Rhinology Future Debates 2018, a EUFOREA Report.

The third Rhinology Future Debates was organized by the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) in 2018 in Brussels. Experts from different specialties and countries, alongside patients, health policy makers and industry representatives discussed relevant topics in Rhinology, in an attempt to improve current clinical practices, through implementation of precision medicine, by empowering patients' participation and the use of eHealth tools. The debates which are available on-line (www.rhinology-future.com) dealt with 5 topics in Rhinology: the adoption of allergen-specific immunotherapy (AIT) by implementing change management strategies, the needs and obstacles in care delivery in respiratory diseases, 3D technology in nose and sinus surgery, ambulatory nasal surgery, and clinical evidence for efficacy of biologicals in CRSwNP and asthma. This report summarizes the outcomes of the brainstorming sessions highlighting novel approaches and unmet needs in the field of respiratory diseases by focusing on integrated care pathways.

ARIA masterclass 2018: From guidelines to real-life implementation.

Over the past 20 years, ARIA (Allergic Rhinitis and its Impact on Asthma) has developed various guidelines for the treatment of allergic rhinitis (AR) and asthma multimorbidity. Over time, the ARIA initiative has evolved to ensure the highest level of bestpractices adoption in real life settings. It has evolved towards Integrated Care Pathways (ICPs) using mobile technology, and has now entered a new phase in which change management is key to provide an active and healthy life to all AR patients. With that in mind, the first ARIA masterclass was held on 12th September 2018 in Brussels, Belgium. The masterclass aimed at informing clinicians about the principles of change management, providing unbiased education on diagnosis and treatments, sharing the most recent research data on AR and multimorbidities, and creating a snowball effect to increase the adoption of best practices around the globe. This report provides an overview of the ARIA masterclass concept, summarizes the key lectures and discussions, and gives an outline of the future key development.

Patient Advisory Board for Chronic Rhinosinusitis - A EUFOREA initiative.

Despite the high prevalence of chronic rhinosinusitis (CRS) and its impact on patients' quality of life, no European patient organization that advocates for patients with CRS currently exists. To fill this gap and give a voice to CRS patients, EUFOREA has created a patient advisory board, whose goal is to better understand the real-life needs of patients, to raise awareness at political level and to involve patients in the development of novel integrated solutions to accelerate access to accurate diagnosis and treatments. This report summarizes the key discussion points from the kick-off meeting of the board on the 8th June 2018 and provides an outline of the key objectives for the future.

Cost-effectiveness of open versus endovascular repair of abdominal aortic aneurysm.

BACKGROUND: Patients with a large unruptured abdominal aortic aneurysm with a diameter >5.0 cm are treated with open surgical repair (OSR) or endovascular aneurysm repair (EVAR). Because many studies have assessed the cost-effectiveness of these treatments with conflicting results, this systematic review examined published cost-effectiveness analyses of elective EVAR vs OSR in patients with abdominal aortic aneurysm. METHODS: A systematic search strategy using three databases was conducted to find all relevant studies. Characteristics extracted from these studies included study characteristics (eg, age of the population), input parameters (eg, costs of the EVAR procedure), general results, and sensitivity analyses. The quality of each study was assessed using the Drummond checklist. RESULTS: The search identified 1141 potentially relevant studies, of which 13 studies met inclusion criteria. Most studies found that EVAR was more expensive and more effective than OSR. However, most studies concluded that the health gained from EVAR did not offset the higher total costs, leading to an unacceptably high incremental cost-effectiveness ratio. EVAR was considered more cost-effective in patient groups with a high surgical risk. The quality of most studies was judged as reasonably good. CONCLUSIONS: Overall, published cost-effectiveness analyses of EVAR do not provide a clear answer about whether elective EVAR is a cost-effective solution because the incremental cost-effectiveness ratio varies considerably among the studies. This answer can best be provided through a cost-effectiveness analysis of EVAR that incorporates more recent technologic advances and the improved experience that clinicians have with EVAR.

Stepwise approach towards adoption of allergen immunotherapy for allergic rhinitis and asthma patients in daily practice in Belgium: a BelSACI-Abeforcal-EUFOREA statement.

Allergic rhinitis (AR) affects 23-30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontrolled. Allergen immunotherapy (AIT) has been shown to improve the level of control up to 84% of patients being controlled by AIT. Recently, new guidelines for AIT have been published, supporting the clinical evidence for effectiveness of various subcutaneous and sublingual products for AIT in patients who are allergic to airborne allergens. AIT in AR patients not only reduces nasal and/or ocular symptoms but also induces tolerance and has preventive potential. Adoption of AIT into daily clinical practice in Belgium and other European countries is hampered primarily by reimbursement issues of each of the single products but also by several patient- and physician-related factors. Patients need to be better informed about the effectiveness of AIT and the different routes of administration of AIT. Physicians dealing with AR patients should inform patients on tolerance-inducing effects of AIT and are in the need of a harmonized and practical guide that supports them in selecting eligible patients for AIT, in choosing evidence-based AIT products and in following treatment protocols with proven efficacy. Therefore, a stepwise and holistic approach is needed for better adoption of AIT in the real-life setting in Belgium.

Counterimmunoelectrophoresis with serum prediffusion: an improved method for the detection and identification of antibodies against extractable nuclear and cytoplasmic antigens.

In the technique of counterimmunoelectrophoresis (CIE) with serum prediffusion (SPD) serum is allowed to diffuse freely into the gel before pouring the antigenic extract in its trough (or wells) and starting the electrophoresis. Both the immunoprecipitations and the interactions with reference sera are strongly intensified by SPD, leading to higher sensitivity and specificity for the detection of anti-SSA/Ro, anti-SSB/La, anti-U1RNP, anti-Sm, anti-Jo1 and even anti-Scl-70 antibodies. We found that the optimal SPD time was 2 h. To evaluate the relevance of SPD for the clinical laboratory, 92 antinuclear antibody (ANA) positive sera were tested on CIE without SPD and with 2 h SPD in identification tests with SSA/Ro, SSB/La, Sm, U1RNP and Jo1 reference sera (rsa). The precipitation lines and their interactions were evaluated by three independent observers. It was observed that SPD considerably improved the efficiency of CIE for antibody identification. The mechanisms underlying the intensification of the precipitation lines by SPD are discussed as are the characteristics of the CIE in comparison with other test systems such as the enzyme linked immunosorbent assay (ELISA) and immunoblot.

Predictive value of bronchoalveolar lavage in pulmonary sarcoidosis.

We investigated whether analysis of cellular composition (including lymphocyte subsets) in bronchoalveolar lavage (BAL) fluid at the start of follow-up in patients with untreated sarcoidosis has any predictive value for further evolution of the disease. The outcome was evaluated by the chest roentgenograms, the lung volumes, and the single breath diffusing capacity for CO (DCO) after 22 to 36 months. In contrast to the general belief, patients who improved radiologically had a significantly higher T4 cell count (as percentage of BAL lymphocytes) (p less than 0.02) and a higher T4-T8 ratio in the initial BAL sample (9.3 vs 3.2; p less than 0.05) than those whose chest roentgenogram showed deterioration or remained unchanged. Total cell count and the percentage of lymphocytes in BAL fluid were not different between both groups. The change in DCO at the end of the follow-up period correlated positively with the baseline BAL T4 cells (Rs = 0.44; p less than 0.05) and with the BAL T4-T8 ratio (Rs = 0.51; p less than 0.03) and negatively with the baseline BAL T8 cells (Rs = -0.48; p less than 0.04). In only three patients progression of the disease necessitated steroid therapy, and they all had a low to normal T4-T8 ratio in the initial BAL sample. Bronchoalveolar lavage was repeated at least once in ten patients. Improvement of the chest roentgenograms in these patients was accompanied by a decrease of the BAL T4 cell count (as percentage of lymphocytes) and of the T4-T8 ratio. We conclude that a high lymphocyte count, a high T4 cell count (as percentage of lymphocytes), and a high T4-T8 ratio in BAL fluid reflect an intense alveolitis at the time of the procedure, but they are not indicators of poor prognosis on which therapeutic decisions can be based.

Monoclonal IgM: difficulties with correct measurement.

We describe three monoclonal IgM paraproteins for which nephelometric IgM quantification generated inaccurate results.

Screening for autoantibodies to SS-A/RO by indirect immunofluorescence using HEp-2000 cells.

We evaluated indirect immunofluorescence (IF) using HEp-2000 slides, which are transfected with SS-A cDNA, for screening for anti-SS-A antibodies, by comparing it with counterimmunoelectrophoresis (CIE). A total of 2427 specimens were screened for IF reactivity and for SS-A precipitins, of which 1033 (43%) were negative on both IF and CIE. There were 1271 SS-A precipitin-negative specimens (52%) which were IF-positive but lacked the distinctive SS-A staining pattern. One precipitin-negative serum was IF-positive with the distinctive SS-A pattern in the HEp-2000 system. One hundred and twenty-two specimens (5%) were positive for anti-SS-A precipitins on CIE, 107 showed the distinctive SS-A fluorescence staining pattern, whereas 15 of these precipitin-positive samples (12%) were IF-positive but did not display the distinctive SS-A pattern on the transfected cells. Fourteen of the 15 samples in which the distinctive SS-A pattern was not observed displayed other significant antinuclear antibody (titre equal or >1:320) patterns. In conclusion, the presence of the typical 'distinctive' SS-A pattern on IF using the HEp-2000 slides is highly specific for the presence of autoantibodies to SS-A and has a sensitivity of 88% for detecting these antibodies.

Influence of common cold and of parenteral administration of influenza virus antigens on bronchoalveolar lavage cells.

We investigated in a pilot study on healthy young subjects whether a common cold or a vaccination with influenza virus antigens within 10 days influenced the number and subsets of inflammatory cells in the bronchoalveolar lavage (BAL) fluid. The total number of BAL-cells was about doubled in the common cold group, yet no consistent changes in overall cell distribution was found. Among BAL-lymphocytes the ratio of helper-inducer over suppressor-cytotoxic lymphocytes (THI/TCS) tended to be increased in both groups, due to a lower percentage of TCS-cells, which was significant in the vaccination group only. In the blood, on the contrary, the THI/TCS ratio was significantly decreased in both groups due to a drop in THI-cells; in addition, the proportions of E-Rosette (+) T-cells and of activated (Ia+) T-cells were slightly increased. In conclusion, only minor changes in inflammatory BAL-cells were observed, which, however, may interfere with the effects of other diseases.

Clinical spectrum associated with positive ANCA titres in 94 consecutive patients: is there a relation with PR-3 negative c-ANCA and hypergammaglobulinaemia?

OBJECTIVE: To calculate the positive predictive value (ppv) of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) and anti-proteinase 3 (PR 3) antibodies for Wegener's granulomatosis (WG) and to evaluate their association with other diseases. METHODS: The clinical files of all 94 patients who had a positive c- or perinuclear (p)-ANCA test, or both, in the laboratory of the University Hospital, Leuven between April 1995 and March 1996 and who attended the Internal Medicine Department of the hospital were retrospectively studied. RESULTS: Of the 94 patients with ANCAs (fluorescence titre > or = 1/40), 57 were c-ANCA positive and 45 p-ANCA positive (eight were simultaneously c- and p-ANCA positive). Of the 57 c-ANCA positive patients, 23 had WG. The ppv for WG thus was 40%. This value did not increase by defining a higher threshold for a positive ANCA. There was not a good relation between ANCA titres and disease activity in the WG patients, nor was there a relation between anti-PR 3 antibody levels and WG disease activity. The ppv of anti-PR 3 antibodies for WG however was very high (85%). There was a positive correlation between the level of (hyper) gammaglobulinaemia and c-ANCA titres in those patients with final diagnoses not known to be associated with c-ANCA. Forty five patients had positive p-ANCAs. The largest group were those with inflammatory bowel disease (n = 20, of whom the majority had colitis ulcerosa or primary sclerosing cholangitis, or both); the great majority of these patients had no anti-myeloperoxidase antibodies. Vasculitis was present in eight patients, of whom two had WG (both were also c-ANCA positive). CONCLUSION: There is a low ppv of c-ANCAs for WG, caused by a high percentage of PR 3 negative, positive c-ANCA determinations, possibly related to hypergammaglobulinaemia. Anti-PR 3 antibodies have a high ppv for WG. However, neither c-ANCA titre, nor the level of anti-PR 3 antibodies correlated with the activity of the disease.

Endocarditis caused by Staphylococcus warneri on a normal aortic valve following vasectomy.

Endocarditis caused by Staphylococcus warneri and necessitating valve replacement occurred in a previously healthy 32-year-old patient following vasectomy. No sign of an underlying valvular defect was noted during the operation. S. warneri is a recently identified species of coagulase-negative staphylococci. Endocarditis caused by coagulase-negative staphylococci is uncommon in young, healthy patients with normal heart valves and has not previously been described as a complication of vasectomy. Similarly, infections caused by S. warneri have not previously been described in humans.

PIP: Endocarditis caused by Staphylococcus warneri and necessitating valve replacement occurred in a previously health 32 year old patient following vasectomy. No sign of an underlying valvular defect was noted during the operation. S. warneri is a recently identified species of coagulase-negative staphylococci. Endocarditis caused by coagulase-negative staphylococci is uncommon in young, healthy patients with normal heart valves and has not previously been described as a complication of vasectomy. Similarly, infections caused by S. warneri have not previously been described in humans.

Decreased haptoglobin levels in respiratory allergy.

As unusually high frequency of decreased haptoglobin levels in patients with asthma and/or rhinitis is described. The condition is significantly associated with haptoglobin 2-2 phenotype. Decreased haptoglobin levels are more frequently associated with young age, atopic antecedents, positive skin tests for pollens, higher IgE and higher RAST activity for pollens and housedust mite. Whether the association of decreased haptoglobin levels and IgE-mediated respiratory disease has a physiopathological significance or is solely the expression of a common genetic determinate remains to be investigated.

Elimination of paraprotein interference in determination of plasma inorganic phosphate by ammonium molybdate method.

Phosphate concentrations were determined in 52 cases of paraproteinemia. The unmodified acidic ammonium molybdate method produced 19% spuriously high results. The false increase of phosphate concentration was attributable to formation of precipitate in the reaction mixture. The precipitate was formed by interaction between immunoglobulins and the unmodified acidic ammonium molybdate reagent. The magnitude of interference bore no relation to the type, concentrations, or isoelectric point of the paraproteins or to the presence or absence of free light chains. Diluting the sample to approximately 40 g/L total protein reduced but did not always eliminate the interference. In some cases paraprotein concentration as low as 8 g/L falsely increased plasma phosphate results. Apparently, only IgG and IgM but not IgA paraproteins produced the interference. Deproteination by ultrafiltration or by treatment with trichloroacetic acid removed the interference. The Kodak slide method and the new modified Boehringer Mannheim phosphate test were found to be interference-free. However, in some cases the latter new formulation is sensitive to substantial changes in ionic concentration of the reaction mixture.

Simultaneous macroamylasemia and macrolipasemia.

The first case of the simultaneous presence of macroamylasemia and macrolipasemia in a patient with gluten enteropathy (celiac disease) is described. Both macroenzymes were formed by association of polyclonal IgA with amylase and lipase. Both macroenzymes had molecular masses > 300 kDa.

Methods of assessing diabetic control.

Control of diabetes from complete normalisation to less adequate degrees of metabolic regulation needs to be assessed with regard to conditions of evaluation and to severity of the disease. Under optimal conditions the therapeutic events should occur with well-timed regularity. Different assessment criteria are appropriate depending on the severity of the deficiency of endogenous insulin. Plasma and urine glucose and ketone body measurements remain the practical standards for assessing diabetic control. Abnormalities of lipid and protein metabolites serve to augment the scope of the assessment. Triglycerides and haemoglobin AIc are also useful indicators of control. In mild (Type II) diabetes it may be possible to achieve normal plasma glucose measurements two hours after meals. Such aims carry a risk of hypoglycaemia in severe (Type I) diabetes. Normoglycaemia and aglycosuria in severe diabetes are feasible only preprandially in most cases. The use of urine glucose tests requires evaluation of blood-to-urine glucose relationships. Practical and convenient methods for identifying patients with high or low "renal thresholds" are described. Investigational methods for characterising diabetic patients assess the variability of glucose and other variables during therapy, as well as the degree to which normal values are attained. Such assessment methods may gain increasing practical importance as therapeutic approaches to diabetic control which are experimental at present come into practice.

Efficacy of moxalactam in an animal model of subcutaneous abscesses: penetration into infected sites and in vivo activity against Bacteroides fragilis.

Moxalactam was compared with alternative antimicrobial agents for in vivo activity against Bacteroides fragilis. Mice were challenged with one of 15 strains and evaluated by quantitative bacteriologic analysis of abscess contents after five days of treatment. Optimal results were achieved with clindamycin, moxalactam, and cefoxitin. The mean decrease in bacteria with these three drugs was significantly greater than with chloramphenicol, cefotaxime, carbenicillin, cephalothin, ampicillin, and cefoperazone. The penetration of antimicrobial agents into subcutaneous abscesses was examined. The mean peak level in sterile abscesses of moxalactam was 27% of the mean peak serum level, a result indicating relatively good penetration compared with other beta-lactam antimicrobial agents. Stability of moxalactam to the beta-lactamase of B. fragilis was demonstrated in vivo by comparing levels of biologically active drug in sterile and infected abscesses and in vitro by comparing levels of antibiotic incubated in sterile exudate and exudate infected with B. fragilis. Moxalactam compares favorably with clindamycin and cefoxitin in activity against B. fragilis.

Alveolar T-cell subsets in pulmonary sarcoidosis. Correlation with disease activity and effect of steroid treatment.

Alveolar lymphocytes, obtained by bronchoalveolar lavage in 35 patients with sarcoidosis, were analyzed with monoclonal antibodies to lymphocyte subsets. Untreated patients had significantly higher percentages of Leu 3a (+) T helper-inducer cells (THI) and significantly lower Leu 2a (+) T cytotoxic-suppressor cells (TCS) within the alveolar lymphocyte population than did normal control subjects (p less than 0.002). The mean ratio of alveolar THI to TCS cells was 6.20 +/- 3.76 versus 1.44 +/- 0.54 in control subjects (p less than 0.002). Untreated patients had a percentual enrichment of THI cells among alveolar lymphocytes relative to blood (p less than 0.0002), whereas TCS cells in percent of lymphocytes were lower in alveolar lavage fluid than in blood (p less than 0.002). These shifts were not observed in the control subjects. Patients with high-intensity alveolitis (i.e., T cells constituted 28% or more of alveolar inflammatory cells) had significantly greater proportions of THI cells among alveolar lymphocytes than did those with low-intensity alveolitis (p less than 0.01). This percent of alveolar THI cells correlated positively with the number of lymphocytes and T cells in percent of alveolar cells (p less than 0.03), which both are indexes of disease activity. In untreated patients who were lavaged at least twice, a decrease in the THI/TCS ratio was found to accompany or precede radiologic and clinical improvement, but the initial THI/TCS ratio was not predictive of further evolution. Steroid treatment decreased the THI/TCS ratio with a marked increase in the proportion of TCS cells. These changes were independent of an effect on the number of alveolar lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of ASCA (Anti-Saccharomyces cerevisiae antibody) assays in inflammatory bowel disease.

BACKGROUND & AIMS: Anti-Saccharomyces cerevisiae antibody (ASCA) is a serologic marker associated with Crohn's disease (CD). Although there is still discussion on its clinical value, several companies each promote their own ASCA assay to be used in the gastroenterologist's practice at considerable expense. The aim of this study was to determine whether different ASCA assays agree sufficiently well for the results to be used interchangeably. METHODS: Blood obtained from a large cohort of IBD patients with inflammatory bowel disease (IBD; 100 with CD, 100 with ulcerative colitis [UC]) and 178 controls (100 healthy blood donors and 78 patients with non-IBD diarrheal illnesses) was studied with 4 different ASCA assays. Sensitivity, specificity, and positive predictive value were compared. Agreement between assays was evaluated. RESULTS: Sensitivity of ASCA for CD ranged between 41% and 76%. Sensitivity was inversely related to specificity and positive predictive value. Results correlated well overall (range = 0.54-0.90) and the different ROC curves showed good agreement. When recalculated cutoff points were used, interchangeability increased. However, large differences were seen when absolute values were compared. CONCLUSIONS: A large range in sensitivities and specificities of ASCA for CD is seen with different ASCA assays, mainly as a consequence of the cutoff value chosen for each individual assay. Although agreement between and within assays is good, caution is important when absolute values are used. Standardization of ASCA measurements is greatly needed.