Vaccine Delivery by Precipitation (VDBP) is the precipitation of hundreds of thousands to millions of micron-sized particles of a water-insoluble antigen within a volume of a recipient tissue as a water-miscible solvent in which the antigen was administered is diluted by the water content of the recipient tissue.Particles sized 0.5 to 5 microns, taken up by dendritic cells by "macropinocytosis," are presented to naive T cells for immunomodulation with sufficient potency to have achieved the world's first induction of tolerance in patients previously sensitized to poison ivy.Here, we discuss VDBP applications to therapeutic modulation of immunologic reactivity to proteins.These include immunomodulation from sensitization to tolerance in allergic diseases.They also include immunomodulation from tolerance ro protective sensitization in cancer and from immunological naivete (lack of any current response because of lack of prior exposure) to protective sensitization for infectious diseases.We discuss the development of a VDBP vaccine for SARS Cov-V2 as a specific application of the latter technology.

PURPOSE:This study supports the use of thin-film micro-electro-mechanical system (MEMS) airflow sensors in the forced oscillation technique.MATERIALS AND METHODS:The study employed static testing using air flow standards and computer-controlled sound attenuations at 8 Hz. Human feasibility studies were conducted with a testing apparatus consisting of a pneumotach and thin-film MEMS air flow sensors in series. Short-time Fourier transform spectra were obtained using SIGVIEW software.RESULTS:Three tests were performed, and excellent correlations were observed between the probes. The thin-film MEMS probe showed superior sensitivity to higher frequencies up to 200 Hz.CONCLUSION:The results suggest that lower-cost thin-film MEMS can be used for forced oscillation technique applications (including home care devices) that will benefit patients suffering from pulmonary diseases such as asthma, COPD, and cystic fibrosis.

Previous poison ivy vaccines, comprising urushiol in sterile vegetable oils injected subcutaneously, were withdrawn from the market in 1994 for failure to demonstrate statistical efficacy (J. Slater, personal email communication, March 25, 1999). We had anecdotally found these vaccines to be safe and effective in some patients.

As a device for measuring lung function in pulmonary medicine, we have developed a probe containing a strain gauge housed in a plastic form with two wires that connect to an audio jack, for communication with electronic equipment. This device is proposed as an alternative to sensors currently employed in instruments, such as spirometers and forced oscillation technique devices (FOT). The ruggedness and low cost of the probe make it suitable for personal monitoring devices. The physical properties of our sensor appears to be responsible for two classes of anomaly, in its ability to measure airflow. The first is polymer creep, for which we have developed a correction algorithm yielding a square wave voltage output to a square wave airflow input. The second anomaly is a “hump” in the voltage airflow curve that slightly lowers the accuracy at low flow rates. Other tests show minimal airflow resistance, promise for conformity to American Thoracic Society spirometry waveform standards, utility as a device for measuring bidirectional airflow, and promise for FOT applications. The probes have a simple form factor and are easily manufactured.

This article was originally published online on 03 February 2014 Further study delivery system of precipitation of micron-sized particles of insoluble allergen in muscle for immunotherapy (IT) to PI urushiol and adapt it to treat allergy to PN. At AAAAI 2010 we reported induction of tolerance in 2 patients highly allergic to PI with cumulative doses of less than 1 mg urushiol administered IM in small volumes of 95-100% ethanol. Sensitivity on a quantitative patch test mirrors clinical response. Induction of complete clinical tolerance to poison ivy urushiol has not been reported in sensitized humans or animals with any other vaccine delivery technique. We believe the mechanism is rapid dilution of the ethanol by tissue fluid precipitating urushiol in particles of a size that is efficiently taken up by local antigen processing cells. We believe this is functionally similar to SQ IT with antigen on a carrier of 2μ sepharose beads and of IT by direct injection of vaccine into lymph nodes. The same mechanism of T-regulatory cell tolerogenesis is common to humoral and cell mediated immunity. We propose to make allergoids of Ara h2 that are soluble in ethanol but insoluble in water, and study the same vaccine delivery system in a mouse model of peanut allergy. PI: A patient who responded to poison ivy vaccine but lost tolerance by 12 months is scheduled for re-treatment this fall. PN: Allergoids of Ara h2 are made either by cross-linking with glutaraldehyde +/- formaldehyde or by carbamylation of lysine residues with potassium cyanate. Polymerization reduces solubility in water. There are known and novel methods to further reduce solubility in water and increase it in ethanol. PI: Four of 5 patients highly sensitive on a quantitative poison ivy patch test achieved tolerance with cumulative urushiol doses of 0.8 to 4 mg. Tolrance lastied 9-36+ months and was accompanied by 22 to 5000-fold reduction in patch test sensitivity. PN: Vaying parameters of allergoid formation changes water solubility. We expect to have additional data for both PI and PN by the time of the meeting. Precipitation of water-insoluble allergy vaccine from ethanol injected IM is a novel method of IT, effective in patients highly allergic to PI. We are trying to adapt the same delivery system to allergoids of Ara h2 for allergy to PN.

Shortly after I mentioned the review of indications for intradermal skin tests by Calabria and Hagan 1 Calabria CW Hagan L The role of intradermal skin testing in inhalant allergy. Ann Allergy Asthma Immunol. 2008; 101: 337-347 Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar to my nonphysician wife, she showed me an article on allergies in the elderly from the Wall Street Journal. The consultant for that article, whose name I do not recall, stated that because of reduced skin test sensitivity with advancing age, she depends more on intradermal skin tests for the diagnosis of inhalant allergies in older adults. Could Drs Calabria and Hagan comment on the extent to which available evidence supports, refutes, or fails to definitively evaluate this practice and whether it supports age-based modification of the conclusions and recommendations contained in their review. Authors Response:Annals of Allergy, Asthma & ImmunologyVol. 102Issue 4PreviewWe thank Coifman et al for their comments regarding intradermal skin testing (IDST) and elderly individuals, an important question relevant to a group expected to double by 2020 and eventually outnumber children.1 In elderly individuals, the prevalence of allergic rhinitis (AR) appears to decrease, whereas nonallergic origins increase.2 In addition, skin test reactivity to aeroallergens in the general population increases through childhood, peaks in young adulthood, and decreases after the age of 50 years. Full-Text PDF

It has long been recognized, even during biblical times, that physical exercise may induce asthma symptoms in susceptible individuals.1 Nevertheless, the term exercise-induced asthma (EIA) only became popular in the 1960s and 1970s when several reports addressed the pattern of airway response to exercise and the influence of drugs on EIA, particularly in children.2,3 Subsequently, reports of studies of the mechanisms causing EIA4 often asserted that EIA represents a distinct clinical category of asthma.

To the Editor: A 25-item Zoomerang questionnaire on immunotherapy practice patterns and concerns was posted for 6 weeks in May-June 2006 and publicized to the 6100 American Academy of Allergy, Asthma & Immunology (AAAAI) members by 2 e-mail messages with links to the online questionnaire. AAAAI records list 3113 allergists in part-time or full-time clinical practice in the United States and Canada, 161 international member physicians in part-time or full-time clinical practice, and 161 advance practice allied health professionals (nurse practitioners and physician assistants) licensed to independently examine patients and prescribe treatments among the 6100 e-mail recipients. The number of clinician Academy members to whom a questionnaire about immunotherapy practice patterns and concerns might apply is thus 3435. The web page had 768 visits, and 554 questionnaires were completed. Questionnaires were completed at 72% of web page visits and by 16.1% of clinician Academy members if we can assume that all completed questionnaires were by clinician Academy members and that no individual completed the questionnaire more than once. The 2004 and 2006 questionnaire responses are posted in Table E1 in this article's Online Repository at www.jacionline.org. As regards oral β-blockers: 67% of respondents perform skin tests on such patients, and 33% do not. A total of 48% never place patients on oral β-blockers on immunotherapy, 21% do so only for venom immunotherapy, 24% do so “occasionally” for inhalant aeroallergens, and 7% do not see oral β-blockers as a contraindication to skin testing or immunotherapy. As regards β-blockers eye drops: 33% of respondents never place such patients on immunotherapy, 13% do so only for venom immunotherapy, 29% do so “occasionally” for inhalant aeroallergens, and 21% do not see β-blockers eye drops as a contraindication. As regards angiotensin-converting enzyme (ACE) inhibitors: 37% of respondents are concerned about the safety of immunotherapy in patients taking these drugs. As regards HIV: 74% of respondents skin test patients known to have HIV, 40% start them on immunotherapy as they would other patients, and 9% start immunotherapy for insect venoms only. A total of 60% continue all immunotherapy on learning that a patient is HIV-positive, and 6% do so only for venoms. Medicare's unique billing and administrative requirements were not viewed as an obstacle to offering skin testing and immunotherapy to Medicare patients. As regards staffing: Physician always present, 83%; nurse practitioner or physician's assistant, 8%; registered nurse, 7%; medical assistant, 2%. Regarding the wait period after immunotherapy: None, 1%; 20 minutes, 54%; 30 minutes, 45%; >30 minutes, 1%. Overall, 66% of respondents increase the wait period for patients who continue on immunotherapy after systemic reactions, 60% to 30-45 minutes, 31% to 45-60 minutes, and 9% to greater than 60 minutes. As regards medications to have immediately available for 4-6 hours after each allergy shot: Epinephrine, 37%; H-1 blockers, 40%; H-2 blockers, 5%; LTC receptor blockers, 2%; other medications, 7%; none, 45%. A total of 69% of respondents ask patients to avoid strenuous physical exercise after immunotherapy, 51% for up to 2 hours, and 18% for 3-4 hours. Overall, 16% of respondents allow some home immunotherapy, 2% as an option during build-up and maintenance, 1% as an option at maintenance, and 13% occasionally or rarely for patients in particular circumstances. Although only 88 respondents stated that they allow some home immunotherapy, 145 answered the question, “If you allow home immunotherapy, do you provide emergency medications to use in case of reactions and instruct patients in their use?” Of these, 108 (74%) said “yes.” A total of 96% of respondents use a preimmunotherapy injection health survey, 49% by informal verbal questionnaire, 31% recording results on a written checklist, and 16% providing a written preinjection questionnaire for patients or their parents. Overall, 88% of respondents perform some preimmunotherapy peak expiratory flow rate screening, 5% for all patients, 37% for all patients with asthma, and 46% for selected high-risk patients with asthma. A total of 52% of respondents ascertain and document antihistamine use before each allergy shot, 20% for all immunotherapy patients and 32% for selected known high-risk immunotherapy patients. Overall, 81% recommend premedication to reduce the risk of immunotherapy reactions, 15% for all immunotherapy patients, and 66% for selected high-risk patients only. Overall, 78% of questionnaire respondents give H-1 antihistamines alone or with other drugs to prevent or mitigate immunotherapy reactions, 10% give H-2 antihistamines, 14% give leukotriene receptor blockers, and 4% give other drugs. As regards skin tests: 7% record the longest diameter of wheal, 31% record longest the diameter of wheal and erythema, and 14% record the longest diameter of wheal and erythema + the longest orthogonal diameter of each. A total of 27% record as a numeric score with the scoring criteria included when records are transferred, 12% as a numeric score without attaching scoring criteria, and 10% as a measurement of wheal and/or erythema + a numeric score. Either the skin test record form or accompanying documentation when records are transferred list the type of skin test device for 49% of respondents, concentration of testing material for 58%, extract manufacturer for 38%, anatomic location where skin tests placed for 36%, name of testing technician for 71%, and patient date of birth for 73%. Immunotherapy prescription forms or accompanying documentation when records are transferred include the name of extract manufacturer for 59% of respondents, concentration of extract used for 92%, volumes of extract and diluent used for 85%, lot number of each extract present in each vial for 32%, expiration date of each extract present in each vial for 37%, and a vial expiration date not to exceed the expiration date of any individual ingredient for 71%. Responses to the questionnaire indicate 4 areas in which data collection from interested Academy members who give immunotherapy under these circumstances may give us otherwise unavailable quantitative risk estimates. Three involve immunotherapy under conditions already identified by our Practice Parameters Task Force as probably associated with increased risk, although data are currently lacking to quantify that risk. These conditions are immunotherapy in patients receiving β-blockers, patients receiving ACE inhibitors, and patients receiving immunotherapy at home. The wide scatter in use of prophylactic medications before immunotherapy identifies this as another area worthy of study. With regard to ACE inhibitors, case reports exist of anaphylaxis after both insect stings and venom immunotherapy,1Tunon-de-Lara J.M. Villanueva P. Marcos M. Taytard A. ACE inhibitors and anaphylactoid reactions during venom immunotherapy.Lancet. 1992; 340: 908Abstract PubMed Scopus (71) Google Scholar, 2Stumpf J.L. Shehab N. Patel A.C. Safety of angiotensin-converting enzyme inhibitors in patients with insect venom allergies.Ann Pharmacother. 2006; 40: 699-703Crossref PubMed Scopus (44) Google Scholar with 1 report suggesting that 24-hour interruption of ACE inhibitor dosing reduces the risk. However, no quantitative risk data exist. If enough AAAAI members are electing to offer immunotherapy to significant numbers of these patients and wish to share their safety experience, we may be able to estimate risk by tracking these patients prospectively. It may be possible study the prophylactic value of H-1 and LTC receptor blockers, singly and in combination, in a similar prospective manner. The findings of Akdis et al3Akdis M. Blaser K. Akdis C.A. T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases.J Allerg Clin Immunol. 2005; 116: 961-968Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar that H-2 receptor activation is important for tolerance and successful immunotherapy is a reason not to include H-2 antihistamines in prophylactic regimens, at least initially. Collection of safety data from members who have given immunotherapy to patients receiving β-blockers or at home and wish to share their data may permit quantitative estimation of the fatality risk of immunotherapy under those conditions. No consistent difference was found in responses to questions asked in both 2004 and 2006. In summary, variability continues to occur in the immunotherapy and allergy skin test practices of AAAAI member allergists. Unanswered questions include the safety of immunotherapy in certain medical conditions (eg, HIV, autoimmune disease), of immunotherapy administered without medical supervision, of immunotherapy with certain medications (eg, β-blockers, ACE inhibitors), and the role of prophylactic medications. Prospective studies may answer some of these questions, and retrospective data analysis may answer others. Download .pdf (.03 MB) Help with pdf files Online Repository