Ofatumumab Desensitization Protocol: A Case of Refractory Immune Thrombocytopenic Purpura.

Chronic immune thrombocytopenic purpura (ITP) is an acquired hematologic condition that involves immune-mediated platelet destruction with resultant bleeding of variable severity. Refractory ITP occurs when patients fail to tolerate and/or respond to multiple treatment modalities. In this case, we examine the clinical course of a 39-year-old female with refractory ITP and discuss how we navigated a multitude of challenges by adapting an established desensitization protocol to meet our patient's needs. To our knowledge, we describe the first successful desensitization to ofatumumab for use in ITP in the current literature.

A Failure of Rapid Drug Desensitization.

We present the case of a patient who was unable to tolerate rapid drug desensitization protocol to receive a continuous penicillin (PCN) G infusion for the treatment of neurosyphilis. A 38-year-old male with past medical history for human immunodeficiency virus, migraines, PCN allergy, doxycycline allergy, shellfish allergy, and untreated latent syphilis presented to the emergency room for a posterior migraine with associated nausea, vomiting, photophobia, right-sided paresthesias, and "shaky" vision. He was diagnosed with neurosyphilis and underwent rapid drug desensitization with the goal to receive a continuous infusion of PCN G. The patient's hospital course was complicated by intermittent drug reactions consisting of tachycardia, rash, and dyspnea, followed by periods of being able to tolerate the infusion. After being able to tolerate the recommended dose of PCN infusion, the patient was discharged home to complete the course. However, he returned almost immediately after a recurrence of symptoms at home requiring the use of intramuscular epinephrine. Ultimately, the patient was transitioned to ceftriaxone and completed the infusion course as an inpatient because of continued intermittent recurrence of drug reaction symptoms.

Long-term adherence to imported fire ant subcutaneous immunotherapy.

BACKGROUND: Imported fire ant (IFA) whole-body extract subcutaneous immunotherapy (IT) is a safe and effective treatment for IFA hypersensitivity, with a recommended length of treatment of 3 to 5 years. OBJECTIVE: To evaluate long-term IFA IT adherence in patients with IFA allergy living in an endemic area. METHODS: During 2007 to 2014, patients with IFA-sting systemic reactions and a recommendation to start IFA IT were prospectively enrolled in this study. Subjects were contacted annually for interval IT adherence. Institutional review board approval was obtained. RESULTS: A total of 87 subjects, ages 2 to 64 years, with a recommendation to initiate IFA IT, were enrolled. Subjects were predominantly adult (76%) and female (55%), and 30% had asthma. Of these patients, 77 (89%) initiated treatment within 1 year of recommendation; 18 (23%) adhered to a 3-year course; and 10 (13%) adhered to a 5-year course. At 3 years, there were no significant differences in adherence between male and female subjects (28% vs 19%, P = .33), children and adults (25% vs 22%, P = .79), or those with or without asthma (30% vs 20%, P = .31). Adherence in subjects with mild initial reactions was lower than in subjects with moderate-to-severe reactions (0% vs 25%, P = .05) at 3 years only. Conventional buildup and concurrent flying Hymenoptera venom immunotherapy were predictive of adherence. Reasons for discontinuation were relocation to a nonendemic area (29%) and inconvenience (27%). CONCLUSION: This study showed poor long-term adherence to IFA IT at 3 and 5 years. Initial sting severity, buildup protocol, and concurrent flying Hymenoptera venom immunotherapy were predictors for long-term IT adherence.

Pulmonary Procedures During the COVID-19 Pandemic: A Work Group Report of the AAAAI Asthma Diagnosis and Treatment (ADT) Interest Section.

The COVID-19 pandemic has placed increased demands on the ability to safely perform pulmonary procedures in keeping with Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), and the Occupational Safety and Health Administration (OSHA) recommendations. Accordingly, the American Academy of Allergy, Asthma & Immunology (AAAAI) Asthma Diagnosis and Treatment convened this work group to offer guidance. The work group is composed of specialist practitioners from academic and both large and small practices. Individuals with special expertise were assigned sections on spirometry, fractional exhaled nitric oxide, nebulized treatments, and methacholine challenge. The work group met periodically to achieve consensus. This resulting document has recommendations for the allergy/asthma/immunology health care setting based on available evidence including reference documents from the CDC, ATS, and OSHA.

Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors.

The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.

Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide-drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression. In vitro, PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation. In vivo, PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma. Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G2-M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3. PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic. The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control. Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC.

Characteristics of venom allergy at initial evaluation: Is fire ant hypersensitivity similar to flying Hymenoptera?

BACKGROUND: Hymenoptera venom allergy (HVA) is a well-established cause of anaphylaxis; however, studies comparing patients with imported fire ant (IFA) to flying hymenoptera (FH) allergies are lacking. OBJECTIVE: This study sought to characterize the initial presentation and examine differences between patients with IFA and FH reactions. METHODS: A multiyear (2007-2014), observational, single-institution analysis of patients referred for evaluation of HVA was performed. Data was obtained via physician interview, chart review and specific IgE results. RESULTS: 175 patients were enrolled with no difference between FH and IFA patients when analyzing mean age, sex or likelihood to seek emergency department (ED) care. Asthma was similar in all groups at 21%. ED treatments were also similar (epinephrine: 32/150, 21%; antihistamines: 141/155, 91%; corticosteroids: 67/148, 45%). Reaction severity correlated with likelihood of ED visit (P <.001), use of epinephrine (P <.001) and corticosteroid use (P <.05). Patients presenting to the ED with anaphylaxis received epinephrine in 27/73 (37%) of cases. Overall, 149/175 (85%) patients in our cohort were confirmed to be sensitized to hymenoptera. Of those with positive testing 127/149 (85%) chose to pursue VIT. CONCLUSION: IFA and FH patients have many similarities at presentation. Asthma occurred 2.5 times more frequently our cohort compared to the general US population. Epinephrine administration in our cohort was suboptimal. Children have initial reactions and are treated in the ED similarly to adults, with a notable (although not statistically significant) reduced use of epinephrine. The majority of patients seen in the ED and subsequently followed up in an allergy clinic had their venom allergy confirmed and initiated life-saving immunotherapy.

Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo.

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3-octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently under evaluation in human clinical trials.

A side-by-side comparison of Rotorod and Burkard pollen and spore collections.

BACKGROUND: The Rotorod sampler and Burkard spore trap are 2 devices commonly used to quantify airborne particles. OBJECTIVE: To evaluate the differences in collections between the 2 devices for a wide range of plant pollens and fungal spores. METHODS: Pollens and spores were collected simultaneously with each device on 167 days during a 1-year period. RESULTS: The Burkard yielded significantly higher total and individual mold spore counts. It yielded statistically higher total grass, total weed, and Urticaceae daily pollen counts, although the absolute differences were small. Daily counts were positively correlated between the 2 devices for the most abundant pollens and mold spores. CONCLUSION: The Burkard spore trap collects many more mold spores than the Rotorod over a wide variety of species. The Burkard also yielded higher total grass, total weed, and Urticaceae daily pollen counts. Despite these differences, however, either device can be used to follow trends in the most abundant pollen and mold spores.

Adherence to imported fire ant subcutaneous immunotherapy.

BACKGROUND: Imported fire ant (IFA) subcutaneous immunotherapy (SCIT) is safe and effective. For optimal protection, SCIT is given monthly for 3 to 5 years. Successful outcomes require patient adherence. OBJECTIVE: To evaluate SCIT adherence in IFA allergic patients in an endemic area. METHODS: Patients with systemic reactions to an IFA sting, with detectable specific IgE, who received a recommendation to start IFA SCIT were included. Initial reaction severity and demographic data were collected. Patients were contacted at 1 year regarding interval reactions to stings, SCIT adherence, and reason for nonadherence. Adherence rates were analyzed for association with age, sex, and severity of initial reaction. RESULTS: Seventy-six patients were enrolled, and 71% adhered to the recommendation to start IFA SCIT. Subgroup analysis did not find significant differences. At 1 year, 97% completed follow-up for analysis, and only 35% remained adherent. Subgroup analysis did not find significant differences. Inconvenience and fear were reported as reasons for not following the recommendation to start or continue with IFA SCIT. CONCLUSION: IFA SCIT is a life-saving therapy that is safe and effective. Despite this, only 71% followed the recommendation to start, and at 1 year only 35% remained adherent. Adherence was not statistically related to age, sex, or severity of initial reaction. Logistical constraints and fear were significant impediments.

Aspirin therapy in aspirin-exacerbated respiratory disease: a risk-benefit analysis for the practicing allergist.

This study was designed to investigate the risks associated with aspirin (ASA) therapy that is used in high doses for the treatment of ASA-exacerbated respiratory disease (AERD) and to review therapeutic strategies for the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced side effects. A PubMed search was performed using the key words "aspirin" and "adverse effects." Additional citations were generated by surveying the reference lists of the pulled articles. More than 120 articles were reviewed and references were selected based on their relevance to the subject matter. Prevalence rates of ASA hypersensitivity in the general population have been reported to be 0.6-2.5%. Asthmatic patients have higher rates of ASA hypersensitivity. The allergy/immunology specialty is unique in the use of prolonged high-dose ASA therapy for the treatment of AERD. ASA use is associated with an increased risk for the development of serious gastrointestinal (GI) events including GI bleeding, ulcers, and perforation. Established risk factors for GI ulcer development include advanced age, history of ulcer or GI bleed, concomitant use of corticosteroids or anticoagulants, high-dose ASA/NSAID therapy, and possibly concomitant Helicobacter pylori infection. Effective strategies to prevent GI complications include initiation of a proton pump inhibitor (PPI), misoprostol, or double dose H(2)-receptor antagonists (H(2)RAs) at the start of ASA therapy. Allergist/immunologists are involved in treatment decisions regarding high-dose ASA use in AERD. The primary risk of using ASA therapy is the development of GI complications. Cotherapy with a PPI, misoprostol, or double dose H(2)RAs can reduce GI complications associated with high-dose ASA therapy.

The environment, the airway, and the athlete.

OBJECTIVE: To review the interaction of environmental factors with host conditions, including atopy, the potential resulting impaired upper and lower airway function, and diagnostic and therapeutic considerations in the athlete. DATA SOURCES: OVID, MEDLINE, and PubMed searches were performed cross-referencing the keywords asthma, athlete, atopy, bronchospasm, exercise, pollution, and rhinitis. STUDY SELECTION: Articles were selected based on relevance to the subject matter. RESULTS: Recent studies have yielded significant advances in our understanding of how intrinsic and extrinsic factors can potentially result in impaired function of the airways of athletes. Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution. Intrinsic factors include atopy, allergic rhinitis, asthma, and anatomical variants. These intrinsic and extrinsic factors can affect both the athlete's quality of life and athletic performance. However, uncertainty remains regarding relative contributions of these factors in explaining the high degree of bronchospasm seen in various populations of athletes with and without asthma, and no consensus exists regarding the most appropriate diagnostic and therapeutic modalities. CONCLUSIONS: Great variability exists in the presentation, laboratory findings, diagnostic maneuvers, and response to therapeutic measures among populations of athletes in different sports and among individuals. An improved understanding of the unique exposures faced by athletes in different disciplines, of the available tests for pursuing the appropriate diagnosis, and of the available therapies will allow the allergist to provide clinical improvement and allow the athlete to find relief and achieve his/her full potential.

Inpatient allergy/immunology consultations in a tertiary care setting.

Few studies have examined inpatient referral patterns for fellowship training programs and none for allergy/immunology (AI) since 2003. The primary end point was the reason for consultation, and secondary end points included the AI diagnosis made and outcomes. We retrospectively reviewed all inpatient AI consultations from July 1, 2001 through June 30, 2007. These 6 years of data were combined with 14 years of data examining the reason for consult from a previous study. The data were analyzed for trends and changes over the entire 20-year period. A total of 254 AI inpatient consults were reviewed over the 6 years studied. Thirty-six percent (92/254) of inpatient consults were for evaluation of adverse drug reactions (ADRs), 22% (55/254) miscellaneous reasons, 17% (43/254) urticaria/angioedema, 13% (32/254) for possible immunodeficiency, 9% (23/254) for anaphylaxis, and 3% (8/254) for asthma. AI inpatient consults show a significant decline over the recent 6-year period (p = 0.0023) despite stable total hospital admissions since 1998. Over the last 20 years, an 85% decrease (p < 0.00001) in inpatient asthma consults and increases (p < 0.05) in immunodeficiency, rash, and urticaria/angioedema evaluations have been observed. Not following AI recommendations resulted in a 16.6 odds ratio (95% CI, 5.55-49.93) that a patient's clinical status would be worse or unchanged. Inpatient AI consults have declined with associated reduction in asthma inpatient consults. Although ADRs and anaphylaxis consults have been stable, evaluations for immunodeficiency, rash, and urticaria/angioedema have increased. Following inpatient AI recommendations is associated with improved patient outcomes.

Imported fire ant field reaction and immunotherapy safety characteristics: the IFACS study.

BACKGROUND: Imported fire ants (IFAs) are endemic in the southeastern United States, including Texas; can sting multiple times; and are a well-known cause of anaphylaxis. There are few data available on how many stings typically lead to systemic reactions (SRs). Likewise, there are no reports currently in the literature that characterize the safety of IFA subcutaneous immunotherapy (SCIT). OBJECTIVE: We sought to analyze a case-cohort sample of patients for IFA SCIT risk factors and to characterize the index field reactions of these patients. METHODS: A case-cohort study based on a 3-year retrospective chart review (2005-2008) at a single institution was performed for patients receiving IFA SCIT. Field reactions leading to initiation of IFA SCIT were also reviewed. RESULTS: Seventy-seven patients (40 female patients; mean age, 34 years) received 1,887 injections, and 7 patients experienced 8 SRs, for a rate of 0.4% per injection and 9.1% per patient. SRs were mild. Having an SR to skin testing was associated with increased odds of having an SR to IFA SCIT (odds ratio, 4.75; 95% CI, 1.13-20.0), as were large local reactions (odds ratio, 34.5; 95% CI, 6.52-182). No other risk factors were identified. Of the index field reactions leading to IFA SCIT, 59% were the result of 1 sting, and 87% of subjects experienced only 1 SR before initiation of IFA SCIT. Two of 4 patients who experienced loss of consciousness during the index field reaction required an increased maintenance dose for optimal response. CONCLUSIONS: IFA SCIT is safe; however, having an SR to skin testing or the presence of large local reactions increases the odds of having an SR to IFA SCIT. The majority of SRs to IFA field stings resulted from 1 sting.

Quantitative immunoglobulins in adulthood.

Although age-related changes in serum immunoglobulins are well described in childhood, alterations in immunoglobulins in the elderly are less well described and published. This study was designed to better define expected immunoglobulin ranges and differences in adults of differing decades of life. Sera from 404 patients, aged 20-89 years old were analyzed for quantitative immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA). The patients with diagnoses or medications known to affect immunoglobulin levels were identified while blinded to their immunoglobulin levels. A two-factor ANOVA was performed using decade of life and gender on both the entire sample population as well as the subset without any disease or medication expected to alter immunoglobulin levels. A literature review was also performed on all English language articles evaluating quantitative immunoglobulin levels in adults >60 years old. For the entire population, IgM was found to be higher in women when compared with men (p < 0.001) and lower in the oldest sample population compared with the youngest population (p < 0.001). For the population without diseases known to affect immunoglobulin levels, the differences in IgM with gender and age were maintained (p < or = 0.001) and IgA levels were generally higher in the older population when compared with the younger population (p = 0.009). Elderly patients without disease known to affect immunoglobulin levels have higher serum IgA levels and lower serum IgM levels. Women have higher IgM levels than men throughout life. IgG levels are not significantly altered in an older population.

Frequency of imported fire ant stings in patients receiving immunotherapy.

BACKGROUND: Imported fire ant (IFA) stings are an important cause of stinging insect hypersensitivity in endemic areas. IFA stings are difficult to avoid, and many studies have shown high field sting rates. No studies report the natural IFA sting rate that patients experience while receiving IFA immunotherapy. OBJECTIVE: To determine the frequency of IFA stings in patients receiving IFA immunotherapy compared with an aeroallergen immunotherapy control group. METHODS: Patients were surveyed by telephone to characterize the frequency of stings, reactions, and attitudes toward IFA avoidance. RESULTS: A total of 23 of 28 patients reported IFA stings during their IFA immunotherapy compared with 16 of 28 patients during their aeroallergen immunotherapy. More of the IFA immunotherapy-treated patients were stung than the aeroallergen immunotherapy patients, which is inconsistent with our hypothesis (chi2 = 4.139, P < .042). The annualized sting rates between the IFA immunotherapy and aeroallergen immunotherapy groups were similar (1.82 vs 1.72 stings per year, P < .55). The IFA immunotherapy patients were more likely to report any kind of reaction (chi2 = 9.124, P < .003) compared with the control group. Most patients reported feeling careful to avoid stings. CONCLUSIONS: Patients with IFA hypersensitivity treated with IFA immunotherapy do not experience a decreased frequency of stings resulting from attention to sting avoidance. IFA stings are frequent and difficult to avoid. Rush IFA immunotherapy is a good option for many patients to achieve protection quickly.