection via antigen presentation, activation of dendritic cells, and by providing co-stimulatory help to T cells. B-cell transcript signatures275 and dense B-cell infiltrates in biopsies of pediatric kidney transplant recipients have been associated with poor graft survival311 and are predictive of graft loss. Small children who have adult-sized allografts have a large renal reserve relative to their muscle mass. Therefore, a small increase in serum creatinine can represent significant renal dysfunction. Children with acute rejection can present with low-grade fever and mild hypertension, but can also be asymptomatic. Successful use of the proteasome inhibitor, bortezomib (Velcade, Millennium Pharmaceuticals), for treatment of antibody-mediated rejection has been reported for adult kidney transplant59 and pediatric heart214 and multivisceral146 transplant recipients. Therefore, the long-term management of these patients is focused on maintaining good quality of life and minimizing significant long-term side effects of immunosuppression. Outpatient management of pediatric kidney transplant recipients includes identifying and reducing the cardiovascular and metabolic effects of long-term immunosuppressive therapy, preventing infection and chronic rejection, ensuring good long-term quality of life, and managing a smooth transition into adulthood. In addition to the concerns for long-term cardiovascular risk associated with uncontrolled hypertension, a retrospective analysis of pediatric kidney transplant recipients in Cincinnati has also suggested that systolic hypertension independently predicts poor long-term allograft survival. Furthermore, a recent cross-sectional study reported masked hypertension and nocturnal hypertension in a significant portion of pediatric kidney transplant recipients with stable graft function, suggesting the use of ambulatory blood pressure monitoring may be a beneficial tool to identify patients with hidden cardiovascular risk factors. The development of obesity and/or posttransplant diabetes with tacrolimus and/or corticosteroids is another risk factor for cardiovascular morbidity and mortality. Hypercholesterolemia and hypertriglyceridemia were more commonly seen in the era of cyclosporine use. Weight gain should be monitored closely following transplant to identify children early who are at risk for obesity, as weight gain and increases in body mass index in the first 3 months following transplant are likely to be persistent. In addition, semiannual screening for hypercholesterolemia, hypertriglyceridemia, and impaired glucose tolerance is suggested. Lifestyle modification, including dietary changes and increased physical activity, are typically preferred for young children with hyperlipidemia. Although kidney transplantation leads to a dramatic improvement in renal function and elimination of many traditional risk factors, cardiovascular disease still accounts for over onethird of the cause of death for patients who received kidney transplant prior to age 21 years. The use of antihypertensive medications is highest in the immediate posttransplant period, with 83% of deceased donor and 78% of living donor recipients at the time of transplant. In particular, pediatric transplant recipients are at increased risk for developing virus-related complications due to immunological naivet鮍 Prophylaxis is generally recommended for this highest-risk group for at least 100 days, but some centers extend the period of prophylaxis to 6 months. Despite satisfactory renal function following transplant, spontaneous catch-up growth is often insufficient. Children under the age of 6 years have increased growth rates following transplant compared to older children. A recent systematic review estimated that non-adherence accounts for an estimated 44% of graft losses and 23% of late acute rejection episodes. Adolescent patients were at higher risk, with weighted mean prevalence of nonadherence of 43% in the same review. The use of self-reporting of missed doses likely underrepresents the true incidence as patients and families are often reluctant to report non-adherence. Missed clinic appointments and schedule tests are also common forms of non-adherence reported for pediatric solid-organ transplant patients. Adolescent female transplant recipients have successfully become pregnant while receiving cyclosporine or tacrolimus. The effect of contraception on the metabolism of immunosuppressant medications needs to be considered when counseling adolescent girls about pregnancy prevention. Teenagers also need to balance their developing sexuality with changes in body image following transplant. It is difficult for teenagers to accept the cosmetic side effects of immunosuppressant medications, including weight gain, cushingoid features, acne, and gum hypertrophy. The accompanying psychological stress and impact on self-image for teenagers can provide a dangerous disincentive to adhere to medication regimens. Transitional Care Several reports have demonstrated a high risk of graft failure, particularly at the time of transfer from pediatric to adult care. Although the timing should be individualized, there is a growing consensus that preparation for transition should begin early (between 10 and 14 years of age). This rapidly changing and volatile developmental period places adolescent transplant recipients at increased risk for medication nonadherence, acute rejection episodes, and graft loss. Psychosocial Development the adolescent strives to establish an identity independently from parents and other adult authority figures and this can result in oppositional and defiant behaviors. The need for independence coupled with a sense of invulnerability and evolving capacity for abstract thought can result in illogical thinking and risk-taking behaviors. Beyond the normal psychological conflicts present during adolescence, transplant recipients are exposed to additional psychosocial stress related to their chronic illness. Developmental delay, issues with body image from drug side effects, difficulty interacting with peers, fastidious schedules required of immunosuppressant medication regimens, symptoms of posttraumatic stress, and family disruption due to financial burden or role strain may all exacerbate psychosocial difficulties in the transplanted adolescent. Collaboration with psychologists, psychiatrists, and social workers may be beneficial in the early identification and intensified treatment of high-risk individuals. There are few reports describing puberty and sexual maturity in children following kidney transplant, with most focusing on pubertal growth velocity. Mechanisms to monitor and assess the readiness for transfer have been described but are not standardized. Furthermore, there are still significant systems issues (insurance coverage, healthcare policies, resource allocations) to overcome. There is a need for longitudinal analyses of the outcomes of children who are transitioned to adult care. A great opportunity exists to form collaborative efforts between pediatric and adult transplant communities to improve outcomes for this high-risk population. Current kidney allocation rules and their impact on a pediatric transplant center. An update on immunizations before and after transplantation in the pediatric solid organ transplant recipient. Changes in pediatric renal transplantation after implementation of the revised deceased donor kidney allocation policy. American Society of Pediatric Nephrology position paper on linking reimbursement to quality of care. Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis. Efficacy of nephrectomy for the treatment of nephrogenic hypertension in a pediatric population. Streptococcus pneumoniaeassociated hemolytic uremic syndrome among children in North America. Outcome after transplantation of young patients with systemic lupus erythematosus: a report of the North American pediatric renal transplant cooperative study. Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis. Adolescent transition to adult care in solid organ transplantation: a consensus conference report. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Growth rate in children receiving alternate-day corticosteroid treatment after kidney transplantation. Factors that influence nonadherence in immunosuppressant treatment in pediatric transplant recipients: a proposal for an educational strategy. Late presentation of Alport posttransplantation anti-glomerular basement membrane disease. Immune profile of pediatric renal transplant recipients following alemtuzumab induction. Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Effects of urinary tract infection on outcomes after renal transplantation in children. Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review. Basiliximab induced non-cardiogenic pulmonary edema in two pediatric renal transplant recipients. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. Renal transplantation in children managed with lymphocyte depleting agents and lowdose maintenance tacrolimus monotherapy. Growth impairment at renal transplantation a determinant of growth and final height. Current treatment for primary hyperoxaluria type 1: when should liver/kidney transplantation be considered. Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1.

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In sporadic cases asthma definition quorum purchase advair diskus 500mcg, detailed microbiological tests may be inappropriate asthma over the counter medication buy advair diskus 250 mcg online, but clinicians need to be aware of the local antibiotic sensitivities of organisms such as Shigella asthma symptoms vs heart attack buy line advair diskus, Salmonella and Campylobacter if they are to use empirical antimicrobial therapy in a responsible and effective manner asthma definition 7 killings buy cheap advair diskus. Other investigations asthma what is it advair diskus 250 mcg generic, such as serum electrolytes asthma symptoms natural remedies buy advair diskus 500mcg visa, peripheral white cell count and blood cultures, are performed in a hospital setting but again may not be available routinely. Management Detailed management of individual pathogens is beyond the scope of this brief chapter. Intravenous fluid can be supplemented and rapidly replaced by oral rehydration, which is more successful if small volumes of fluid are taken steadily rather than large volumes at a time. Alternative oral rehydration therapy mixtures can also be used for adults and food, including milk products, is usually reintroduced as early as possible after initial resuscitation of children. Fluid balance should be carefully Gastrointestinal presentations monitored and a cholera bed is useful for less mobile patients with profuse diarrhoea. The fluid faeces can then be collected through a hole in the middle of the bed directly into a measuring bucket. Laxatives should be stopped, as should other drugs and traditional/complementary therapies that may cause diarrhoea. Antidiarrhoeal agents such as codeine or loperamide should be avoided in patients with acute invasive or large bowel disease, and should not be used in young children. Zinc supplementation is beneficial for children, but the roles of probiotics and use of lactose free feeds are less clear. Empirical or specific antimicrobial treatment should be reserved for specific situations such as proven amoebiasis, prolonged severe infection in a vulnerable host, or in outbreak settings. In a refugee camp outbreak setting, logistical support must be requested at an early stage for detailed epidemiological investigation, triage and treatment facilities; as well as provision of an adequate water supply, rehydration solutions and latrines (Chapter 60). A Manual for Physicians and Other 2 Respiratory presentations Stephen Gordon1 and Neil French2 1 Liverpool School of Tropical Medicine; 2University of Liverpool Disorders of the respiratory tract are among the most important cause of ill health in human populations around the world. The normal physiological functioning of the respiratory tract exposes it to prolonged and intimate contact with the external environment, leading to a steady exposure to airborne pollutants and pathogens with disease-causing potential. Infectious diseases dominate acute respiratory illness in the tropics in all age groups; acute viral and bacterial infections in childhood, and tuberculosis and bacterial pneumonia in adults. Global concern regarding the health effects of tobacco smoke has now resulted in important international treaties to limit tobacco products and smoking bans effective in public places have had a positive impact both in developed (Scotland) and tropical countries (Kenya). Breathlessness Shortness of breath should be characterized by duration, progression and whether it is constant or intermittent. Orthopnoea (breathlessness on lying flat) suggests a cardiac cause or a structural abnormality of the thoracic cage. The effort required to precipitate breathlessness provides a good gauge of the level of respiratory impairment. Breathless at rest or inability of a young child to feed indicate severe restriction. Shortness of breath in an adult should be quantified in terms of tasks completed or failed, or distance walked. Cough Cough is both a reflex (from any organ supplied by the vagus nerve) and a conscious act, therefore discriminating between causes of cough can be difficult. Cough may be productive or non-productive but a productive cough is often evidence of pulmonary infection and investigation for tuberculosis should be prompted by any persistent cough. The quantity of sputum produced may provide diagnostic information about chronic obstructive pulmonary disease or bronchiectasis. The expectoration of mucopurulent material is an indicator of neutrophil activity and infection. Haemoptysis is often an indicator of serious underlying pathology, but it is important to establish that blood is being coughed and not coming from the upper airway, throat or upper gastrointestinal tract. Extreme paroxysms of coughing in a child, particularly in association with the characteristic whoop, Assessment History the predominant symptoms of respiratory illness are breathlessness, cough and chest pain. Symptom duration and the concurrence of fever are useful descriminators common presentations in adults and children are summarized in (Table 2. Examination in respiratory cases A respiratory examination is used to test hypotheses generated by the history. In particular, cachexia, or failure to thrive in a young child, will indicate malnutrition or chronic underlying illness. In the context of an acute presentation, rates in adults above 30/min suggest severe disease particularly in association with systolic blood pressure below 90 mmHg and/or tachycardia pulse greater than 120. It is diagnosed only if the respiratory rate is over 60/min before the age of 2 months, over 50/min from 2ͱ2 months, over 40/min from 1͵ years and over 30/min (as for adults) above the age of 5 years. Pulse oximetry is now affordable in most settings and provides accurate information to guide the use of supplemental oxygen. Altered consciousness and confusion usually indicate severe acute disease and can necessitate specific management to protect the airway. Meningism can be found with severe pneumonia, with or without pneumococcal meningitis. Lobar consolidation is common in pneumonia or tuberculosis and can be diagnosed on the basis of bronchial breathing. Many patients Chest pain Complaints of chest pain should be assessed for their association with breathing and coughing. Tracheal pain has a tearing or burning quality and is felt retrosternally, particularly on coughing. Non-respiratory illness Non-respiratory illness may present with predominantly respiratory symptoms most commonly anaemia or heart failure presenting with dyspnoea. Breathlessness is a feature of metabolic acidosis which may be caused by diabetic ketoacidosis, poisoning, severe sepsis or renal failure. Alteration of breathing pattern and breathlessness can occur with neurological injury, during the early stages of tetanus and botulism and following envenomation. In these cases, a suggestive history should lead to further investigation as a normal chest examination does not exclude significant pathology. Recovery of a pathogen allows confident treatment and is frequently the investigation by which an unusual cause of pneumonia is established. Salmonella typhi, Cryptococcus spp, Burkholderia pseudomallei (melioidosis), Rhodococcus equi. Investigation of respiratory disease Chest X-ray Limited resources must be carefully rationed in order to optimally investigate respiratory patients in the tropics. In particular, a chest X-ray should be used to extend the examination in difficult cases and not simply to confirm diagnoses made confidently on auscultation. Patients with severe acute respiratory illness or those who fail to respond to therapy including smear-negative cases of chronic cough are the ones most frequently requiring a chest X-ray. Pleural fluid Sampling of pleural fluid is simple to perform and should be considered for most effusions as the management of simple effusion and empyema are different. Fluid is aspirated by use of a needle and syringe, avoiding the neurovascular bundle at the inferior margin of each rib. Occasionally, this fails because pleural fluid is loculated, has formed a thick empyema or the chest examination findings result from chronic pleural scarring. Pleural fluid should be defined as transudate (protein below 30 g/dl) or exudate and exudates subjected to pH, amylase, microscopy and culture. Occasionally, an unstained wet preparation of sputum examined under low power may be useful for identifying strongyloidiasis, paragonimiasis or fungal elements. Cytology for malignant cells can also be performed on sputum but requires a skilled pathologist. Other sputum include direct immunofluorescence for viruses and Pneumocystis jirovecii, urinary antigen detection for pneumococci (Gram stain described in Chapter 12) and molecular techniques for several organisms in sputum including tuberculosis, but these methods are not yet resource-efficient in developing countries. When sputum cannot be produced, placing the patient in a head-down position or simple chest physiotherapy (drumming) for 2ͳ minutes will help. Lung aspiration increases the diagnostic yield in young children with lung consolidation. A needle and syringe primed with 1 mL normal saline or sterile water is passed into the consolidated tissue through the thoracic wall and aspirated. The aspirated material can be smeared onto slides for examination and injected into liquid culture media. In young children when sputum is difficult to collect, early morning gastric washings yield swallowed sputum for the Lung function testing Chronic lung disease cannot be precisely defined without spirometry. Lung function can now be measured using handheld technology and stored on a laptop computer. Common presentations In general, respiratory presentations in the general medical clinic tend to fall into a small number of syndromes. Vaccination against pneumococcal and Haemophilus influenzae infections are also global priorities. Pleural effusion Symptoms associated with pleural effusions can be of short or long duration, depending on the nature of the underlying problems, but large effusions are straightforward to find on examination. Parapneumonic effusions, empyema or tuberculous effusions should be suggested by the history. Malignant effusions must be considered when an infective aetiology is not readily apparent. Acute breathlessness, cough and fever in adults Acute bacterial pneumonia is the principal diagnostic consideration and the diagnosis and management of this is covered in Chapter 28. It is important to exclude or confirm tuberculosis, which represents a serious public health threat but is readily treatable (Chapter 12). A small number of conditions are specific to the tropics and may need to be considered under the right epidemiological circumstances: paragonimiasis in South East Asia and restricted areas of West Africa (Chapter 29); endemic mycoses in South and Central America (Chapter 54); and pulmonary complications of schistosomiasis in endemic regions (Chapter 17). The incidence of tobacco smoking associated lung cancer is increasing in developing countries. The expiratory wheeze or whistling associated with lower airways obstruction must be differentiated from inspiratory phase stridor, which indicates upper airway obstruction. The presence of paroxysmal or diurnal cough, breathlessness and wheeze preferably supported by variation in peak flow measurements reliably indicates airways obstruction. Ezzati M, Kammen D (2002) Indoor air pollution from biomass combustion and acute respiratory infections in Kenya: an exposure-response study. Careful consideration must be made about when symptom-directed palliative care is the most appropriate strategy. Infectious diseases make a major contribution, but non-infectious causes are also important (Table 3. A complex mixture of socioeconomic and environmental factors contribute to the increased incidence. Patterns of vascular disease are catching up with those in the developed world, but the usage of drugs to control them lags behind. Environmental factors include the close proximity of homes to zoonotic infections. Neurological syndromes Neurological diseases particularly infections can present with a range of syndromes. Leigh syndrome Uraemia Tumours/trauma/toxins Alcohol Drugs (medical, recreational, traditional) Pesticides Poisons Other Degenerative Epilepsy (non-convulsive status epilepticus) Hydrocephalus Hypertensive encephalopathy Inflammatory. Pathological processes these neurological syndromes are explained by a range of pathological processes. This may occur across the whole cord (causing transverse myelitis, which is often post-infectious) or be confined to the anterior horn cells). A detailed description of the neurological examination is beyond the scope of this chapter. Unreactive pupils occur in brainstem lesions (mid-sized in midbrain or pontine lesions; large in medullary lesions). Pinpoint pupils occur following opiate or organophosphate overdose, or in isolated pontine lesion. The importance of these syndromes is being increasingly recognized in nontraumatic coma (particularly that caused by infections). Transtentorial herniation - intact survival possible Neurological presentations 3 Assess eye movements (holding eyelids open if necessary). A normal response indicates that the brainstem is intact (diffuse encephalopathy). Reduced or absent responses occur in uncal herniation, brainstem damage or, rarely, deep metabolic coma. Check that the eardrum is not perforated, then irrigate by injecting 20 mL ice-cold water. CheyneΓtokes breathing and hyperventilation occur in reversible herniation syndromes. Hyperventilation also occurs in acidosis or may be caused by aspiration pneumonia, which is common in coma. Symmetrical posturing (decorticate or decerebrate) and hemiparetic focal signs are also occasionally seen in metabolic encephalopathies. Other pointers to metabolic disease include asterixis, tremor and myoclonus preceding the onset of coma. It has gone out of fashion in the latter, following concerns that it was being performed on patients with contraindications, and may have precipitated herniation. In patients with a contraindication, treatment should be started and then a lumbar puncture reconsidered later. Neurological presentations appropriate treatment may outweigh the theoretical risk of herniation, and even patients with relative contraindications often receive lumbar punctures with no apparent harm. Ideally, the decision about starting antibiotics should await the result of the lumbar puncture (if it is available quickly). However, antibiotics should be started immediately for patients with a typical meningococcal rash, because of the speed with which meningococcal septicaemia can become fatal. In such patients, if it is certain that the rash is meningococcal it has been argued that the lumbar puncture is not necessary, because the diagnosis is already made, though others advocate always doing a lumbar puncture. Antipyretics in common use act by inhibition of pyrogenic prostaglandin production: these are either nonsteroidal anti-inflammatory drugs or paracetamol (acetaminophen). Although antipyretics are widely used and have beneficial properties in terms of analgesic effects and reducing discomfort, they do not improve mortality.