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1.  Economic benefits of subcutaneous rapid push versus intravenous immunoglobulin infusion therapy in adult patients with primary immune deficiency 
SUMMARY
Objective
The objective of this study is to evaluate the economic benefits of immunoglobulin replacement therapy achieved subcutaneously (subcutaneous immunoglobulin, SCIG) by the rapid push method compared to intravenous infusion therapy (intravenous immunoglobulin, IVIG) in primary immune deficiency (PID) patients from the healthcare system perspective in the context of the adult SCIG home infusion program based at St Paul's Hospital, Vancouver, Canada.
Materials and methods
SCIG and IVIG options were compared in cost-minimisation and budget impact models (BIMs) over 3 years. Sensitivity analyses were performed for both models to evaluate the impact of varying modality of IVIG treatments and proportion of patients switching from IVIG to SCIG.
Results
The cost-minimisation model estimated that SCIG treatment reduced cost to the healthcare system per patient of $5736 over 3 years, principally because of less use of hospital personnel. This figure varied between $5035 and $8739 depending on modality of IVIG therapy. Assuming 50% of patients receiving IVIG switched to SCIG, the BIM estimated cost savings for the first 3 years at $1·308 million or 37% of the personnel and supply budget. These figures varied between $1·148 million and $2·454 million (36 and 42%) with varying modalities of IVIG therapy. If 75% of patients switched to SCIG, the reduced costs reached $1·962 million or 56% of total budget.
Conclusion
This study demonstrated that from the health system perspective, rapid push home-based SCIG was less costly than hospital-based IVIG for immunoglobulin replacement therapy in adult PID patients in the Canadian context.
doi:10.1111/j.1365-3148.2012.01201.x
PMCID: PMC3580879  PMID: 23167310
budget impact model; cost minimisation; IVIG; primary immune deficiencies; SCIG
2.  Experience with Subgam, a Subcutaneously Administered Human Normal Immunoglobulin (ClinicalTrials.gov - NCT02247141) 
PLoS ONE  2015;10(7):e0131565.
Background and Objectives
A multi-centre, non-comparative study examining the efficacy and safety of Subgam, a normal immunoglobulin (IgG) given weekly as a rapid subcutaneous infusion to patients with primary immune deficiency (PID), is reported. Also included is a summary of adverse drug reactions associated with the use of marketed Subgam in the UK.
Materials and Methods
50 patients with stable PID on IgG therapy were enrolled: Stage 1 included three infusions with prior IgG product followed by 6 months with Subgam, Stage 2 involved long-term Subgam therapy up to 4 years.
Results
Stage 1, 85% of the subjects aged >12 years and 93% of the subjects aged <12 years achieved IgG levels ≥6 and ≥4 g/L, respectively at all observations. There were 3.62 infections/patient/year during Subgam treatment. The most common product-related events were infusion site reactions (50% of patients). Recent post-hoc pharmacokinetics analysis of the post-infusion serum total IgG concentration indicated that the mean dose-normalised incremental IgG AUCτ following intravenous dosing (120.5 g.day/L) was 1.64-fold that of the dose-normalised mean incremental IgG AUCτ following subcutaneous dosing (73.6 g.day/L), corresponding to an estimated IgG bioavailability for subcutaneous dosing of 61%. Only 34 post-licensing adverse reactions have been received in 30 patients over a period of 10 years; fourteen were classed as serious as defined by the ICH guidelines on good clinical practice. The most common post-licensing adverse reaction was infusion site reaction (7 reports). There were 7 reports of flu-like symptoms (pyrexia/shivering/rigors/feeling hot or cold), 2 other reports of combined flu-like symptoms and infusion site reactions, 5 reports of generalised skin reactions, and 3 reports of combined infusion site and skin reactions. There were also reports of anaphylaxis (2 reports) and 8 other adverse events (including headache). In conclusion, Subgam is effective and well tolerated in the treatment of PID.
Trial Registration
ClinicalTrials.gov NCT02247141
doi:10.1371/journal.pone.0131565
PMCID: PMC4519338  PMID: 26222441
3.  Calculating the Dose of Subcutaneous Immunoglobulin for Primary Immunodeficiency Disease in Patients Switched From Intravenous to Subcutaneous Immunoglobulin Without the Use of a Dose-Adjustment Coefficient 
Pharmacy and Therapeutics  2013;38(12):768-770.
Intravenous immunoglobulin (IVIG), a standard therapy for immune deficiency disorders, is not appropriate for all patients. As a result, a subcutaneous form (SCIG) has emerged as an alternative. The authors propose a tailored dosing approach for SCIG.
Primary immunodeficiency disease (PIDD) is an inherited disorder characterized by an inadequate immune system. The most common type of PIDD is antibody deficiency. Patients with this disorder lack the ability to make functional immunoglobulin G (IgG) and require lifelong IgG replacement therapy to prevent serious bacterial infections.
The current standard therapy for PIDD is intravenous immunoglobulin (IVIG) infusions, but IVIG might not be appropriate for all patients. For this reason, subcutaneous immunoglobulin (SCIG) has emerged as an alternative to IVIG. A concern for physicians is the precise SCIG dose that should be prescribed, because there are pharmacokinetic differences between IVIG and SCIG. Manufacturers of SCIG 10% and 20% liquid (immune globulin subcutaneous [human]) recommend a dose-adjustment coefficient (DAC). Both strengths are currently approved by the FDA. This DAC is to be used when patients are switched from IVIG to SCIG.
In this article, we propose another dosing method that uses a higher ratio of IVIG to SCIG and an incremental adjustment based on clinical status, body weight, and the presence of concurrent diseases.
PMCID: PMC3875267  PMID: 24391400
4.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
5.  Prophylactic Perioperative Sodium Bicarbonate to Prevent Acute Kidney Injury Following Open Heart Surgery: A Multicenter Double-Blinded Randomized Controlled Trial 
PLoS Medicine  2013;10(4):e1001426.
In a double-blinded randomized controlled trial, Anja Haase-Fielitz and colleagues find that an infusion of sodium bicarbonate during open heart surgery did not reduce the risk for acute kidney injury, compared with saline control.
Background
Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery.
Methods and Findings
In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04–2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90–2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07–14.2], p = 0.031).
Conclusions
Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified.
Trial registration
ClinicalTrials.gov NCT00672334
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Open heart surgery is a type of cardiac surgery that is used to treat patients with severe heart disease, where the patient's chest is cut open and surgery is performed on the internal structures of the heart. During open heart surgery, surgeons may use a technique called cardiopulmonary bypass to temporarily take over the function of the heart and lungs. This type of surgery may be used to prevent heart attack or heart failure in patients with conditions such as angina, atherosclerosis, congenital heart disease, or valvular heart disease. There are a number of complications associated with open heart surgery and one of these is the rapid loss of kidney function, known as acute kidney injury (AKI), and formerly known as acute renal failure. Symptoms of AKI can be variable, with diagnosis of AKI based on laboratory findings (such as elevated blood urea nitrogen and creatinine), or clinical signs such as inability of the kidneys to produce sufficient amounts of urine. Globally, more than 10 million people are affected by AKI each year. AKI occurs in about one quarter of patients undergoing cardiac surgery and is associated with longer stays in the hospital and an increased risk of death. Treatment of AKI includes administration of intravenous fluids, diuretics, and, in severe cases, patients may require kidney dialysis.
Why Was This Study Done?
The mechanism for why AKI occurs during cardiac surgery is complex and thought to involve multiple factors relating to blood circulation, the immune system, and toxins released by the kidneys. In addition to treating AKI after it occurs, it is important to identify patients who are at risk for developing AKI prior to cardiac surgery and then apply techniques to prevent AKI during cardiac surgery. A number of interventions have been tested for preventing AKI during cardiac surgery, but there is currently no strong evidence for a standard way to prevent AKI. One intervention that has potential for preventing AKI is the administration of sodium bicarbonate during cardiac surgery. Sodium bicarbonate causes alkalinization of the urine, and it is thought that this could reduce the effect of toxins in the kidneys. A previous pilot study showed promising effects for sodium bicarbonate to reduce the likelihood of AKI. In a follow-up to this pilot study, here the researchers have performed an international randomized controlled trial to test whether administration of sodium bicarbonate compared to sodium chloride (saline) during cardiac surgery can prevent AKI.
What Did the Researchers Do and Find?
350 patients undergoing open heart surgery with at least one risk factor for developing AKI were recruited across four sites in different countries (Germany, Canada, Ireland, and Australia). These patients were randomly assigned to receive either sodium bicarbonate (treatment) or saline control solution, given as a continuous infusion into the blood stream for 24 hours during surgery. Neither the researchers nor the patients were aware of which patients were assigned to the treatment group. The researchers measured the occurrence of AKI within the first 5 days after surgery and they found that a greater proportion of those patients receiving sodium bicarbonate developed AKI, as compared to those patients receiving saline control. On the basis of these findings the study was terminated before planned recruitment was completed. A key issue with this study is that a greater proportion of the patients in the sodium bicarbonate group had chronic kidney disease prior to open heart surgery. After adjusting for this difference in the statistical analysis, the researchers observed that the difference between the groups was not significant—that is, it could have happened by chance. The authors also observed that a significantly greater proportion of patients receiving sodium bicarbonate died in the hospital after surgery compared to patients receiving saline control.
What Do These Findings Mean?
These findings suggest that giving an infusion of sodium bicarbonate to induce alkalinization of the urine during open heart surgery is not a useful treatment for preventing AKI. Furthermore, this treatment may even increase the likelihood of death. The researchers do not recommend the use of sodium bicarbonate infusion to reduce the risk of AKI after open heart surgery and stress the need for discontinuation of this therapy. Key limitations of this research study are the early termination of the study and the greater proportion of patients with chronic kidney disease prior to surgery.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001426.
The Renal Association, a professional association for kidney doctors and researchers, provides information about acute kidney injury
The International Society for Nephrology and the International Federation of Kidney Foundations provide information about preventing acute kidney injury around the world and jointly initiated World Kidney Day
MedlinePlus has information on open heart surgery
doi:10.1371/journal.pmed.1001426
PMCID: PMC3627643  PMID: 23610561
6.  Variation in Modes of Chemotherapy Administration for Breast Carcinoma and Association with Hospitalization for Chemotherapy-Related Toxicity 
Cancer  2005;104(5):913-924.
BACKGROUND
To the authors’ knowledge, few studies to date have addressed the patterns of how chemotherapy was administered (administration modes) over time. In the current study, the goal of the authors was to describe how chemotherapy for breast carcinoma was administered and to determine whether chemotherapy administration modes were associated with toxicity in a community-based large cohort.
METHODS
The authors studied 5256 women who were diagnosed with breast carcinoma at age 65 years or older between 1992-1999 and received chemotherapy. The patients were identified from the Surveillance, Epidemiology, and End Results (SEER)Program-Medicare linked databases. Chemotherapy drugs and modes of administration were determined through procedure codes in Medicare claims.
RESULTS
Of the 5256 patients who received chemotherapy, 33% received it through an intravenous infusion for less than 1 hour; 39% through an intravenous infusion lasting 1-8 hours; 15% through an intravenous infusion lasting longer than 8 hours and requiring a pump; 12% through an intravenous push technique; and 1% through a subcutaneous, intramuscular, or intralesional injection. These modes varied substantially across the 11 SEER areas. The risks of hospitalization for chemotherapy-related toxicities (neutropenia, fever, thrombocytopenia, and adverse effects of systemic therapy) were not found to be significantly associated with different modes of chemotherapy after adjusting for other factors. Compared with patients receiving 5-flurouracil using an intravenous infusion for longer than 8 hours, the risk of toxicity was determined to be 0.96 (95% confidence interval [95% CI], 0.63-1.47) for patients treated with an intravenous infusion lasting 1-8 hours; 0.94 (95% CI, 0.62-1.41) for patients treated with an intravenous infusion lasting less than 1 hour; and 0.66 (95% CI, 0.38-1.08) for patients treated with subcutaneous, intramuscular, or intralesional injection or an intravenous push technique.
CONCLUSIONS
There were substantial geographic variations noted in the modes of administering chemotherapy; however, these variations did not appear to be associated with the risk of toxicities (neutropenia, fever, thrombocytopenia, and adverse effects of systemic therapy).
doi:10.1002/cncr.21271
PMCID: PMC2566845  PMID: 15991239
breast carcinoma; chemotherapy; therapy mode; toxicity; cancer registry; Medicare
7.  Immune Globulin Subcutaneous (Human) 20% 
Drugs  2012;72(8):1087-1097.
Immune globulin subcutaneous 20% is a new high-concentration (200 g/L) solution of highly purified human IgG (≥98%) indicated in the EU and the US for antibody replacement therapy in patients with primary immunodeficiency with antibody deficiency, and in the EU for replacement therapy in humoral immunodeficiency secondary to myeloma or chronic lymphocytic leukaemia.
Immune globulin subcutaneous 20% is formulated with L-proline, which imparts long-term stability at room temperature and a relatively low viscosity.
In two pivotal phase III trials in stably treated patients with primary immunodeficiency, immune globulin subcutaneous 20% at weekly subcutaneous dosages either equivalent to each patient’s previous intravenous or subcutaneous replacement therapy, or providing equivalent systemic exposure to previous intravenous therapy, produced mean serum IgG trough levels equal to or greater than pre-study levels. In each trial, there were no serious bacterial infections during treatment throughout the 28-week or 12-month efficacy periods. The rates of infectious episodes, days missed from work/school, days hospitalized or days with antibiotics were low.
Immune globulin subcutaneous 20% was generally well tolerated. A high proportion of patients experienced local infusion-site reactions, but infusion-related systemic adverse events were relatively infrequent. Most adverse events were of mild or moderate intensity and did not interfere with therapy.
doi:10.2165/11209490-000000000-00000
PMCID: PMC3582812  PMID: 22621695
8.  Optimization of Immunoglobulin Substitution Therapy by a Stochastic Immune Response Model 
PLoS ONE  2009;4(5):e5685.
Background
The immune system is a complex adaptive system of cells and molecules that are interwoven in a highly organized communication network. Primary immune deficiencies are disorders in which essential parts of the immune system are absent or do not function according to plan. X-linked agammaglobulinemia is a B-lymphocyte maturation disorder in which the production of immunoglobulin is prohibited by a genetic defect. Patients have to be put on life-long immunoglobulin substitution therapy in order to prevent recurrent and persistent opportunistic infections.
Methodology
We formulate an immune response model in terms of stochastic differential equations and perform a systematic analysis of empirical therapy protocols that differ in the treatment frequency. The model accounts for the immunoglobulin reduction by natural degradation and by antigenic consumption, as well as for the periodic immunoglobulin replenishment that gives rise to an inhomogeneous distribution of immunoglobulin specificities in the shape space. Results are obtained from computer simulations and from analytical calculations within the framework of the Fokker-Planck formalism, which enables us to derive closed expressions for undetermined model parameters such as the infection clearance rate.
Conclusions
We find that the critical value of the clearance rate, below which a chronic infection develops, is strongly dependent on the strength of fluctuations in the administered immunoglobulin dose per treatment and is an increasing function of the treatment frequency. The comparative analysis of therapy protocols with regard to the treatment frequency yields quantitative predictions of therapeutic relevance, where the choice of the optimal treatment frequency reveals a conflict of competing interests: In order to diminish immunomodulatory effects and to make good economic sense, therapeutic immunoglobulin levels should be kept close to physiological levels, implying high treatment frequencies. However, clearing infections without additional medication is more reliably achieved by substitution therapies with low treatment frequencies. Our immune response model predicts that the compromise solution of immunoglobulin substitution therapy has a treatment frequency in the range from one infusion per week to one infusion per two weeks.
doi:10.1371/journal.pone.0005685
PMCID: PMC2685018  PMID: 19479057
9.  Subcutaneous Immunoglobulin-G Replacement Therapy with Preparations Currently Available in the United States for Intravenous or Intramuscular Use: Reasons and Regimens 
For patients who require replacement therapy for primary immunodeficiency, subcutaneous infusions of immunoglobulin G (IgG) may be preferable to intravenous infusions for several reasons. However, at present, there is no preparation marketed for use by this route in North America. In this article, we describe the reasons patients have selected this route of therapy and the range of treatment regimens used. Approximately 20% of our patients have chosen the subcutaneous route, mainly because of adverse effects from intravenous (IV) infusions or difficulties with venous access. Unit dose regimens using whole bottles of currently available 16% intramuscular preparations or sucrose-containing lyophilized preparations intended for IV use but reconstituted to 15% IgG for subcutaneous administration were individually tailored to each patient. In most cases, self-infusions or home infusions were administered once or twice a week, most commonly requiring two subcutaneous sites and 2 to 3 hours per infusion. On average, patients took 0.18 mL of IgG per kilogram of body weight per site per hour. There were no systemic adverse effects. In patients for whom comparative data were available, trough serum IgG levels were higher with subcutaneous therapy than with IV therapy.
doi:10.1186/1710-1492-1-3-120
PMCID: PMC2877065  PMID: 20529223
10.  Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment 
Background
Subcutaneous or intravenous immunoglobulin replacement is the mainstay of treatment for most patients with primary immunodeficiency disease (PID). The purpose of this study was to gain an understanding of how existing PID therapies affect patient lives and to identify desired improvements to immunoglobulin treatments.
Methods
An online questionnaire was made available through the International Patient Organisation for Primary Immunodeficiencies to patients with PID and their caregivers regarding current treatment satisfaction, living with PID, and patient preferences using a conjoint approach. Health-related quality of life was canvassed via questionnaires using the Short Form 12 Health Survey and EuroQoL 5 Dimensions.
Results
A total of 300 responded to the survey (72% patients with PID and 28% caregivers) from across 21 countries, mostly the UK, Sweden, Canada, France, Germany, and Spain. Fifty-three percent and 45% of patients received intravenous and subcutaneous therapy, respectively. Most respondents (76%) were satisfied with their current treatment, reflecting the benefits that immunoglobulin therapy provides for patient health and well-being. However, patients remained below the physical and mental well-being norms for health-related quality of life as determined by the questionnaire. All respondents expressed a desire for 4-weekly infusions, the ability to administer these at home, self-administration, shorter duration of administration, and fewer needle sticks.
Conclusion
The results of this survey highlight the importance of providing access to different treatment options and modes of administration to ensure individual patient needs are best met.
doi:10.2147/PPA.S60771
PMCID: PMC4014377  PMID: 24833896
primary immunodeficiency; immunoglobulins; quality of life; patient needs; patient satisfaction; conjoint analysis
11.  Efficacy and Safety of IgPro20, a Subcutaneous Immunoglobulin, in Japanese Patients with Primary Immunodeficiency Diseases 
Journal of Clinical Immunology  2014;34(2):204-211.
Purpose
Intravenous (IVIG) and subcutaneous (SCIG) immunoglobulin infusions are widely used for the treatment of patients with primary immunodeficiency (PID) worldwide. This prospective, multicenter, open-label, single-arm Phase III study evaluated the efficacy, tolerability, and safety of IgPro20 (Hizentra®; L-proline–stabilized 20 % human SCIG) in adult and pediatric Japanese patients with PID.
Methods
Patients received three IVIG infusions at 3–4-week intervals followed by a dose-equivalent switch to weekly SCIG infusions. A 12-week wash-in/wash-out period was followed by a 12-week SCIG efficacy period. The primary efficacy endpoint was the comparison of total serum IgG trough levels during the IVIG and SCIG efficacy periods by calculating the geometric mean ratio (GMR).
Results
The GMR of IgG trough levels on SCIG versus IVIG was 1.09 (2-sided 90 % confidence interval: 1.06–1.13). No serious bacterial infections were reported. Eleven patients (52.4 %) had infectious episodes with an overall rate of 2.98 infections/patient/year; 7 patients (33.3 %) missed school/work/daycare due to infection (3.48 days/patient/year). Sixteen patients (76.2 %) were treated with antibiotics for an adverse event (AE; 47.6 %) or prophylaxis (23.8 %), resulting in 167.42 days/patient/year of antibiotic use. During SCIG treatment, 24 patients (96.0 %) had 269 AEs (0.461 AEs per/infusion) including local reactions as the most common AE (20 patients, 80.0 %). Local tolerability of IgPro20 was assessed as “very good” or “good” after 85.4 % of SCIG infusions. One patient (4.0 %) experienced a serious AE of moderate severity (bacterial infection) that was considered unrelated to study medication.
Conclusion
IgPro20 was effective and well tolerated in Japanese patients with PID.
doi:10.1007/s10875-013-9985-z
PMCID: PMC3937544  PMID: 24504846
Primary immunodeficiency; PID; primary antibody deficiency; SCIG; Hizentra®; IgPro20; Japan
12.  Implications to payers of switch from hospital-based intravenous immunoglobulin to home-based subcutaneous immunoglobulin therapy in patients with primary and secondary immunodeficiencies in Canada 
Background
Switching primary/secondary immunodeficiency (PID/SID) patients from intravenous immunoglobulin (IVIg) to home-based subcutaneous immunoglobulin (SCIg) therapy reduces nurse time. A nurse shortage in Canada provides an important context to estimate the net economic benefit, the number of patients needed to switch to SCIg to recoup one full-time equivalent (FTE), and potential population-wide savings of reduced nurse time to a payer.
Methods
The net economic benefit was estimated by multiplying the hourly compensation for nurses in Canada by the hours required for each administration route. The number needed to switch to SCIg to gain one nurse FTE was estimated by dividing the work hours in a year by the average annual savings in nursing time in a PID population in Canada. The prevalence of treated PID/SID in Canada was calculated using provincial IgG audit data to extrapolate the potential population-wide savings of switching patients to SCIg therapy.
Findings
The net economic gain from switching one patient to home-based SCIg care would be C$2,603 (Canadian Dollars) in year 1 and C$2,948 each year thereafter. Switching 37 IVIg patients to SCIg would gain one nurse FTE. Switching 50% of the estimated 5,486 PID and SID patients in Canada receiving IVIg therapy to SCIg has the potential to save 223.3 nurse FTEs (C$23.2 million in labor costs).
Conclusions
A shift from IVIg to less labor-intensive SCIg has the potential to help alleviate nurse shortages and reduce overall health care costs in Canada. Health care professionals might consider advocating for home-based SCIg therapy for PID/SID patients when clinically appropriate.
doi:10.1186/1710-1492-10-23
PMCID: PMC4036390  PMID: 24872821
IVIg; SCIg; Labor costs; Full time equivalents; FTEs; PID; SID; Nurse time
13.  Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease 
Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD) and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg) in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg) provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life.
PMCID: PMC2817783  PMID: 20169031
subcutaneous immunoglobulin; primary immunodeficiency disease; antibody deficiency; X-linked agammaglobulinemia; common variable immune deficiency
14.  Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study 
Annals of the Rheumatic Diseases  2007;66(7):977-979.
Background
In systemic sclerosis (SSc), joint involvement may reduce the functional capacity of the hands. Intravenous immunoglobulins have previously been shown to benefit patients with SSc.
Aim
To verify the efficacy of intravenous immunoglobulins on joint involvement and function in SSc.
Patients and methods
7 women with SSc, 5 with limited and 2 with diffuse SSc, with a severe and refractory joint involvement were enrolled in the study. Methotrexate and cyclophosphamide pulse therapy did not ameliorate joint symptoms. Hence, intravenous immunoglobulins therapy was prescribed at a dosage of 2 g/kg body weight during 4 days/month for six consecutive courses. The presence of joint tenderness and swelling, and articular deformities (due to primary joint involvement and not due to skin and subcutaneous changes) were evaluated. Before and after 6 months of treatment, patients were subjected to (1) Ritchie Index (RI) evaluation of joint involvement; (2) Dreiser Algo‐Functional Index (IAFD) evaluation of hand joint function; (3) pain visual analogue scale (VAS) to measure joint pain; (4) Health Assessment Questionnaire (HAQ) to evaluate the limitations in everyday living and physical disability; and (5) modified Rodnan Skin Score for skin involvement.
Results
After 6 months of intravenous immunoglobulins therapy, joint pain and tenderness, measured with the VAS, decreased significantly (p<0.03), and hand function (IAFD) improved significantly (p<0.02), together with the quality of life (HAQ; p<0.03). All patients significantly improved, except for one. The skin score after 6 months of intravenous immunoglobulins therapy was significantly reduced (p<0.003).
Conclusion
This pilot study suggests that intravenous immunoglobulins may reduce joint pain and tenderness, with a significant recovery of joint function in patients with SSc with severe and refractory joint involvement. The cost of intravenous immunoglobulins might limit their use only to patients who failed disease‐modifying antirheumatic drugs.
doi:10.1136/ard.2006.060111
PMCID: PMC1955090  PMID: 17344244
15.  Analgesic effects of ketamine infusion therapy in korean patients with neuropathic pain: A 2-week, open-label, uncontrolled study 
Background: The overexcitation of the N-methyl-D-aspartate receptor complex appears to play a critical role in the development of neuropathic pain, and ketamine acts as an antagonist to that receptor. Some publications have reported on the prominent relief of neuropathic pain with intravenous or subcutaneous ketamine infusions or a single-dose intravenous ketamine injection despite adverse effects.
Objectives: The primary objective of this study was to determine the analgesic effect of intravenous ketamine infusion therapy for neuropathic pain refractory to conventional treatments. Secondary objectives included identifying the variables related to the analgesic effect and the pain descriptors susceptible to ketamine infusion.
Methods: This 2-week, open-label, uncontrolled study was conducted in Korean patients with neuropathic pain recruited from the Samsung Seoul Hospital (Seoul, Republic of Korea) outpatient pain management unit. Patients were required to have a pain severity score >5 (visual analog scale [VAS], where 0 = no pain and 10 = worst pain imaginable) over a period of ≥1 month while on standard treatment. The patients were required to have shown no benefit from standard treatment and no pain relief lasting over 1 month. The ketamine infusion therapy was composed of 3 sessions performed consecutively every other day. Midazolam was administered concomitantly to reduce the occurrence of central nervous system-related adverse events (AEs) secondary to ketamine. Each session was as follows: ketamine 0.2 mg/kg and midazolam 0.1 mg/kg were administered intravenously for 5 minutes as a loading dose, followed by a continuous infusion of ketamine 0.5 mg/kg/h and midazolam 0.025 mg/kg/h for 2 hours. AEs were assessed in the following ways: close monitoring of ECG, blood pressure, oxygen saturation, and evaluating the need for treatment of AEs during infu- sion and until discharge by an attending anesthesiologist; an open question about discomfort at the end of each session; spontaneous reports about AEs during each session; and the patients' and caregivers' checklist of AEs occurring at home for 2 weeks after discharge. All the descriptors of pain expressed by the patients in Korean were recorded and translated into appropriate English terminology on the basis of the literature on Korean verbal descriptors of pain. Each of the translated pain descriptors was then classified into 1 of 18 sensory items.
Results: The overall VAS score for pain decreased from a baseline mean (SD) of 7.20 (1.77) to 5.46 (2.29) (P < 0.001) 2 weeks after treatment in 103 patients (53 males and 50 females; mean age, 52.56 [17.33] years) who completed the study. Variables such as age, sex, and the duration and diagnosis of pain were not found to be associated with analgesic effect. Seven of the 18 pain descriptors were found to have a significant response to ketamine infusion treatment between baseline and 2 weeks follow-up: burning pain (P = 0.008); dull, aching pain (P < 0.001); overly sensitive to touch (P = 0.002); stabbing pain (P = 0.008); electric pain (P = 0.031); tingling pain (P < 0.001); and squeezing pain (P < 0.001). A total of 52 patients reported AEs: 33 during infusion and 44 during recovery and up to 2 weeks follow up. The most commonly reported AEs were snoring (15 [15%]) during infusion and dizziness (43 [42%]) during recovery.
Conclusions: Ketamine infusion therapy was associated with reduced severity of neuropathic pain and generally well tolerated for up to 2 weeks in these patients with neuropathic pain refractory to standard treatment. Variables such as sex, age, and the diagnosis and duration of pain had no association with the analgesic effect of this treatment. Randomized controlled trials are needed to evaluate the efficacy and tolerability of treatment with ketamine infusion.
doi:10.1016/j.curtheres.2010.04.001
PMCID: PMC3967276  PMID: 24683255
ketamine; infusion therapy; neuropathic pain; pain descriptor
16.  Comparison of Diagnostic Criteria for Common Variable Immunodeficiency Disorder 
Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.
doi:10.3389/fimmu.2014.00415
PMCID: PMC4164032  PMID: 25309532
common variable immunodeficiency; diagnostic criteria; HGUS
17.  Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency 
Background
Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy.
Methods
We evaluated the efficacy and safety of the SCIG Vivaglobin® (formerly known as Beriglobin® SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children < 14 years) using the Short Form 36 (SF-36) for patients ≥ 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children < 14 years of age. Treatment preferences were assessed in adults.
Results
The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p < 0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by ≥ 5 points were observed in 5 of 8 SF36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p ≤ 0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%).
Conclusion
This study confirms that therapy with Vivaglobin® at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.
doi:10.1186/2047-783X-15-6-238
PMCID: PMC3351992  PMID: 20696632
antibody deficiency; subcutaneous immunoglobulin therapy; quality of life; children; adults
18.  Gene Expression Profiling in Peripheral Blood Mononuclear Cells of Patients with Common Variable Immunodeficiency: Modulation of Adaptive Immune Response following Intravenous Immunoglobulin Therapy 
PLoS ONE  2014;9(5):e97571.
Background
Regular intravenous immunoglobulin treatment is used to replace antibody deficiency in primary immunodeficiency diseases; however the therapeutic effect seems to be related not only to antibody replacement but also to an active role in the modulation of the immune response. Common variable immunodeficiency is the most frequent primary immunodeficiency seen in clinical practice.
Methods
We have studied the effect of intravenous immunoglobulin replacement in patients with common variable immunodeficiency by evaluating the gene-expression profiles from Affimetrix HG-U133A. Some of the gene array results were validated by real time RT-PCR and by the measurement of circulating cytokines and chemokines by ELISA. Moreover we performed FACS analysis of blood mononuclear cells from the patients enrolled in the study.
Results
A series of genes involved in innate and acquired immune responses were markedly up- or down-modulated before therapy. Such genes included CD14, CD36, LEPR, IRF-5, RGS-1, CD38, TNFRSF25, IL-4, CXCR4, CCR3, IL-8. Most of these modulated genes showed an expression similar to that of normal controls after immunoglobulin replacement. Real time RT-PCR of selected genes and serum levels of IL-4, CXCR4 before and after therapy changed accordingly to gene array results. Interestingly, serum levels of IL-8 remained unchanged, as the corresponding gene, before and after treatment. FACS analysis showed a marked decrease of CD8+T cells and an increase of CD4+T cells following treatment. Moreover we observed a marked increase of CD23−CD27−IgM−IgG− B cells (centrocytes).
Conclusions
Our results are in accordance with previous reports and provide further support to the hypothesis that the benefits of intravenous immunoglobulin therapy are not only related to antibody replacement but also to its ability to modulate the immune response in common variable immunodeficiency.
doi:10.1371/journal.pone.0097571
PMCID: PMC4022614  PMID: 24831519
19.  Feasibility of fully automated closed-loop glucose control using continuous subcutaneous glucose measurements in critical illness: a randomized controlled trial 
Critical Care  2013;17(4):R159.
Introduction
Closed-loop (CL) systems modulate insulin delivery according to glucose levels without nurse input. In a prospective randomized controlled trial, we evaluated the feasibility of an automated closed-loop approach based on subcutaneous glucose measurements in comparison with a local sliding-scale insulin-therapy protocol.
Methods
Twenty-four critically ill adults (predominantly trauma and neuroscience patients) with hyperglycemia (glucose, ≥10 mM) or already receiving insulin therapy, were randomized to receive either fully automated closed-loop therapy (model predictive control algorithm directing insulin and 20% dextrose infusion based on FreeStyle Navigator continuous subcutaneous glucose values, n = 12) or a local protocol (n = 12) with intravenous sliding-scale insulin, over a 48-hour period. The primary end point was percentage of time when arterial blood glucose was between 6.0 and 8.0 mM.
Results
The time when glucose was in the target range was significantly increased during closed-loop therapy (54.3% (44.1 to 72.8) versus 18.5% (0.1 to 39.9), P = 0.001; median (interquartile range)), and so was time in wider targets, 5.6 to 10.0 mM and 4.0 to 10.0 mM (P ≤ 0.002), reflecting a reduced glucose exposure >8 and >10 mM (P ≤ 0.002). Mean glucose was significantly lower during CL (7.8 (7.4 to 8.2) versus 9.1 (8.3 to 13.0] mM; P = 0.001) without hypoglycemia (<4 mM) during either therapy.
Conclusions
Fully automated closed-loop control based on subcutaneous glucose measurements is feasible and may provide efficacious and hypoglycemia-free glucose control in critically ill adults.
Trial Registration
ClinicalTrials.gov Identifier, NCT01440842.
doi:10.1186/cc12838
PMCID: PMC4056260  PMID: 23883613
20.  Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study 
Clinical Drug Investigation  2015;35(3):179-185.
Background and Objectives
Subcutaneous immunoglobulin (SCIG) therapy is becoming increasingly popular as self-administration is possible because intravenous access is unnecessary, and there is a lower frequency of systemic adverse events. The aim of this study was to evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with primary immunodeficiency (PID) in a routine real-life situation.
Methods
In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for 24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human IgG 16 %, Vivaglobin®, CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume 15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections (SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization.
Results
Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat (ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months. Local reactions were observed in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site. Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 (P < 0.01) at 6 months; there was an improvement also in the overall patients’ evaluation.
Conclusions
A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III clinical studies.
doi:10.1007/s40261-015-0270-1
PMCID: PMC4335091  PMID: 25672929
21.  Comparison of routes for achieving parenteral access with a focus on the management of patients with Ebola virus disease 
Background
Dehydration is an important cause of death in patients with Ebola virus disease (EVD). Parenteral fluids are often required in patients with fluid requirements in excess of their oral intake. The peripheral intravenous route is the most commonly used method of parenteral access, but inserting and maintaining an intravenous line can be challenging in the context of EVD. Therefore it is important to consider the advantages and disadvantages of different routes for achieving parenteral access (e.g. intravenous, intraosseous, subcutaneous and intraperitoneal).
Objectives
To compare the reliability, ease of use and speed of insertion of different parenteral access methods.
Search methods
We ran the search on 17 November 2014. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R), Embase Classic + Embase (OvidSP), CINAHL (EBSCOhost), clinicaltrials.gov and screened reference lists.
Selection criteria
Randomised controlled trials comparing different parenteral routes for the infusion of fluids or medication.
Data collection and analysis
Two review authors examined the titles and abstracts of records obtained by searching the electronic databases to determine eligibility. Two review authors extracted data from the included trials and assessed the risk of bias. Outcome measures of interest were success of insertion; time required for insertion; number of insertion attempts; number of dislodgements; time period with functional access; local site reactions; clinicians' perception of ease of administration; needlestick injury to healthcare workers; patients' discomfort; and mortality. For trials involving the administration of fluids we also collected data on the volume of fluid infused, changes in serum electrolytes and markers of renal function. We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach for the following outcomes: success of insertion, time required for insertion, number of dislodgements, volume of fluid infused and needlestick injuries.
Main results
We included 17 trials involving 885 participants. Parenteral access was used to infuse fluids in 11 trials and medications in six trials. None of the trials involved patients with EVD. Intravenous and intraosseous access was compared in four trials; intravenous and subcutaneous access in 11; peripheral intravenous and intraperitoneal access in one; saphenous vein cutdown and intraosseous access in one; and intraperitoneal with subcutaneous access in one. All of the trials assessing the intravenous method involved peripheral intravenous access.
We judged few trials to be at low risk of bias for any of the assessed domains.
Compared to the intraosseous group, patients in the intravenous group were more likely to experience an insertion failure (risk ratio (RR) 3.89, 95% confidence interval (CI) 2.39 to 6.33; n = 242; GRADE rating: low). We did not pool data for time to insertion but estimates from the trials suggest that inserting intravenous access takes longer (GRADE rating: moderate). Clinicians judged the intravenous route to be easier to insert (RR 0.15, 95% CI 0.04 to 0.61; n = 182). A larger volume of fluids was infused via the intravenous route (GRADE rating: moderate). There was no evidence of a difference between the two routes for any other outcomes, including adverse events.
Compared to the subcutaneous group, patients in the intravenous group were more likely to experience an insertion failure (RR 14.79, 95% CI 2.87 to 76.08; n = 238; GRADE rating: moderate) and dislodgement of the device (RR 3.78, 95% CI 1.16 to 12.34; n = 67; GRADE rating: low). Clinicians also judged the intravenous route as being more difficult to insert and patients were more likely to be agitated in the intravenous group. Patients in the intravenous group were more likely to develop a local infection and phlebitis, but were less likely to develop erythema, oedema or swelling than those in the subcutaneous group. A larger volume of fluids was infused into patients via the intravenous route. There was no evidence of a difference between the two routes for any other outcome.
There were insufficient data to reliably determine if the risk of insertion failure differed between the saphenous vein cutdown (SVC) and intraosseous method (RR 4.00, 95% CI 0.51 to 31.13; GRADE rating: low). Insertion using SVC took longer than the intraosseous method (MD 219.60 seconds, 95% CI 135.44 to 303.76; GRADE rating: moderate). There were no data and therefore there was no evidence of a difference between the two routes for any other outcome.
There were insufficient data to reliably determine the relative effects of intraperitoneal or central intravenous access relative to any other parenteral access method.
Authors' conclusions
There are several different ways of achieving parenteral access in patients who are unable meet their fluid requirements with oral intake alone. The quality of the evidence, as assessed using the GRADE criteria, is somewhat limited because of the lack of adequately powered trials at low risk of bias. However, we believe that there is sufficient evidence to draw the following conclusions: if peripheral intravenous access can be achieved easily, this allows infusion of larger volumes of fluid than other routes; but if this is not possible, the intraosseous and subcutaneous routes are viable alternatives. The subcutaneous route may be suitable for patients who are not severely dehydrated but in whom ongoing fluid losses cannot be met by oral intake.
A film to accompany this review can be viewed here (http://youtu.be/ArVPzkf93ng).
PLAIN LANGUAGE SUMMARY
Comparison of the different ways of giving fluids to patients who cannot drink enough, such as patients with Ebola virus disease
Background
Many patients with Ebola virus disease (EVD) die because they are dehydrated. Patients with EVD often experience severe vomiting and diarrhoea, which causes them to lose fluids that are difficult to replace by drinking alone. It is possible to give fluids in ways that do not involve the digestive tract; this is known as parenteral access. This includes infusing fluids into a vein (intravenously), into bone marrow (intraosseously), into fatty tissue under the skin (subcutaneously) or into the abdominal space (intraperitoneally). Giving fluids intravenously is the usual method, but can be problematic in patients with EVD because starting intravenous fluids can be difficult in very dehydrated patients, and infection control practices may make maintaining the infusion challenging. It is therefore useful if those caring for patients with EVD know the advantages and disadvantages of the other ways to give fluids, so that they can decide which is the most suitable for their patients.
Searches for trials
We carried out searches for trials comparing different parenteral access methods on 17 November 2014.
Trial characteristics
We found 17 trials involving 885 participants. None involved patients with EVD. Fifteen trials involved patients who required parenteral access for the infusion of fluids or medicines and two trials assessed different methods under simulated conditions, such as on a training manikin. Many trials were of poor quality.
Key results
When the results of these trials were gathered together, they suggested that both the intraosseous and subcutaneous routes may be easier and quicker to insert into patients than the intravenous route, but more fluid can be given intravenously than by either the intraosseous or subcutaneous method. There has not been enough research into the intraperitoneal method to know how it compares to the other methods.
Conclusions
Healthcare workers caring for patients with EVD should be aware of the alternative ways of giving fluids. The trials we found were not of very high quality, therefore we need to be cautious when drawing conclusions based on their results. However, together they suggest if intravenous access can be achieved easily, then this should be used as it allows the infusion of larger volumes of fluid. However, if intravenous access is not possible, intraosseous and subcutaneous routes are alternatives that can be inserted quickly. Many of the trials conducted so far are of poor quality and none involved patients with EVD, therefore more trials should be carried out.
A film to accompany this review can be viewed here.
doi:10.1002/14651858.CD011386.pub2
PMCID: PMC4455225  PMID: 25914907
22.  Protocol for a multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE) 
BMJ Open  2015;5(5):e008312.
Introduction
Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord which causes motor and sensory disturbance and limited recovery in 50% of patients. Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). Intravenous immunoglobulin (IVIG) has also been used as an adjunct to steroids, but evidence is lacking. We propose the first randomised control trial in adults and children, to determine the benefit of additional treatment with IVIG.
Methods and analysis
170 adults and children aged over 1 year with acute first episode TM or neuromyelitis optica (with myelitis) will be recruited over a 2.5-year period and followed up for 12 months. Participants randomised to the control arm will receive standard therapy of intravenous methylprednisolone (IVMP). The intervention arm will receive the above standard therapy, plus additional IVIG.
Primary outcome will be a 2-point improvement on the American Spinal Injury Association (ASIA) Impairment scale at 6 months postrandomisation by blinded assessors. Additional secondary and tertiary outcome measures will be collected: ASIA motor and sensory scales, Kurtzke expanded disability status scale, International Spinal Cord Injury (SCI) Bladder/Bowel Data Set, Client Services Receipt Index, Pediatric Quality of Life Inventory, EQ-5D, SCI Pain and SCI Quality of Life Data Sets. Biological samples will be biobanked for future studies. After 6-months' follow-up of the first 52 recruited patients futility analysis will be carried out. Health economics analysis will be performed to calculate cost-effectiveness. After 6 months’ recruitment futility analysis will be performed.
Ethics and dissemination
Research Ethics Committee Approval was obtained: 14/SC/1329. Current protocol: v3.0 (15/01/2015). Study findings will be published in peer-reviewed journals.
Trial registration numbers
This study is registered with EudraCT (REF: 2014-002335-34), Clinicaltrials.gov (REF: NCT02398994) and ISRCTN (REF: 12127581).
doi:10.1136/bmjopen-2015-008312
PMCID: PMC4452744  PMID: 26009577
HEALTH ECONOMICS; IMMUNOLOGY; NEUROLOGY; STATISTICS & RESEARCH METHODS
23.  Clinical Utility of Serologic Testing for Celiac Disease in Ontario 
Executive Summary
Objective of Analysis
The objective of this evidence-based evaluation is to assess the accuracy of serologic tests in the diagnosis of celiac disease in subjects with symptoms consistent with this disease. Furthermore the impact of these tests in the diagnostic pathway of the disease and decision making was also evaluated.
Celiac Disease
Celiac disease is an autoimmune disease that develops in genetically predisposed individuals. The immunological response is triggered by ingestion of gluten, a protein that is present in wheat, rye, and barley. The treatment consists of strict lifelong adherence to a gluten-free diet (GFD).
Patients with celiac disease may present with a myriad of symptoms such as diarrhea, abdominal pain, weight loss, iron deficiency anemia, dermatitis herpetiformis, among others.
Serologic Testing in the Diagnosis Celiac Disease
There are a number of serologic tests used in the diagnosis of celiac disease.
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibodies (DGP)
Serologic tests are automated with the exception of the EMA test, which is more time-consuming and operator-dependent than the other tests. For each serologic test, both immunoglobulin A (IgA) or G (IgG) can be measured, however, IgA measurement is the standard antibody measured in celiac disease.
Diagnosis of Celiac Disease
According to celiac disease guidelines, the diagnosis of celiac disease is established by small bowel biopsy. Serologic tests are used to initially detect and to support the diagnosis of celiac disease. A small bowel biopsy is indicated in individuals with a positive serologic test. In some cases an endoscopy and small bowel biopsy may be required even with a negative serologic test. The diagnosis of celiac disease must be performed on a gluten-containing diet since the small intestine abnormalities and the serologic antibody levels may resolve or improve on a GFD.
Since IgA measurement is the standard for the serologic celiac disease tests, false negatives may occur in IgA-deficient individuals.
Incidence and Prevalence of Celiac Disease
The incidence and prevalence of celiac disease in the general population and in subjects with symptoms consistent with or at higher risk of celiac disease based on systematic reviews published in 2004 and 2009 are summarized below.
Incidence of Celiac Disease in the General Population
Adults or mixed population: 1 to 17/100,000/year
Children: 2 to 51/100,000/year
In one of the studies, a stratified analysis showed that there was a higher incidence of celiac disease in younger children compared to older children, i.e., 51 cases/100,000/year in 0 to 2 year-olds, 33/100,000/year in 2 to 5 year-olds, and 10/100,000/year in children 5 to 15 years old.
Prevalence of Celiac Disease in the General Population
The prevalence of celiac disease reported in population-based studies identified in the 2004 systematic review varied between 0.14% and 1.87% (median: 0.47%, interquartile range: 0.25%, 0.71%). According to the authors of the review, the prevalence did not vary by age group, i.e., adults and children.
Prevalence of Celiac Disease in High Risk Subjects
Type 1 diabetes (adults and children): 1 to 11%
Autoimmune thyroid disease: 2.9 to 3.3%
First degree relatives of patients with celiac disease: 2 to 20%
Prevalence of Celiac Disease in Subjects with Symptoms Consistent with the Disease
The prevalence of celiac disease in subjects with symptoms consistent with the disease varied widely among studies, i.e., 1.5% to 50% in adult studies, and 1.1% to 17% in pediatric studies. Differences in prevalence may be related to the referral pattern as the authors of a systematic review noted that the prevalence tended to be higher in studies whose population originated from tertiary referral centres compared to general practice.
Research Questions
What is the sensitivity and specificity of serologic tests in the diagnosis celiac disease?
What is the clinical validity of serologic tests in the diagnosis of celiac disease? The clinical validity was defined as the ability of the test to change diagnosis.
What is the clinical utility of serologic tests in the diagnosis of celiac disease? The clinical utility was defined as the impact of the test on decision making.
What is the budget impact of serologic tests in the diagnosis of celiac disease?
What is the cost-effectiveness of serologic tests in the diagnosis of celiac disease?
Methods
Literature Search
A literature search was performed on November 13th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st 2003 and November 13th 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Studies that evaluated diagnostic accuracy, i.e., both sensitivity and specificity of serology tests in the diagnosis of celiac disease.
Study population consisted of untreated patients with symptoms consistent with celiac disease.
Studies in which both serologic celiac disease tests and small bowel biopsy (gold standard) were used in all subjects.
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, and retrospective cohort studies.
At least 20 subjects included in the celiac disease group.
English language.
Human studies.
Studies published from 2000 on.
Clearly defined cut-off value for the serology test. If more than one test was evaluated, only those tests for which a cut-off was provided were included.
Description of small bowel biopsy procedure clearly outlined (location, number of biopsies per patient), unless if specified that celiac disease diagnosis guidelines were followed.
Patients in the treatment group had untreated CD.
Studies on screening of the general asymptomatic population.
Studies that evaluated rapid diagnostic kits for use either at home or in physician’s offices.
Studies that evaluated diagnostic modalities other than serologic tests such as capsule endoscopy, push enteroscopy, or genetic testing.
Cut-off for serologic tests defined based on controls included in the study.
Study population defined based on positive serology or subjects pre-screened by serology tests.
Celiac disease status known before study enrolment.
Sensitivity or specificity estimates based on repeated testing for the same subject.
Non-peer-reviewed literature such as editorials and letters to the editor.
Population
The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease.
Serologic Celiac Disease Tests Evaluated
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibody (DGP)
Combinations of some of the serologic tests listed above were evaluated in some studies
Both IgA and IgG antibodies were evaluated for the serologic tests listed above.
Outcomes of Interest
Sensitivity
Specificity
Positive and negative likelihood ratios
Diagnostic odds ratio (OR)
Area under the sROC curve (AUC)
Small bowel biopsy was used as the gold standard in order to estimate the sensitivity and specificity of each serologic test.
Statistical Analysis
Pooled estimates of sensitivity, specificity and diagnostic odds ratios (DORs) for the different serologic tests were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance for differences in sensitivity and specificity between serologic tests was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. The bivariate regression analyses were performed using SAS version 9.2 (SAS Institute Inc.; Cary, NC, USA). Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced using Review Manager 5.0.22 (The Nordiac Cochrane Centre, The Cochrane Collaboration, 2008). The area under the sROC curve (AUC) was estimated by bivariate mixed-efects binary regression modeling framework. Model specification, estimation and prediction are carried out with xtmelogit in Stata release 10 (Statacorp, 2007). Statistical tests for the differences in AUC estimates could not be carried out.
The study results were stratified according to patient or disease characteristics such as age, severity of Marsh grade abnormalities, among others, if reported in the studies. The literature indicates that the diagnostic accuracy of serologic tests for celiac disease may be affected in patients with chronic liver disease, therefore, the studies identified through the systematic literature review that evaluated the diagnostic accuracy of serologic tests for celiac disease in patients with chronic liver disease were summarized. The effect of the GFD in patiens diagnosed with celiac disease was also summarized if reported in the studies eligible for the analysis.
Summary of Findings
Published Systematic Reviews
Five systematic reviews of studies that evaluated the diagnostic accuracy of serologic celiac disease tests were identified through our literature search. Seventeen individual studies identified in adults and children were eligible for this evaluation.
In general, the studies included evaluated the sensitivity and specificity of at least one serologic test in subjects with symptoms consistent with celiac disease. The gold standard used to confirm the celiac disease diagnosis was small bowel biopsy. Serologic tests evaluated included tTG, EMA, AGA, and DGP, using either IgA or IgG antibodies. Indirect immunoflurorescence was used for the EMA serologic tests whereas enzyme-linked immunosorbent assay (ELISA) was used for the other serologic tests.
Common symptoms described in the studies were chronic diarrhea, abdominal pain, bloating, unexplained weight loss, unexplained anemia, and dermatitis herpetiformis.
The main conclusions of the published systematic reviews are summarized below.
IgA tTG and/or IgA EMA have a high accuracy (pooled sensitivity: 90% to 98%, pooled specificity: 95% to 99% depending on the pooled analysis).
Most reviews found that AGA (IgA or IgG) are not as accurate as IgA tTG and/or EMA tests.
A 2009 systematic review concluded that DGP (IgA or IgG) seems to have a similar accuracy compared to tTG, however, since only 2 studies identified evaluated its accuracy, the authors believe that additional data is required to draw firm conclusions.
Two systematic reviews also concluded that combining two serologic celiac disease tests has little contribution to the accuracy of the diagnosis.
MAS Analysis
Sensitivity
The pooled analysis performed by MAS showed that IgA tTG has a sensitivity of 92.1% [95% confidence interval (CI) 88.0, 96.3], compared to 89.2% (83.3, 95.1, p=0.12) for IgA DGP, 85.1% (79.5, 94.4, p=0.07) for IgA EMA, and 74.9% (63.6, 86.2, p=0.0003) for IgA AGA. Among the IgG-based tests, the results suggest that IgG DGP has a sensitivity of 88.4% (95% CI: 82.1, 94.6), 44.7% (30.3, 59.2) for tTG, and 69.1% (56.0, 82.2) for AGA. The difference was significant when IgG DGP was compared to IgG tTG but not IgG AGA. Combining serologic celiac disease tests yielded a slightly higher sensitivity compared to individual IgA-based serologic tests.
IgA deficiency
The prevalence of total or severe IgA deficiency was low in the studies identified varying between 0 and 1.7% as reported in 3 studies in which IgA deficiency was not used as a referral indication for celiac disease serologic testing. The results of IgG-based serologic tests were positive in all patients with IgA deficiency in which celiac disease was confirmed by small bowel biopsy as reported in four studies.
Specificity
The MAS pooled analysis indicates a high specificity across the different serologic tests including the combination strategy, pooled estimates ranged from 90.1% to 98.7% depending on the test.
Likelihood Ratios
According to the likelihood ratio estimates, both IgA tTG and serologic test combinationa were considered very useful tests (positive likelihood ratio above ten and the negative likelihood ratio below 0.1).
Moderately useful tests included IgA EMA, IgA DGP, and IgG DGP (positive likelihood ratio between five and ten and the negative likelihood ratio between 0.1 and 0.2).
Somewhat useful tests: IgA AGA, IgG AGA, generating small but sometimes important changes from pre- to post-test probability (positive LR between 2 and 5 and negative LR between 0.2 and 0.5)
Not Useful: IgG tTG, altering pre- to post-test probability to a small and rarely important degree (positive LR between 1 and 2 and negative LR between 0.5 and 1).
Diagnostic Odds Ratios (DOR)
Among the individual serologic tests, IgA tTG had the highest DOR, 136.5 (95% CI: 51.9, 221.2). The statistical significance of the difference in DORs among tests was not calculated, however, considering the wide confidence intervals obtained, the differences may not be statistically significant.
Area Under the sROC Curve (AUC)
The sROC AUCs obtained ranged between 0.93 and 0.99 for most IgA-based tests with the exception of IgA AGA, with an AUC of 0.89.
Sensitivity and Specificity of Serologic Tests According to Age Groups
Serologic test accuracy did not seem to vary according to age (adults or children).
Sensitivity and Specificity of Serologic Tests According to Marsh Criteria
Four studies observed a trend towards a higher sensitivity of serologic celiac disease tests when Marsh 3c grade abnormalities were found in the small bowel biopsy compared to Marsh 3a or 3b (statistical significance not reported). The sensitivity of serologic tests was much lower when Marsh 1 grade abnormalities were found in small bowel biopsy compared to Marsh 3 grade abnormalities. The statistical significance of these findings were not reported in the studies.
Diagnostic Accuracy of Serologic Celiac Disease Tests in Subjects with Chronic Liver Disease
A total of 14 observational studies that evaluated the specificity of serologic celiac disease tests in subjects with chronic liver disease were identified. All studies evaluated the frequency of false positive results (1-specificity) of IgA tTG, however, IgA tTG test kits using different substrates were used, i.e., human recombinant, human, and guinea-pig substrates. The gold standard, small bowel biopsy, was used to confirm the result of the serologic tests in only 5 studies. The studies do not seem to have been designed or powered to compare the diagnostic accuracy among different serologic celiac disease tests.
The results of the studies identified in the systematic literature review suggest that there is a trend towards a lower frequency of false positive results if the IgA tTG test using human recombinant substrate is used compared to the guinea pig substrate in subjects with chronic liver disease. However, the statistical significance of the difference was not reported in the studies. When IgA tTG with human recombinant substrate was used, the number of false positives seems to be similar to what was estimated in the MAS pooled analysis for IgA-based serologic tests in a general population of patients. These results should be interpreted with caution since most studies did not use the gold standard, small bowel biopsy, to confirm or exclude the diagnosis of celiac disease, and since the studies were not designed to compare the diagnostic accuracy among different serologic tests. The sensitivity of the different serologic tests in patients with chronic liver disease was not evaluated in the studies identified.
Effects of a Gluten-Free Diet (GFD) in Patients Diagnosed with Celiac Disease
Six studies identified evaluated the effects of GFD on clinical, histological, or serologic improvement in patients diagnosed with celiac disease. Improvement was observed in 51% to 95% of the patients included in the studies.
Grading of Evidence
Overall, the quality of the evidence ranged from moderate to very low depending on the serologic celiac disease test. Reasons to downgrade the quality of the evidence included the use of a surrogate endpoint (diagnostic accuracy) since none of the studies evaluated clinical outcomes, inconsistencies among study results, imprecise estimates, and sparse data. The quality of the evidence was considered moderate for IgA tTg and IgA EMA, low for IgA DGP, and serologic test combinations, and very low for IgA AGA.
Clinical Validity and Clinical Utility of Serologic Testing in the Diagnosis of Celiac Disease
The clinical validity of serologic tests in the diagnosis of celiac disease was considered high in subjects with symptoms consistent with this disease due to
High accuracy of some serologic tests.
Serologic tests detect possible celiac disease cases and avoid unnecessary small bowel biopsy if the test result is negative, unless an endoscopy/ small bowel biopsy is necessary due to the clinical presentation.
Serologic tests support the results of small bowel biopsy.
The clinical utility of serologic tests for the diagnosis of celiac disease, as defined by its impact in decision making was also considered high in subjects with symptoms consistent with this disease given the considerations listed above and since celiac disease diagnosis leads to treatment with a gluten-free diet.
Economic Analysis
A decision analysis was constructed to compare costs and outcomes between the tests based on the sensitivity, specificity and prevalence summary estimates from the MAS Evidence-Based Analysis (EBA). A budget impact was then calculated by multiplying the expected costs and volumes in Ontario. The outcome of the analysis was expected costs and false negatives (FN). Costs were reported in 2010 CAD$. All analyses were performed using TreeAge Pro Suite 2009.
Four strategies made up the efficiency frontier; IgG tTG, IgA tTG, EMA and small bowel biopsy. All other strategies were dominated. IgG tTG was the least costly and least effective strategy ($178.95, FN avoided=0). Small bowel biopsy was the most costly and most effective strategy ($396.60, FN avoided =0.1553). The cost per FN avoided were $293, $369, $1,401 for EMA, IgATTG and small bowel biopsy respectively. One-way sensitivity analyses did not change the ranking of strategies.
All testing strategies with small bowel biopsy are cheaper than biopsy alone however they also result in more FNs. The most cost-effective strategy will depend on the decision makers’ willingness to pay. Findings suggest that IgA tTG was the most cost-effective and feasible strategy based on its Incremental Cost-Effectiveness Ratio (ICER) and convenience to conduct the test. The potential impact of IgA tTG test in the province of Ontario would be $10.4M, $11.0M and $11.7M respectively in the following three years based on past volumes and trends in the province and basecase expected costs.
The panel of tests is the commonly used strategy in the province of Ontario therefore the impact to the system would be $13.6M, $14.5M and $15.3M respectively in the next three years based on past volumes and trends in the province and basecase expected costs.
Conclusions
The clinical validity and clinical utility of serologic tests for celiac disease was considered high in subjects with symptoms consistent with this disease as they aid in the diagnosis of celiac disease and some tests present a high accuracy.
The study findings suggest that IgA tTG is the most accurate and the most cost-effective test.
AGA test (IgA) has a lower accuracy compared to other IgA-based tests
Serologic test combinations appear to be more costly with little gain in accuracy. In addition there may be problems with generalizability of the results of the studies included in this review if different test combinations are used in clinical practice.
IgA deficiency seems to be uncommon in patients diagnosed with celiac disease.
The generalizability of study results is contingent on performing both the serologic test and small bowel biopsy in subjects on a gluten-containing diet as was the case in the studies identified, since the avoidance of gluten may affect test results.
PMCID: PMC3377499  PMID: 23074399
24.  Infusion-Related Reaction Following Daptomycin Two-Minute Rapid Intravenous Administration 
Hospital Pharmacy  2014;49(7):644-646.
Abstract
Background:
Erythroderma, or red man’s syndrome, is a common infusion-related reaction following vancomycin administration. Erythroderma following daptomycin rapid infusion has not been documented.
Objective:
To report a case of erythroderma following daptomycin 2-minute intravenous (IV) injection.
Case Report:
A review of published literature suggests that this is the first published case of a flushing (nonallergic) reaction resulting from a 2-minute IV injection of daptomycin that is not present with standard IV infusion. A 69-year-old woman following right knee reconstructive surgery presented with right knee joint swelling, purulent discharge, and fever. Subsequently, she was diagnosed with a presumed postsurgical infection and was initiated on vancomycin therapy. Following removal of the infected hardware, the patient was discharged and continued outpatient vancomycin therapy. The patient’s renal function began to decline and therapy was discontinued. Daptomycin 6 mg/kg every 48 hours was initiated via 2-minute IV push. On the initial dose, approximately 2 hours post IV infusion, the patient began to notice redness and a warm sensation on her face, neck, and upper part of the chest. Diphenhydramine 25 mg provided limited immediate relief, but all symptoms subsided within 3 to 4 hours. The patient received her next dose 48 hours later over a 40-minute IV infusion with no adverse effects. Subsequent infusions continued at the same dose over 30 minutes for 4 weeks with no further adverse effects.
Conclusion:
A 2-minute intravenous injection of daptomycin in this patient yielded a reaction that was not present on rechallenge with standard, extended infusion.
doi:10.1310/hpj4907-644
PMCID: PMC4252235  PMID: 25477584
daptomycin; erythroderma; rapid infusion; red man’s syndrome; Staphylococcus aureus
25.  Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders 
Objective:
Intravenous immunoglobulin administration has long been used in the treatment of autoimmune neuromuscular disorders. Immunoglobulins may be administered by intramuscular, intravenous or subcutaneous routes.
Methods:
This is a report on the long-term clinical follow up of six patients with inflammatory neuromuscular disorders, that is, three chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy (MMN), one inclusion body myositis (IBM) and one myasthenia gravis (MG), treated with subcutaneous immunoglobulins for a mean of 3.25 years.
Results:
One MMN and two CIDP patients received a weekly dose of subcutaneous immunoglobulins equivalent to intravenous immunoglobulin. One CIDP patient received a 50% dose reduction, the IBM patient received a 30% reduction and the MG patient a 20% reduction. The lower dose chosen in the majority of patients was based not only on clinical effects, but also on studies of primary immunodeficiency syndromes. One patient with CIDP showed clinical fluctuation, which was successfully treated with an adaptation of the dose of subcutaneous immunoglobulins, while the remaining patients with neuromuscular disorders had a stable clinical course for 2 years. No serious side effects were observed.
Conclusions:
Our results suggest that subcutaneous immunoglobulins can be an attractive alternative therapy in autoimmune neuromuscular disorders.
doi:10.1177/1756285615584739
PMCID: PMC4480529  PMID: 26136842
chronic inflammatory demyelinating polyneuropathy; inclusion body myositis; multifocal motor neuropathy; myasthenia gravis; subcutaneous immunoglobulin

Results 1-25 (974958)