Distance optical sensor for quantitative endoscopy.

We present a novel optical sensor able to mea- sure the distance between the tip of an endoscopic probe and the anatomical object under examination. In medical endoscopy, knowledge of the real distance from the endo- scope to the anatomical wall provides the actual dimen- sions and areas of the anatomical objects. Currently, en- doscopic examination is limited to a direct and qualitative observation of anatomical cavities. The major obstacle to quantitative imaging is the inability to calibrate the ac- quired images because of the magnification system. How- ever, the possibility of monitoring the actual size of ana- tomical objects is a powerful tool both in research and in clinical investigation. To solve this problem in a satisfac- tory way we study and realize an absolute distance sensor based on fiber optic low-coherence interferometry FOLCI. Until now the sensor has been tested on pig tra- chea, simulating the real humidity and temperature 37°C conditions. It showed high sensitivity, providing correct and repeatable distance measurements on biologi- cal samples even in case of very low reflected power down to 2t o 3n W, with an error lower than 0.1 mm. © 2008 Society of Photo-Optical Instrumentation Engineers. DOI: 10.1117/1.287013

Clinical effectiveness of hymenoptera venom immunotherapy

Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors. Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters with the frequency of VIT failure during the maintenance phase. In this observational prospective multicenter study, we followed 357 patients with established honey bee or vespid venom allergy after the maintenance dose of VIT had been reached. In all patients, VIT effectiveness was either verified by sting challenge (n = 154) or patient self-reporting of the outcome of a field sting (n = 203). Data were collected on BTC, age, gender, preventive use of anti-allergic drugs (oral antihistamines and/or corticosteroids) right after a field sting, venom dose, antihypertensive medication, type of venom, side effects during VIT, severity of index sting reaction preceding VIT, and duration of VIT. Relative rates were calculated with generalized additive models. 22 patients (6.2%) developed generalized symptoms during sting challenge or after a field sting. A strong association between the frequency of VIT failure and BTC could be excluded. Due to wide confidence bands, however, weaker effects (odds ratios <3) of BTC were still possible, and were also suggested by a selective analysis of patients who had a sting challenge. The most important factor associated with VIT failure was a honey bee venom allergy. Preventive use of anti-allergic drugs may be associated with a higher protection rate. It is unlikely that an elevated BTC has a strong negative effect on the rate of treatment failures. The magnitude of the latter, however, may depend on the method of effectiveness assessment. Failure rate is higher in patients suffering from bee venom allergy

Hymenoptera Venom Immunotherapy (printer-friendly)

Abstract and Introduction Abstract Subcutaneous venom immunotherapy is the only effective treatment for patients who experience severe hymenoptera sting-induced allergic reactions, and the treatment also improves health-related quality of life. This article examines advances in various areas of this treatment, which include the immunological mechanisms of early and long-term efficacy, indications and contraindications, selection of venom, treatment protocols, duration, risk factors for systemic reactions in untreated and treated patients as well as for relapse following cessation of treatment. Current and future strategies for improving safety and efficacy are also examined. However, although progress in the past few years has been fruitful, much remains to be accomplished. Introduction Hymenoptera stings can induce allergic systemic and occasionally fatal reactions. The offending hymenoptera belong to the suborder Aculeate, which are made up of the Apoidea (Apis mellifera and Bombus species) and Vespidae (Vespinae and Polistinae subfamilies) superfamilies, [1] Detailed clinical features of insect sting reactions and their pathogenesis are described elsewhere. Authors and Disclosures Classification by HL Mueller Grade I -Generalized urticaria, itching, malaise and anxiety Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 1 of 22 6/4/2011 9:10 μμ In the USA, the prevalence of SRs to hymenoptera sting in the general population ranges from 0.5 to 3.3%. European epidemiological studies from the last decade report a prevalence of 0.3-8.9% for SRs, with anaphylaxis reported in 0.3-42.8% of cases. To date, there is no existing parameter that enables clinicians to predict who will have a future reaction and whether it will be a LLR or generalized anaphylaxis. Several concomitant factors, which include the environment, genetics and individual elements, may account for the occurrence of a SR in any one patient. [11] Mechanisms of Action of VIT The underlying immunological mechanisms of VIT are continuously being elucidated. Different mechanisms involving specific cell populations, play a role in the different phases of VIT, [10] The proposal of blocking antibodies has been Grade II -Any of the above plus two or more of the following: angioedema, chest constriction, nausea, vomiting, diarrhea, abdominal pain and dizziness Grade III -Any of the above plus two or more of the following: dyspnea, wheezing, stridor, dysarthria, hoarseness, weakness, confusion and feeling of impending disaster Grade IV -Any of the above plus two or more of the following: fall in blood pressure, collapse, loss of consciousness, incontinence and cyanosis Classification by J Ring Grade I -Generalized skin symptoms (e.g., flush, generalized urticaria and angioedema) Grade II -Mild to moderate pulmonary, cardiovascular and/or gastrointestinal symptoms Grade III -Anaphylactic shock and loss of consciousness Grade IV -Cardiac arrest and apnea Adapted from Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 2 of 22 6/4/2011 9:10 μμ re-evaluated on the basis of observations of altered specificity and affinity during immunotherapy and effects on memory B cells and antigen-presenting cells. Very early effects of VIT are also associated with an early decreased mediator release from mast cells and basophils, although the mechanism of this desensitization effect is, as yet, unknown. [24] Indications &amp; Contraindications Indications for VIT are based on the history of a SR, a positive venom skin or specific IgE, knowledge of the natural history and established risk factors for a severe outcome. Patient History The history is especially important as diagnostic tests with venoms are positive in 10-20% of asymptomatic individuals. The patient is asked to describe his/her symptoms and course of the sting reaction, number of stings, cues to the type of insect involved and individual risk factors for anaphylaxis. In general, cutaneous manifestations are more common in children than in adults, respiratory symptoms occur with equal frequency in approximately 40% of children and adults, while cardiovascular signs and symptoms are common in adults, whereas these are infrequent in children. Diagnostic Testing The decision to commence VIT requires confirmation of allergic sensitivity to venom allergens by positive venom skin tests and/or detection of venom-specific IgE antibodies in the serum. The European Academy of Allergology and Clinical Immunology (EAACI) [1] However, some patients reported having only manifest sensitization in the first week after being stung. Even at venom concentrations of 100 µg/ml, the sensitivity of the skin prick test is lower than that of the intradermal test, which has to be used in order to confirm the negative result (from a concentration of 0.001 up to 1 µg/ml). [1] Skin tests with hymenoptera venoms are generally safe; nevertheless, SRs do occur, although these are very rare. [2] Hymenoptera venom products, such as lyophilized protein extract for honey bee, bumble bee, yellow jacket and Polistes wasp venoms, are commercially available in many countries, the latter two being mixtures of the clinically relevant species. Due to incomplete cross-reactivity between venoms of the European and American species of Polistes, [1] If in vitro tests are negative in approximately 20% of positive skin tests, [1] Indeed, the most reactive skin tests often occur in patients with only LLRs, while almost 25% of patients who are referred for evaluation of a sting SR are intradermal skin-test positive only at the 1 µg/ml concentration, thus demonstrating the importance of testing with the full diagnostic range of venoms. [32] Double positivity to both bee and vespid venoms in diagnostic tests has been observed in 25-40% of HVA patients, the majority of whom have a single-positive history and are unable to identify the culprit insect. Double positivity may arise from double sensitization, cross-reactivity between epitopes on hyaluronidase in the two venoms or to cross-reactivity between cross-reactive carbohydrate determinants (CCDs) of venoms and common allergens. [34] Specific IgE to the recombinant nonglycosylated major allergen, Api m 1, was detected in 99% of cases of whole bee venom-positive allergy, while sIgE to Ves v 5 was present in 96% of whole Vespula venom-positive allergic patients when tested by ADVIA Centaur, thus reducing the double positivity to 17%. [36] On the other hand, there are those patients with a clear history of a SR but negative skin and in vitro radioallergosorbent test (RAST) results. [44] Finally, live insect sting challenges should not be used as a diagnostic tool in untreated patients, as the absence of systemic symptoms does not rule out the possibility of a SR to a future sting. [46] Natural History &amp; Risk Factors Reaction severity, confirmation of venom IgE sensitivity, current knowledge of the natural history of HVA and risk factors form the selection criteria for suitable VIT candidates, when deciding whether to start VIT and for how long to treat them for. In general, the risk of recurrence of SRs is linked to the severity of the previous reaction: the more serious the initial reaction, the greater the risk of recurrence. Linking the estimated risk of a future SR with reaction severity, age and sting interval, adults and children with LLRs are a low-risk category for a SR (5-15%) when re-stung. [50] Other risk factors associated with the occurrence of a severe field-sting SRs in untreated patients are represented by an increased baseline tryptase concentration, Contrary to previous findings, [10] Venom immunotherapy is indicated in HVA patients with mast-cell diseases as the treatment can reduce SRs, albeit to a lesser extent than in otherwise healthy subjects with HVA; [25] Venom immunotherapy is able to reduce the severity and duration of LLRs and its efficacy improves over a period of 2-4 years. [57] Although VIT is not usually recommended in patients with such reactions, as the risk of a subsequent systemic sting reaction is low, physicians may consider it as a treatment option when confronted with extremely anxious patients with HRQL impairment or highly exposed subjects who require repeated per annum corticosteroid shots. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 5 of 22 6/4/2011 9:10 μμ Contraindications In Europe, the standards for practical allergen-specific immunotherapy [45] Untreated patients with anaphylaxis should not be given β-blockers, except under circumstances where the administration of these drugs is urgently required as in the case of certain heart rhythm disorders. Administration of VIT to patients receiving β-blockers (even in eye drops) is contraindicated as they can aggravate anaphylactic reactions and also interfere with treatment. However, if the cardiac risk in venom allergic patients outweighs the risk of a systemic reaction during VIT, then VIT is appropriate for use in subjects receiving β-blockers but must be performed in an emergency care setting. [60] Severe allergic reactions, including anaphylaxis, have been described in patients on angiotensin-converting enzyme (ACE)-inhibitors subsequent to being stung or receiving immunotherapy. [25] Currently, there are no data to support or exclude the potentially harmful role of angiotensin-receptor blockers in patients with anaphylaxis in general, or in HVA-untreated patients. [61] As regards the other contraindications, such as serious immunological diseases and cancer, the European guidelines need to be reviewed in order to cater for cases of severe sting allergic reactions, particularly where there is a high risk of sting exposure, a history of a near-fatal sting reaction and perhaps for mast-cell diseases given the treatment&apos;s life-saving potential. Indeed, in some selected cases the advantages of VIT might outweigh the potential negative effects. Venom immunotherapy should not be begun during pregnancy, but well-tolerated maintenance VIT may be continued in order to prevent the risk of further SRs in the mother as well as in the fetus. [59] Selection of Venoms Selection is based on the identification of the hymenoptera species that is involved, on the results of the diagnostic tests and on venom cross-reactivity. In North America, allergists and immunologists believe it prudent to prescribe VIT with any venom, which gives a positive skin test, or sIgE result, since there have been cases where VIT was tailored towards the primary culprit insect but the patients subsequently reacted to an insect to which they had previously been sensitized. In Europe, the geographical distribution of each species and the ample cross-reactivity among venoms of Vespula, Dolichovespula and Vespa, usually makes treatment with Vespula venom alone sufficient in the temperate European climate. Double diagnostic positivities to wasp (Polistes) and yellow jacket (Vespula species) venoms have been observed in Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 6 of 22 6/4/2011 9:10 μμ more than 50% of vespid allergic patients. Owing to the incomplete cross-reactivity between vespinae and paper wasps (Polistes) in the Mediterranean area, patients who test positive to both venoms should be treated with both, unless RAST-inhibition reveals cross-reactivity. [10] The same approach is used in the Gulf states of the USA, where Polistes is common as a species. [31] A weaker cross-reactivity between European and American paper wasps was recently demonstrated. [27] The species P. dominulus and Polistes gallicus are European paper wasps; P. dominulus has spread to northeastern USA and has also been reported in Australia. The species Polistes exclamans, Polistes annularis and Polistes fuscatus are indigenous to North America and are not present in Europe. All these findings raise the need to introduce, at least in Europe, the P. gallicus or P. dominulus extract (the latter only recently being available in some European countries) into clinical practice for diagnostic and therapeutic purposes to replace the American Polistes species mixture presently being used. [55] V. crabro venom has some antigens in common with Vespula venom; however, a third of V. crabro-allergic individuals have positive skin and sIgE tests restricted to only V. crabro venom. Italy, it is a common practice to use V. crabro extract for both diagnostic and therapeutic purposes. Dual positivity of diagnostic tests with Vespula and honeybee is also frequent, especially in some European countries where bee venom allergy is more frequent than vespid venom allergy. [33] Honeybee and bumblebee venoms show high cross-reactivity. [1] Immunotherapy with honeybee venom alone may be sufficient in nonprofessionally exposed bumblebee-allergic patients with bee venom primary sensitization, whose reaction is most likely due to cross-reactivity. In occupationally exposed patients, who are frequently stung by bumblebees, purified bumblebee venom for immunotherapy, when available, is recommended owing to the low or absent cross-reactivity with honeybee venom. [47] In the USA, whole-body fire ant extract immunotherapy, which contain sufficient venom allergens to provide reasonable clinical protection is used; fire ant venoms are available in Australia (Jack Jumper) where a very successful controlled trial was performed. [69] By contrast, allergic reactions to ants are rare in Europe, Efficacy Subcutaneous VIT is probably the most effective allergen treatment currently available to physicians. The efficacy of VIT has been confirmed in prospective controlled and uncontrolled studies [72] The recommended maintenance dose is 100 µg of venom, both in children and adults. This dose was originally proposed because it was believed to be equivalent to two stings. Indeed, between 50 and 140 µg venom are delivered by a bee sting compared with up to 3 µg by that of a Vespula sting and up to 17 µg by that of a Polistes sting. [4] For the first time, a recent paper demonstrated the efficacy of a P. dominulus extract after a field sting. [65] A dose of 200 µg is recommended when a SR follows an insect sting in spite of VIT with 100 µg and in highly exposed populations, such as beekeepers. [51] Most American patients receive mixed vespid venoms, with an injectable maintenance dose of 300-400 µg, which provides approximately 98% protection. [68] Some authors have demonstrated that VIT efficacy in mastocytosis sufferers may be reduced. [75] Box 2 presents risk factors currently known to predispose a patient to a SR at sting challenge or an in-field sting during VIT. Treatment Protocol Many treatment protocols for the VIT induction phase have been designed. [10] They vary with respect to the number of injections, venom doses and time needed to reach the final dose [ Question marks indicate the existence of discordant data on these topics. [76] They performed two different protocols, a rush protocol in 62 inpatients, and a modified rush protocol in 670 outpatients, thereby demonstrating that by starting with 1 µg of venom there was no SR. Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 9 of 22 6/4/2011 9:10 μμ If two or more venoms are required, they should be administered in separate protocols a few days apart. While the build-up phase of VIT should be performed by an allergist, in some countries, maintenance treatment is eventually continued by the general practitioners. In Europe, VIT may be performed with nonpurified aqueous (NPA), purified aqueous (PA) extracts and purified aluminium hydroxide adsorbed (PAHA) preparations (so-called &apos;depot&apos; extracts) of yellow jacket and honeybee venoms, administered by subcutaneous injection. Purified venom extracts do not contain vasoactive amines (e.g., dopamine, histamine and serotonin) and have a reduced presence of small peptides (e.g., apamine, kinins and mast-cell degranulating peptide in the final product). [77] Polistes species and P. dominulus PA and PAHA extracts for diagnostic and therapeutic purposes are not currently commercially available in Europe. The efficacy of PA and depot extracts is supported by studies using both sting challenge and in-field stings, and is comparable to that of nonpurified preparations. [31] The NPA and PA extracts can be used for ultrarush, rush, clustered and maintenance phases, while PAHA preparations are only administered for the conventional build-up and maintenance schedule. Many European specialists switch to depot preparations following the up-dosing phase. [77] The general consensus is that the maintenance interval should be kept at 4 weeks for the first year, extended to 6 weeks in the second year, and then to 8 weeks if VIT is continued for more than 5 years, provided that the treatment is tolerated. [77] A longer interval is not recommended for honeybee allergic patients since beekeepers with less than ten stings a year were those who developed SRs most frequently. Side Effects Although highly effective, patient compliance with VIT may be impaired by LLRs and SRs, Hymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 10 of 22 6/4/2011 9:10 μμ some European countries, only selected allergy centers usually opt for treatment. However, some studies demonstrate that the side effects of VITs are less frequent than those caused by subcutaneous immunotherapy for inhalant allergens. [2] The literature reports a large variation (0-46%) in the incidence of VITs side effects, In a European, multicenter study, published in 2000, a greater risk of SRs was demonstrated during the incremental phase of VIT in female patients, in subjects receiving bee venom vaccines and in patients undergoing the rapid incremental phase, but not in patients with a history of a severe, original SR. [85] Similar findings for several of these parameters were observed in a previously conducted, larger, retrospective study in the USA, which reported that SRs were most likely to occur at venom doses between 1 and 50 µg and at maintenance dosage. [87] However, there may be a difference between honeybee and vespid venoms with respect to the tolerability of the different protocols. [91] At present, ultrarush protocols should only be used by specialists who are experienced in managing VIT and preferably only in an emergency care setting, particularly in bee venom allergic patients. Even though there are good theoretical grounds for the contraindication of β-blockers during immunotherapy, this does not seem to apply to VIT. [60] ACE-inhibitors may possibly contribute to the onset of SRs during VIT in some highly selected patients, [52] However, risk factors for adverse reactions in these patients (e.g., type of mastocytosis and protocol) require further evaluation. [91] Question marks indicate the existence of discordant data on these topics. ymenoptera Venom Immunotherapy (printer-friendly) http://www.medscape.com/viewarticle/739777_print 11 of 22 6/4/2011 9:10 μμ In general, repeated anaphylactic reactions are rare. In these cases, it should be assumed that VIT will not prevent further SRs following a sting. Moreover, treatment should be continued for approximately 6 months with the highest tolerated dose of insect venom (injection interval 1-2 weeks) and then renewed attempt at dose increase. [45] In conclusion, risk factors for VIT-induced SRs must be taken into account and patients with one or more risk factor should be treated and monitored with special care. How can VIT Safety be Improved? Pretreatment with a H1 antihistamine has been demonstrated to reduce the number and severity of LLRs and mild SRs to VIT, such as urticaria and angioedema. Pretreatment with a combination of H1 antihistamine and a corticosteroid have not yet been performed in honeybee and vespid VIT, except in patients with mast-cell diseases. [52] In a prospective, double-blind, randomized, placebo-controlled pilot study the occurrence of local reactions following VIT was significantly delayed by pretreatment with the leukotriene antagonist montelukast. [96] Pretreatment with anti-IgE monoclonal antibodies may permit more rapid and higher doses of allergen immunotherapy while improving its safety. Moreover, this pretreatment could play an important role in insect-venom allergic patients who are intolerant to VIT. There are several case reports of bee venom allergic patients, [99] Until now, the optimal time for its administration during VIT (should it be administered 6 months, 2 weeks, 1 week or 1 h before VIT?), the appropriate dosage (should we use the the recommended dose of 150 or 300 mg?), the long-term effects (should omalizumab be discontinued after first administration or administered before each shot?) and the best incremental protocol of VIT (should the protocol be conventional or rush/ultrarush?) to be used are still unknown. It is important to underline that omalizumab is not approved for the prevention of anaphylaxis and it must be prescribed as off-label. In addition, taking into account its high cost, omalizumab should be limited to patients with repeated severe SAR to VIT injections preventing reaching the maintenance dose. Although the object of a certain amount of criticism, [101] Even though LLRs are not an indication for VIT, in a placebocontrolled, double-blind study on bee venom SLIT in patients with a history of LLRs, the diameter of LLR to a bee sting challenge was reduced by more than 50% in 57% of active-treated patients. [102] H

Clinical effectiveness of hymenoptera venom immunotherapy: a prospective observational multicenter study of the European academy of allergology and clinical immunology interest group on insect venom hypersensitivity

BACKGROUND: Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors. OBJECTIVE: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters with the frequency of VIT failure during the maintenance phase. METHODS: In this observational prospective multicenter study, we followed 357 patients with established honey bee or vespid venom allergy after the maintenance dose of VIT had been reached. In all patients, VIT effectiveness was either verified by sting challenge (n = 154) or patient self-reporting of the outcome of a field sting (n = 203). Data were collected on BTC, age, gender, preventive use of anti-allergic drugs (oral antihistamines and/or corticosteroids) right after a field sting, venom dose, antihypertensive medication, type of venom, side effects during VIT, severity of index sting reaction preceding VIT, and duration of VIT. Relative rates were calculated with generalized additive models. RESULTS: 22 patients (6.2%) developed generalized symptoms during sting challenge or after a field sting. A strong association between the frequency of VIT failure and BTC could be excluded. Due to wide confidence bands, however, weaker effects (odds ratios <3) of BTC were still possible, and were also suggested by a selective analysis of patients who had a sting challenge. The most important factor associated with VIT failure was a honey bee venom allergy. Preventive use of anti-allergic drugs may be associated with a higher protection rate. INTERPRETATION: It is unlikely that an elevated BTC has a strong negative effect on the rate of treatment failures. The magnitude of the latter, however, may depend on the method of effectiveness assessment. Failure rate is higher in patients suffering from bee venom allergy

Predictors of Worse Prognosis in Young and Middle-Aged Adults Hospitalized with COVID-19 Pneumonia: A Multi-Center Italian Study (COVID-UNDER50)

Obesity as well as metabolic and cardiovascular comorbidities are established, significant predictors of worse prognosis in the overall COVID-19 population, but limited information is available on their roles in young and middle-aged adults (aged ≤ 50 years). The main objectives of the present Italian multi-center study were to describe clinical characteristics and role of selected prognostic predictors in a large cohort of young and middle-aged hospitalized patients. Nine pulmonology units, across north and center of Italy, were involved in this retrospective study. Comorbidities were classified according to their known or potential association with COVID-19. A total of 263 subjects were included. The prevalence of obesity was 25.9%, mechanical ventilation (MV) was needed in 27.7%, and 28 in-hospital deaths occurred (10.6%). Obesity and older age were the only independent, significant predictors for MV. Comorbidities, such as hypertension, diabetes, asthma, and increased D-dimer levels were significantly associated with higher mortality risk, regardless of age, body mass index, and MV. Obesity in young and middle-aged adults is a strong predictor of a more complicated COVID-19, without, however, evidence of a significant effect on in-hospital mortality. Selected comorbidities, including hypertension, diabetes and asthma, significantly impact survival even in a younger population, suggesting the need for prompt recognition of these conditions

Distribution of therapy failures during the maintenance phase of VIT with respect to baseline parameters.

<p>Associations are shown between clinical, demographic and therapeutic parameters and the need for an emergency intervention during an in-hospital sting challenge or, after a field sting by the culprit insect, the development of any type of generalized symptom.</p

Smooth function and pointwise 95% confidence bands (dashed lines) for the effect of baseline tryptase concentration on the risk to need an emergency intervention during sting challenge or to develop generalized symptoms after a field sting (final multivariate generalized additive model).

<p>Odds ratios are referred to those of the median of tryptase concentration. The odds ratio of the latter has been set at 1.</p

Results of the final generalized additive model for the risk to need an emergency intervention during an in-hospital sting challenge or, after a field sting by the culprit insect, to develop any type of generalized symptom.

<p>Those variables are shown, which were selected according to the modeling procedure. P-values and widths of confidence intervals are biased downwards due to the effect of subset selection.</p

Receiver operating characteristic (ROC) curve for the final multiple logistic regression model predicting the risk to need an emergency intervention during sting challenge or to develop generalized symptoms after a field sting.

<p>Models were tested without including the effect of BTC, or with including a smoothed or a linear effect. Corresponding areas under the curve were 0.7449, 0.7084 or 0.7240.</p